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Forlenza, Christopher J., Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu. "KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma." Journal of Clinical Oncology 34, no. 21 (July 20, 2016): 2443–51. http://dx.doi.org/10.1200/jco.2015.64.9558.
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Purpose In patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect. Methods KIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry. Results KIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(−)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(−) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4–expressing NB targets. Conclusion We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.
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Alter, Galit, Suzannah Rihn, Katharine Walter, Anne Nolting, Maureen Martin, Eric S. Rosenberg, Jeffrey S. Miller, Mary Carrington, and Marcus Altfeld. "HLA Class I Subtype-Dependent Expansion of KIR3DS1+ and KIR3DL1+ NK Cells during Acute Human Immunodeficiency Virus Type 1 Infection." Journal of Virology 83, no. 13 (April 22, 2009): 6798–805. http://dx.doi.org/10.1128/jvi.00256-09.
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ABSTRACT NK cells are critical in the early containment of viral infections. Epidemiological and functional studies have shown an important role of NK cells expressing specific killer immunoglobulin-like receptors (KIRs) in the control of human immunodeficiency virus type 1 (HIV-1) infection, but little is known about the mechanisms that determine the expansion of these antiviral NK cell populations during acute HIV-1 infection. Here we demonstrate that NK cells expressing the activating receptor KIR3DS1+ and, to a lesser extent, the inhibitory receptor KIR3DL1+ specifically expand in acute HIV-1 infection in the presence of HLA-B Bw480I, the putative HLA class I ligand for KIR3DL1/3DS1. These data demonstrate for the first time the HLA class I subtype-dependent expansion of specific KIR+ NK cells during an acute viral infection in humans.
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O'Connor, Geraldine M., Julian P. Vivian, Emma Gostick, Phillip Pymm, Bernard A. P. Lafont, David A. Price, Jamie Rossjohn, Andrew G. Brooks, and Daniel W. McVicar. "Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1." Journal of Virology 89, no. 10 (March 4, 2015): 5213–21. http://dx.doi.org/10.1128/jvi.03586-14.
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ABSTRACTKiller cell immunoglobulin-like receptors (KIRs) play an important role in the activation of natural killer (NK) cells, which in turn contribute to the effective immune control of many viral infections. In the context of HIV infection, the closely related KIR3DL1 and KIR3DS1 molecules, in particular, have been associated with disease outcome. Inhibitory signals via KIR3DL1 are disrupted by downregulation of HLA class I ligands on the infected cell surface and can also be impacted by changes in the presented peptide repertoire. In contrast, the activatory ligands for KIR3DS1 remain obscure. We used a structure-driven approach to define the characteristics of HLA class I-restricted peptides that interact with KIR3DL1 and KIR3DS1. In the case of HLA-B*57:01, we used this knowledge to identify bona fide HIV-derived peptide epitopes with similar properties. Two such peptides facilitated productive interactions between HLA-B*57:01 and KIR3DS1. These data reveal the presence of KIR3DS1 ligands within the HIV-specific peptide repertoire presented by a protective HLA class I allotype, thereby enhancing our mechanistic understanding of the processes that enable NK cells to impact disease outcome.IMPORTANCENatural killer (NK) cells are implicated as determinants of immune control in many viral infections, but the precise molecular mechanisms that initiate and control these responses are unclear. The activating receptor KIR3DS1 in combination with HLA-Bw4 has been associated with better outcomes in HIV infection. However, evidence of a direct interaction between these molecules is lacking. In this study, we demonstrate that KIR3DS1 recognition of HLA-Bw4 is peptide dependent. We also identify HIV-derived peptide epitopes presented by the protective HLA-B*57:01 allotype that facilitate productive interactions with KIR3DS1. Collectively, these findings suggest a mechanism whereby changes in the peptide repertoire associated with viral infection provide a trigger for KIR3DS1 engagement and NK cell activation.
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Vojvodic, Svetlana, and D. Ademovic-Sazdanic. "Killer-cell immunoglobulin-like receptor genes linkage disequilibrium analysis in population of Vojvodina." Genetika 47, no. 2 (2015): 439–50. http://dx.doi.org/10.2298/gensr1502439v.
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Killer Immunoglobulin-like Receptors (KIRs) form a group of regulatory molecules that modulate cytolytic activity of natural killer cells and T cells through interaction with specific human leukocyte antigen (HLA) molecules on target cells. KIRs are encoded by the family of 16 homologous genes that vary substantially between haplotypes and display sequence polymorphism with allelic variation that also contributes to diversity within the complex. The aim of the study is to estimate two locus linkage disequilibrium for 16 KIR loci. In this study, we report the evaluation of KIR gene content, allele, haplotype and genotype frequencies in 175 unrelated healthy individuals from Vojvodina who were KIR typed by polymerase chain reaction-sequence specific primers genotyping assay. The linkage disequilibrium (LD) was studied at the structural level (presence or absence of 16 KIR genes). Our results revealed that linkage disequilibrium is present between telomeric gene pairs KIR2DL1~KIR2DL4, KIR2DP1~KIR2DL4, KIR2DP1~KIR3DL1, KIR2DL1~KIR3DL2, KIR2DP1~KIR3DL2, KIR2DL4~KIR3DL1, KIR2DL4~KIR2DS4, KIR2DL4~KIR3DL2 where (r2=1), but positive association between KIR genes, with higher observed than expected haplotype frequencies were observed for KIR3DS1~KIR2DS1 and KIR2DL5~KIR2DS1 pair of genes (r2=0.646) and (r2=0.371), respectively. Thirty-eight different genotypes were identified, where 12% of the individuals have unique genotype, present in only one person. Our results will help to understand the genetic background of the Vojvodina population, in illustrating the population migration events in the northern part of Serbia, in explaining the extensive genetic admixture amongst the different ethnic groups of the region and also in KIR-related disease studies.
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Grifoni, Alba, Carla Montesano, Atanas Patronov, Vittorio Colizzi, and Massimo Amicosante. "Immunoinformatic Docking Approach for the Analysis of KIR3DL1/HLA-B Interaction." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/283805.
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KIR3DL1 is among the most interesting receptors studied, within the killer immunoglobulin receptor (KIR) family. Human leukocyte antigen (HLA) class I Bw4 epitope inhibits strongly Natural Killer (NK) cell’s activity through interaction with KIR3DL1 receptor, while Bw6 generally does not. This interaction has been indicated to play an important role in the immune control of different viral infectious diseases. However, the structural interaction between the KIR3DL1 receptor and different HLA-B alleles has been scarcely studied. To understand the complexity of KIR3DL1-HLA-B interaction, HLA-B alleles carrying Bw4/Bw6 epitope and KIR3DL1*001 allele in presence of different peptides has been evaluated by using a structural immunoinformatic approach. Different energy minimization force fields (ff) have been tested and NOVA ff enables the successful prediction of ligand-receptor interaction. HLA-B alleles carrying Bw4 epitope present the highest capability of interaction with KIR3DL1*001 compared to the HLA-B alleles presenting Bw6. The presence of the epitope Bw4 determines a conformational change which leads to a stronger interaction between nonpolymorphic arginine at position 79 of HLA-B and KIR3DL1*001 136–142 loop. The data shed new light on the modalities of KIR3DL1 interaction with HLA-B alleles essential for the modulation of NK immune-mediated response.
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SORGHO, Abel Pegdwendé, Jeremy James MARTINSON, Florencia Wendkuuni Djigma, Albert Théophane YONLI, Bolni Marius NAGALO, Rebeca Tégwindé COMPAORE, Dorcas OBIRI-YEBOAH, et al. "Insights into the interplay between KIR gene frequencies and chronic HBV infection in Burkina Faso." Mediterranean Journal of Hematology and Infectious Diseases 10 (November 1, 2018): e2018060. http://dx.doi.org/10.4084/mjhid.2018.060.
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Background/Objective: The receptors of natural killer cells "Killer Cell Immunoglobulin-Like Receptor" (KIR) regulate the activity of Natural killer cells in the innate response against viral infections. To date there is no accurate method to identify high risk groups for cirrhosis and HCC in Sub-Saharan Africa. Therefore, this investigation was undertaken to assess the association between KIR genes frequencies and chronic infection HBV infection in Burkina Faso’s population. Methods: Chronic HBV carriers and healthy patients were selected for this study. The viral load for HBV were performed to confirm the serological status for HBV of the studied cohort. In addition, SSP-PCR was used to characterize the frequencies of KIR genes.Results: The study suggested that inhibitory genes KIR2DL2, KIR2DL3 and activator gene KIR2DS2 (p˂0.001 for all and OR = 2.82; 2.48 and 3.84 respectively) might be associated with chronic stages of HBV infection. While inhibitory genes KIR3DL1 (p = 0.0018 OR = 0.49), KIR3DL2 (p = 0.005 OR = 0.40), the activator gene KIR2DS1 (p = 0.014 OR = 0.47) and the pseudo gene KIR2DP1 (p = 0.011 OR = 0.49) could be associated with immunity against HBV infection. Patients who carried the KIR3DL2 gene had a high HBV viral load compared to the rest of the study population. Conclusion: Our data showed an evidence of correlation between the propensity of developing chronic HBV infection and certain KIR gene frequencies and that KIR3DL1, KIR3DL2, KIR2DS1 and KIR2DP1 might confer a protective status against chronic HBV infection in Burkina Faso’s patients.
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Ravet, Sophie, Daniel Scott-Algara, Elodie Bonnet, Hung Khiem Tran, Ton Tran, Ngai Nguyen, Lien Xuan Truong, et al. "Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals." Blood 109, no. 10 (February 1, 2007): 4296–305. http://dx.doi.org/10.1182/blood-2006-08-040238.
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Abstract We have previously associated high natural killer (NK)–cell activity and protection against HIV-1 infection in Vietnamese exposed uninfected intravascular drug users (EUs). Considering that activating and inhibitory signals sensed by NK-cell receptors regulate NK-cell activation, we performed phenotypic and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) transcript analyses of the NK-cell receptor (NKR) repertoire in 25 EUs, 19 HIV+ intravenous drug users, and 26 uninfected blood donors. Although NK-cell activation was not linked to a unique NKR repertoire in EUs, various patterns consistent with NK-cell activation were detected in EUs: high KIR3DS1/KIR3DL1 ratio associated with down-regulated KIR3DL1 transcript levels, KIR2DL3+ low-affinity receptor expansion associated to group HLA-C1 ligand in 2DS2−/2DL2− EUs, enhanced NKG2C/NKG2A ratio, and increased CD69 expression. Remarkably, EUs exhibited high constitutive degranulation activity in the absence of exogenous stimulation, as shown by the CD107a assay. Furthermore, CD161 expression was increased within the CD107a+ NK-cell compartment. Our results suggest that in response to viral exposition, particular genetic or regulated features of the NKR repertoire of EUs contribute to their high constitutive NK-cell potential. This might allow NK cells to generate a more rapid and effective immune response to HIV-1, thereby contributing to prevention toward infection.
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Hidajat, Melanny, Dominik Selleslag, Achiel Van Hoof, Jan Van Droogenbroeck, Johan Billiet, and Arnold Criel. "Killer Immunoglobulin-Like Receptors (KIRs) Genotypes in a Belgian Population." Blood 104, no. 11 (November 16, 2004): 3852. http://dx.doi.org/10.1182/blood.v104.11.3852.3852.
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Abstract KIRs (Killer cell Immunoglobulin-like Receptors) are expressed on NK (Natural Killer) cells and a subpopulation of T lymphocytes namely memory CD8+ T cells. The distribution of KIR genes varies among individuals and populations. These genes are encoded on chromosome 19 (19q13.4). Till now 17 KIR genes and pseudogenes have been identified. KIRs recognise groups of HLA class I alleles. NK activity is partially controlled through the interaction between KIRs and their HLA ligands. Several studies report that KIRs may affect the outcome of Hematopoietic Stem-Cell Transplantations. We performed KIR typing of 17 genes and pseudogenes in 100 healthy Belgian unrelated individuals in “West-Vlaanderen” from Caucasoid origin using a PCR-SSP method. Three genes (KIR3DL3, 2DL4 and 3DL2), named frame-work genes, and the pseudogene 3DP1 were found in all individuals. KIR2DL1 and 2DP1 genes were present in a frequency of 99%. In addition, KIR3DL1 and 2DS4 genes represented a frequency of 97. The KIR2DL3 was found in 90% and the frequencies of other genes varied between 56% and 24%. The individual KIR gene content ranged from 8 to 17 genes. A total of 19 KIR locus profiles was observed. The most common KIR locus profile (32%) consisted of a combination of genes characterising A haplotypes (KIR2DL1 and 2DL3) without the presence of genes characteristic of B haplotypes (KIR2DL2 and 2DS2). The second most common KIR locus profile, accounting for 20% contained a combination of genes characteristics for both A and B haplotypes. The allele KIR2DS4*003 was found in 89% and KIR2DS4*00101/00102/002 only in 41%. KIR3DP1*00301/00302 was present in all individuals and KIR3DP1*001/002 only in 35%. Our results show that frequencies of most KIR loci in our Belgian population were comparable to literature data of other Caucasian populations. Only KIR2DS1 was lower (27% vs 47.7% with a p-value of 0.0002). In the future, KIR typing of donor and patient before a Hematopoietic Stem-cell Transplantation may be necessary, due to the diversity in KIR genotypes.
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Sorgho, Pegdwendé Abel, Florencia Wendkuuni Djigma, Jeremy James Martinson, Albert Théophane Yonli, Bolni Marius Nagalo, Tégwindé Rebeca Compaore, Birama Diarra, et al. "Role of Killer cell immunoglobulin-like receptors (KIR) genes in stages of HIV-1 infection among patients from Burkina Faso." Biomolecular Concepts 10, no. 1 (December 19, 2019): 226–36. http://dx.doi.org/10.1515/bmc-2019-0024.
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AbstractObjectivesA cluster of specialized KIR genes of specialized KIR genes has been shown to be associated with susceptibility or resistance to viral infections in humans. Therefore, this pilot study, this pilot investigation sought to determine the frequencies of KIR genes human immunodeficiency virus type 1( HIV-1) patients and establish their potential clinical involvement in disease progression and staging.MethodsHIV-1 infected and healthy individuals were selected for this study. Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and anti-HIV-1/2 antibody/ antigen were screened using a 4th generation ELISA assay (Cobas e 411 Analyzer, Roche Diagnostics GmbH Mannheim, Germany). SSP-PCR was used to evaluate the frequencies of KIR genes. CD4+ T counts and HIV-1 viral load were measured in patients using respectively BD FACSCount and Abbott m2000rt instruments.ResultsWe found a significant association between the frequencies of KIR2DL2 (OR=4.41; p < 0.001), KIR2DS2 (OR=4.76; p < 0.001), KIR2DS3 (OR=2.27; p=0.004), KIR2DS4 (OR=1.76; p=0.026), KIR3DS1 (OR=2.43; p=0.016) and HIV-1 infection; whilst the KIR3DL1 gene (OR= 0.39; p < 0.001) was associated with protection against HIV-1 infection. HIV-1 replication was found to be associated with the presence of KIR2DS2 (OR=6.08, p = 0.024). In contrary the pseudogene KIR2DP1 (OR=0.39; p=0.026) were linked to a protective status with the highest number of lymphocyte T CD4 counts.ConclusionOur data showed that KIR2DL2, KIR2DS2, KIR2DS3, KIR2DS4, and KIR3DS1 were significantly associated with HIV-1 infection whereas KIR3DL1 was associated with protection against HIV-1 infection. Further investigations are needed to fully comprehend the clinical significance of KIR genes in HIV disease progression.
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Harvey, D., J. J. Pointon, C. Sleator, A. Meenagh, C. Farrar, J. Y. Sun, D. Senitzer, D. Middleton, M. A. Brown, and B. P. Wordsworth. "Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis." Annals of the Rheumatic Diseases 68, no. 4 (November 19, 2008): 595–98. http://dx.doi.org/10.1136/ard.2008.095927.
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Objectives:To assess the possible association of killer immunoglobulin-like receptor (KIR) genes, specifically KIR3DL1, KIR3DS1 and KIR3DL2, with ankylosing spondylitis (AS).Methods:14 KIR genes were genotyped in 200 UK patients with AS and 405 healthy controls using multiplex polymerase chain reaction. Sequence-specific oligonucleotide probes were used to subtype 368 cases with AS and 366 controls for 12 KIR3DL2 alleles. Differences in KIR genotypes and KIR3DL2 allele frequencies were assessed using the χ2 test.Results:KIR3DL1 and KIR3DS1 gene frequencies were very similar in cases with AS and controls (odds ratio = 1.5, 95% confidence interval 0.8 to 3.0, and odds ratio = 1.02, 95% confidence interval 0.2 to 5.3, respectively). KIR3DL2 allele frequencies were not significantly different between cases with AS and controls.Conclusions:Neither the KIR gene content of particular KIR haplotypes nor KIR3DL2 polymorphisms contribute to AS.
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Pugh, Jason, Neda Nemat-Gorgani, Zakia Djaoud, Lisbeth A. Guethlein, Paul J. Norman, and Peter Parham. "In vitro education of human natural killer cells by KIR3DL1." Life Science Alliance 2, no. 6 (November 13, 2019): e201900434. http://dx.doi.org/10.26508/lsa.201900434.
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During development, NK cells are “educated” to respond aggressively to cells with low surface expression of HLA class I, a hallmark of malignant and infected cells. The mechanism of education involves interactions between inhibitory killer immunoglobulin–like receptors (KIRs) and specific HLA epitopes, but the details of this process are unknown. Because of the genetic diversity of HLA class I genes, most people have NK cells that are incompletely educated, representing an untapped source of human immunity. We demonstrate how mature peripheral KIR3DL1+ human NK cells can be educated in vitro. To accomplish this, we trained NK cells expressing the inhibitory KIR3DL1 receptor by co-culturing them with target cells that expressed its ligand, Bw4+HLA-B. After this training, KIR3DL1+ NK cells increased their inflammatory and lytic responses toward target cells lacking Bw4+HLA-B, as though they had been educated in vivo. By varying the conditions of this basic protocol, we provide mechanistic and translational insights into the process NK cell education.
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Parham, Peter, Paul J. Norman, Laurent Abi-Rached, and Lisbeth A. Guethlein. "Variable NK Cell Receptors Exemplified by Human KIR3DL1/S1." Journal of Immunology 187, no. 1 (June 20, 2011): 11–19. http://dx.doi.org/10.4049/jimmunol.0902332.
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Shaffer, Brian C., Glenn Heller, Jean-Benoit Le Luduec, Jack Vahradian, Miguel Perales, Sergio A. Giralt, Roni Tamari, et al. "Selection of Unrelated Allogeneic Hematopoietic Cell Donors Based on KIR3DL1 Allotypes Is Feasible and Results in Improved Disease-Free Survival in Transplant Recipients with MDS and AML." Blood 128, no. 22 (December 2, 2016): 990. http://dx.doi.org/10.1182/blood.v128.22.990.990.
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Abstract Donor natural killer (NK) cells impart a potent anti-leukemia effect after allogeneic hematopoietic cell transplantation (allo HCT). The killer Ig-like receptors (KIR) play a central role in modulating NK effector function. Chief among them, the inhibitory KIR3DL1 exhibits a high degree of allelic polymorphism. We previously demonstrated that highly expressed KIR3DL1 alleles (KIR3DL1 allele groups *001 and *002) bind preferentially to HLA-Bw4 with I80 to confer a high degree of inhibitory signaling. Similarly, poorly expressed KIR3DL1 alleles (KIR3DL1 allele groups *005 and *007) bind to HLA-Bw4 with T80 to confer a strong inhibitory signal. In a retrospective cohort of 299 patients undergoing allo HCT for AML, we demonstrated that these highly inhibitory donor KIR3DL1/recipient HLA-Bw combinations (KIR3DL1-HIGH) resulted in a greater incidence of recipient relapse when compared to other donor/recipient KIR3DL1/HLA-Bw pairings with low or absent inhibitory signal (KIR3DL1-LOW/NO). (Giglio F et al, ASH Annual Meeting Abstracts, 2012) Here, we evaluated whether it was feasible to prospectively type and use KIR3DL1 allotypes in unrelated allo HCT donor selection, and whether this intervention would result in improved outcomes in patients undergoing transplant for AML and MDS. We performed PCR-SSP based intermediate resolution KIR3DL1 allele typing on all unrelated adult donors evaluated for patients with MDS and AML at our center from 2013 to present as previously described. (Boudreau J et al, PLoS One, 2014) KIR3DL1 status was provided to the treating physicians, who made the final donor selection. A total of 941 prospective allo HCT donors underwent high resolution HLA typing and KIR3DL1 allotyping for 252 patients (median per patient = 4, range 1-12). Among all donors evaluated, 27% were found to be KIR3DL1-HIGH when considering the respective recipient HLA-Bw. Having multiple donors evaluated improved the likelihood of avoiding a KIR3DL1-HIGH donor: Among recipients with one donor evaluated, 27% had only KIR3DL1-HIGH donors available compared to 12% in recipients with 2-3 donors evaluated and 4% for recipients with >3 donors evaluated (P < 0.0001). Among all evaluated patients, 41% had both KIR3DL1-HIGH and KIR3DL1-LOW/NO donors available, indicating a potential selection based on KIR3DL1 was possible. Among 252 patients evaluated, 115 proceeded to allo HCT (48 with MDS, 67 with AML). The median age at transplant was 62 years (range 3.6-78). Donors were HLA matched in 105 transplants and were single loci mismatched in 10 transplants. Conditioning was myeloablative in 73 (11 with total body irradiation). GVHD prophylaxis was with ex vivo CD34+ selection in 65 patients and with tacrolimus/methotrexate in the remaining patients. The median follow-up in transplanted patients was 13.1 months (range 0.5-43.3 months). On univariate analysis, the 2-year disease-free survival was 64% (95% confidence interval: 54-76%) in those with KIR3DL1-LOW/NO donors versus 39% (22-68%) in recipients with KIR3DL1-HIGH donors (P = 0.05). The incidence of relapse was similar but favored patients with KIR3DL1-LOW/NO donors (26% [15-37%] versus 35% [13-57%], P = 0.5). 2-year overall survival was similar between those with KIR3DL1-LOW/NO versus KIR3DL1-HIGH donors (75% [65-86%] versus 69% [52-91%], P = 0.43). The time from the initiation of a formalized donor search to transplant did not differ between recipients with KIR3DL1-LOW/NO versus KIR3DL1-HIGH donors (median 81 v. 83 days, respectively, P = 0.97). Recipients with KIR3DL1-LOW/NO donors were CIBMTR Transplant Risk Score low = 53, intermediate = 6, and high = 33; whereas recipients of KIR3DL1-HIGH donors were low = 17, intermediate = 2, and high = 4 (P = 0.15). These results indicate that disease severity and transplant urgency did not influence whether a KIR3DL1-LOW/NO donor was able to be selected. In summary, these prospective data on 115 patients from a single center support improved outcomes in patients with AML and MDS undergoing unrelated donor allo HCT using a donor with low or absent KIR3DL1 inhibition. A multi-center, prospective study to evaluate the prospective use of HLA and KIR genotype based selection of URDs for patients undergoing allo HCT for AML is underway (NCT02450708). Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kernan: Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding.
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Stern, Martin, Loredana Ruggeri, Marusca Capanni, Antonella Mancusi, and Andrea Velardi. "Human leukocyte antigens A23, A24, and A32 but not A25 are ligands for KIR3DL1." Blood 112, no. 3 (August 1, 2008): 708–10. http://dx.doi.org/10.1182/blood-2008-02-137521.
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Abstract Inhibitory killer cell immunoglobulin receptors (KIR) bind to major histocompatibility complex antigens. Concise knowledge of KIR ligands allows prediction of natural killer (NK)–cell alloreactivity after hematopoietic stem cell transplantation. KIR3DL1 binds to the Bw4 epitope on HLA-B antigens. Although the same epitope is also found on 4 HLA-A antigens (HLA-A23/24/25/32), these are not currently regarded as KIR3DL1 ligands. We show that expression of HLA A*2301, A*2402, or A*3201 but not HLA A*2501 protects target cells from lysis by KIR3DL1+ NK cells. KIR3DL1+ NK cells from donors expressing the Bw4 epitope on an HLA-A antigen only are fully functional and capable of lysing Bw4− target cells. HLA A25 differs at amino acid 90, close to the serologic Bw4 epitope, from A23/24/32 and from Bw4+ HLA-B antigens. These data suggest that HLA-A antigens should be taken into consideration when assessing the potential for NK alloreactivity after hematopoietic stem cell transplantation.
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Cichocki, Frank, Todd Lenvik, Stephen K. Anderson, and Jeffrey S. Miller. "Antisense Transcripts Negatively Regulate Transcription of Multiple Variegated Killer Immunoglobulin-Like Receptor (KIR) Genes." Blood 112, no. 11 (November 16, 2008): 105. http://dx.doi.org/10.1182/blood.v112.11.105.105.
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Abstract Natural killer cells are CD3 negative large granular lymphocytes that lyse virally infected and malignantly transformed targets. NK cell functions are regulated by an array of inhibitory and activating receptors, including members of the killer immunoglobulin-like receptor (KIR) family. Human KIR genes are expressed in a variegated and clonally restricted manner on the surface of mature NK cells. While it is well established that individual KIR gene expression is strongly correlated with the DNA methylation status of CpG dinucleotides within the promoter region proximal to the transcriptional start site, the mechanisms that regulate variegated KIR expression are largely unknown. Our goal is to uncover the genetic mechanisms governing KIR transcriptional regulation. We have recently identified an active distal promoter element approximately 1 Kb upstream of the transcriptional start site. This region contains c-MYC binding sites, and KIR expression is increased when MYC is overexpressed in developing NK cells or when c-MYC is physiologically increased by IL-15 activation. Bi-directional promoter activity is found within the previously characterized proximal promoter of all KIR genes. Therefore, double-stranded RNA with homology to the KIR promoter can be generated within this non-coding region. The generation of double-stranded RNA has recently been shown to contribute to promoter DNA methylation of the p15 gene in mammalian cells through a Dicer-independent mechanism. Using quantitative real-time PCR, we found that purified peripheral blood CD56+/KIR3DL1− NK cells express 5-fold more KIR3DL1 antisense transcript than purified CD56+/KIR3DL1+ cells. Therefore, the transcriptional activation of the KIR3DL1 gene correlates with a significant decrease in KIR3DL1 antisense expression. To explore the possibility that KIR antisense transcripts can silence KIR expression, we over-expressed the KIR3DL1 antisense transcript in CD34+ hematopoietic precursor cells and differentiated these cells into NK cells in vitro. After 21 days in culture, we assayed KIR3DL1 mRNA levels using quantitative real-time PCR. KIR3DL1 expression was reduced 4-fold compared to eGFP control cultures, further supporting the hypothesis that antisense transcripts negatively regulate KIR expression. Importantly, expression of the KIR2DL4 gene, which does not contain a promoter with significant homology to KIR3DL1 promoter, was not affected by KIR3DL1 antisense overexpression. This provides the first evidence for gene silencing through double-stranded RNA in the immune system and may be the key mechanism for the establishment of DNA promoter methylation within the KIR locus. Understanding the mechanisms of KIR expression, a requisite for NK cell education/licensing, may allow us to understand the acquisition of effector function and manipulate it for therapeutic benefit.
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Draghi, Monia, Nobuyo Yawata, Michael Gleimer, Makoto Yawata, Nicholas M. Valiante, and Peter Parham. "Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I." Blood 105, no. 5 (March 1, 2005): 2028–35. http://dx.doi.org/10.1182/blood-2004-08-3174.
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AbstractNatural killer (NK) cells activate quickly in response to pathogens, tumors, and allogeneic hematopoietic cell transplants. Modulating the NK cell response are clonally distributed NK cell receptors that survey cells for change in the expression of major histocompatibility complex (MHC) class I and structurally related ligands. Here the enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine staining (ICS), and short-term culture were used to quantify the response of bulk NK cell populations from human donors to HLA class I–deficient 221 cells and to 221 cells transfected with single HLA class I allotypes. NK cells in cultures containing interleukin-2 (IL-2) or IL-12 exhibited specificities of HLA class I–mediated inhibition that correlated well with those previously defined using NK cell clones in long-term culture and with the frequencies of cells expressing particular inhibitory HLA class I receptors. Culture with IL-12, but not IL-2, gave an increased frequency of cells expressing CD94: NKG2A but no change in killer immunoglobulin-like receptor (KIR) expression. For some heterozygote combinations of KIR3DL1 alleles, ICS can be used to compare the functional properties of the 2 allotypes. Thus, both the low-expressing KIR3DL1*005 and the high-expressing KIR3DL1*002 gave similar inhibitory response on challenge with an HLA-B*5801 ligand. The single-cell assays developed here should facilitate future population study and clinical analysis of human NK cell regulation by MHC class I.
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Yawata, Nobuyo, Mariko Shirane, Kaing Woon, Xinru Lim, Hidenori Tanaka, Yoh-Ichi Kawano, Makoto Yawata, Soon-Phaik Chee, Jay Siak, and Koh-Hei Sonoda. "Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals." International Journal of Molecular Sciences 22, no. 7 (March 31, 2021): 3623. http://dx.doi.org/10.3390/ijms22073623.
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Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.
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Fang, Xinchen, Xiaoyu Zhu, Baolin Tang, Kaidi Song, Kaidi Song, Wen Yao, Xiang Wan, Huilan Liu, Zimin Sun, and Jun Peng. "DONOR KIR3DL1/RECEPTOR HLA-BW4-80I COMBINATION REDUCES ACUTE LEUKEMIA RELAPSE AFTER UMBILICAL CORD BLOOD TRANSPLANTATION WITHOUT IN VITRO T-CELL DEPLETION." Mediterranean Journal of Hematology and Infectious Diseases 13, no. 1 (December 31, 2020): e2021005. http://dx.doi.org/10.4084/mjhid.2021.005.
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Background: Donor natural killer (NK) cell alloreactivity in umbilical cord bone marrow transplantation (UCBT) can lead to leukemic relapse. However, NK cell function is calibrated by interaction with human leukocyte antigens (HLAs). This study aimed to investigate graft-resistant leukemia after transplantation and compared specific genotypes of killer immunoglobulin-like receptors (KIRs) in donors and human leukocyte antigen ligands in patients.
Methods: We retrospectively analyzed 232 patients with acute leukemia from a single center. Patients had undergone UCBT with myeloablative conditioning and without anti-thymocyte globulin. We identified the KIR genotypes of cord blood donors using polymerase chain reaction with sequence-specific primers. All of the donors contained KIR3DL1.
Results: The patients were divided into three groups according to the HLA-B locus. The donor KIR3DL1 and recipient HLA-Bw4-80I combination was predictive of being highly educated, and was associated with a lower relapse (P = 0.006) and better overall survival (probability of relapse = 0.13, P < 0.001) than the uneducated group. We found no significant increase in the incidence of acute or chronic graft-versus-host disease.
Conclusions: Our data suggest that the donor KIR3DL1/receptor and HLA-Bw4-80I combination in UCBT results in stronger graft-versus-leukemia effects and improved outcomes in patients with acute leukemia.
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Boudreau, Jeanette E., Fabio Giglio, Ted A. Gooley, Philip A. Stevenson, Jean-Benoît Le Luduec, Brian C. Shaffer, Raja Rajalingam, et al. "KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation." Journal of Clinical Oncology 35, no. 20 (July 10, 2017): 2268–78. http://dx.doi.org/10.1200/jco.2016.70.7059.
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Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells—upregulated in the post-HCT environment—signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.
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Fang, Xinchen, Zimin Sun, Huilan Liu, and Lijun Xia. "Donor KIR3DL1/Receptor HLA-Bw4-80I Combination Reduce Acute Leukemia Relapse after Umbilical Cord Blood Transplantation without in Vitro T-Cell Depletion." Blood 132, Supplement 1 (November 29, 2018): 3420. http://dx.doi.org/10.1182/blood-2018-99-117775.
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Abstract Objective: How to reduce relapse is still a puzzle in the treatment of acute leukemia patients with allogeneic umbilical cord blood hematopoietic cell transplantation (UCBT). Donor natural killer (NK) cell alloreactivity in UCBT can control leukemic relapse, However, NK cell function is calibrated through education, that is governed by human leukocyte antigens (HLAs), our study aim to investigate the Graft-resistant leukemia effect after transplantation of KIR3DL1 and its different ligand HLA-B subtypes(BW6, Bw4-80T, Bw4-80I). Design and method: we retrospectivly analysed single center of 232 acute leukemia patients who underwent UCBT(myeloablative conditioning without ATG). The killer immunoglobulin-like receptor (KIR) genotype of cord blood donors was detected by SSP method, they all contains KIR3DL1. There were 104 cases of acute lymphoblastic leukemia, 112 cases of acute myeloid leukemia, 16 cases of myelodysplastic syndrome. 168 cases of transplant patients in remission period, and 64 cases of non-remission. There were 122 males and 110 females with a median age of 13 years (2-45 years). The patients were divided into three groups according to HLA-B locus, 1.patients had BW6 in both two HLA-B locus(group 1, N=86) , which means uneducated; 2.patients had HLA-Bw4-80T in the HLA-B locus(group 2, N=68), which means educated; 3.patients had HLA- Bw4-80I in the HLA-B locus(group 3, N=77), which means highly educated. The receptors were followed-up from July 31, 2012 to December 30,2017, in graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse, overall survival (OS), and leukemia free survival (LFS). Results: In group 3 patients, donor KIR3DL1 and receptor HLA-Bw4-80I combinations that were predictive of highly educated were associated with significantly lower relapse (hazard ratio [HR], HR = 0.49; P =0 .004) and better LFS (HR = 0.68, p = 0.014), compared with the educated(group2) and uneducated (group3) group, with no significant increase in aGVHD and cGVHD incidence. While no difference was observed in the other index in the three group. Conclusion : Alloreactivity of NK cells demonstrated reproducible patterns of strong or weak graft-versus-leukemia (GVL) effect against leukemia blast, which is depend on donor KIR3DL1/receptor HLA-B subtype combinations. Our data suggests that donor KIR3DL1/receptor HLA-Bw4-80I combination in UCBT may achieve superior graft versus leukemia effects, lower risk for relapse among patients with acute leukemia. Keywords: KIR, Umbilical Cord Blood Transplantation, UCBT, GVL Disclosures No relevant conflicts of interest to declare.
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Tandon, Ankit, Kumari Anupam, Jyotsana Kaushal, Preeti Gautam, Aman Sharma, and Archana Bhatnagar. "Altered oxidative stress markers in relation to T cells, NK cells & killer immunoglobulin receptors that are associated with disease activity in SLE patients." Lupus 29, no. 14 (September 30, 2020): 1831–44. http://dx.doi.org/10.1177/0961203320959441.
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Systemic Lupus Erythematosus is an autoimmune disease with symptoms pervasive to all organ systems. It affects more females as compared to males (in the ratio 9:1). Oxidative stress plays a major role in the pathogenesis of SLE and other autoimmune diseases. In order to understand the relationship between cell specific oxidative stress and the severity of SLE, this research study involving the estimation of intracellular ROS accumulation in T and NK cell was conducted on SLE patients of North Indian Population. At the same time, to estimate anti-oxidant defense, Keap1 and Nrf2 levels were estimated in these cell types. The relationship between the expression of Killer immunoglobulin receptors i.e., KIR2DL4 & KIR3DL1 and oxidative stress was also evaluated as these receptors are imperative for the function and self-tolerance of NK cells. Oxidative stress was raised along with Keap1 and Nrf2 in T and NK cell subsets in SLE patients. The expression of KIR2DL4 was raised and that of KIR3DL1 was reduced in the NK cells of patients. The intensity of change in expression and its significance varied among the subsets. Nrf2 expression was raised in these species against oxidative stress as the antioxidant defense mechanism pertaining to Keap1-Nrf2 pathway, but the adequacy of response needs to be understood in further studies. The expression of KIR2DL4 and KIR3DL1 varied among the patient and healthy controls and the expression of the latter was found to have a significant positive relationship with plasma Glutathione(reduced) concentration.
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Umemura, Takeji, Satoru Joshita, Hiromi Saito, Shun-ichi Wakabayashi, Hiroyuki Kobayashi, Yuki Yamashita, Ayumi Sugiura, Tomoo Yamazaki, and Masao Ota. "Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients." Cancers 13, no. 13 (June 29, 2021): 3267. http://dx.doi.org/10.3390/cancers13133267.
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Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.
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Giglio, Fabio, Ted A. Gooley, Jeffrey M. Venstrom, Meighan M. Gallagher, LiHua Hou, Carolyn K. Hurley, Tatiana Lebedeva, et al. "Donor KIR3DL1 and HLA-B Allotypes Control Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation." Blood 120, no. 21 (November 16, 2012): 349. http://dx.doi.org/10.1182/blood.v120.21.349.349.
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Abstract Abstract 349 Natural killer (NK) cells are vital in the control of viral infection and malignancy, in particular AML. Affinity strength between NK receptors and their HLA ligands control both NK effector function and degree of NK inhibition. Differences in binding affinity between allotypes of the NK receptor KIR3DL1 and allotypes of its ligand HLA-Bw4 depend on the expression levels of the receptor and the amino acid residue at position 80 in the ligand. Because receptor-ligand affinities are associated with differences in HIV control, we hypothesized that different affinities between donor KIR3DL1 and donor-recipient HLA-Bw4 allotypes would impact the risk for AML relapse following allogeneic hematopoietic stem cell transplantation (HCT). Methods: We evaluated 299 AML patients who underwent allogeneic HCT from an unrelated donor between 1995 and 2002. Clinical data, HLA allotyping, and donor DNA were provided by the CIBMTR. KIR3DL1 allotyping was executed using PCR- and sequence-based methods. Donors were segregated into those with high-, low- and null expressing KIR3DL1 allele groups [3DL1-H (n=130), 3DL1-L (n=69), 3DL1-N (n=82)] and HLA-B allele groups (Bw6/Bw6, Bw4-I80, Bw4-T80). 3DL1-N genotypes are predictive of poor surface expression and were analyzed separately. Patients and donors were matched at 9 or 10 HLA loci in all cases, with only 3 donor-patient pairs mismatched for HLA-Bw4 ligands. Affinity cohorts were compared using Cox regression for the time-to-event outcomes of relapse and overall mortality (OM). Kaplan-Meier estimates of overall survival and cumulative incidence estimates of relapse were obtained. Results: Recipients of 3DL1-H and 3DL1-L donors were analyzed for high and low-affinity associations with post-HCT AML relapse. Among patients with a 3DL1-H donor, those transplanted from donors with the low-affinity KIR/HLA allotype combination 3DL1-H/Bw4-T80 had lower risk of relapse when compared to those with the high-affinity 3DL1-H/Bw4-I80 combination (HR 0.22; p=.003, Table) and even moreso when compared to the extra-high affinity combinations of 3DL1-H with Bw4-I80-B*2702 or B*57 (HR 0.10; p<.001). Among patients with 3DL1-L donors, those with the low-affinity KIR-HLA combination 3DL1-L/Bw4-I80 were associated with lower relapse in patients when compared to those with the high-affinity 3DL1-L/Bw4-T80 combination (HR 0.21; P=.009). Among the combined patient groups, low-affinity combinations were strongly associated with lower relapse (HR 0.24; P<.001; FigA) and lower mortality (HR 0.62; P=.03; FigB) in patients compared to the high-affinity combinations. Lack of HLA-Bw4 ligand (HLA-Bw6/Bw6) provided intermediate protection from AML relapse compared to patients in the high-affinity group (HR 0.39; P= .002; Fig 1A). Donor 3DL1-N genotypes, predictive of poor receptor expression on the NK cell surface, were not associated with HCT outcome. Conclusions: Protection from relapse of AML after unrelated HCT is associated with the affinity between donor KIR3DL1 and HLA-Bw4, ranging from the highly protective low-affinity donor KIR3DL1/HLA-Bw4 allotype combinations to the susceptible and “super-susceptible” effects of high- and extra-high affinity KIR/HLA combinations. These data support the consideration of KIR and HLA allotype combinations in stem cell donor selection algorithms to minimize the risk of AML relapse following HCT. Because >95% of donors are positive for KIR3DL1 and 69% of patients are positive for HLA-Bw4, incorporation of KIR3DL1/HLA-Bw4 allotypes in donor selection algorithms is a highly relevant and feasible goal. Disclosures: No relevant conflicts of interest to declare.
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Binyamin, Liat, R. Katherine Alpaugh, Kerry S. Campbell, Hossein Borghaei, and Louis M. Weiner. "Rituximab-Mediated ADCC Is Augmented by Concomitant Interference with Inhibitory Self-Recognition by Human NK Cells." Blood 106, no. 11 (November 16, 2005): 2456. http://dx.doi.org/10.1182/blood.v106.11.2456.2456.
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Abstract The anti-CD20 monoclonal antibody, rituximab is widely used in the treatment of non-Hodgkin lymphomas. However, clinical responses to rituximab are variable. It has been demonstrated that rituximab can lead to tumor cell death by engaging the cellular immune system through antibody dependent cellular cytotoxicity (ADCC). NK cells have been shown to play a critical rule in eliminating rituximab coated B-cells, and the efficiency of killing depends on the interaction between the Fc portion of rituximab and the FcγRIII (CD16) activating receptor on NK cells. NK cell function is regulated by a complex balance of inhibitory and activating signals that enable the cells to survey their surrounding and selectively target and kill targets that do not display a “self” ligand (the “missing self hypothesis”). We hypothesized that interference with inhibitory self-recognition would augment rituximab-induced NK cell-mediated ADCC. Initial studies with the 721.221 B51 (HLA Bw4+) CD20+ cell line and NK92.26.5 cells transduced with human CD16 suggested that interference with KIR3DL1 recognition of Bw4 augmented tumor lysis in the presence of rituximab. To further test this hypothesis we employed human NK cells and autologous EBV transformed B cells from normal volunteers, and blocked the KIR3DL1 inhibitory receptor on NK cells using (Fab′)2 fragments of the DX9 antibody, in conjunction with rituximab exposure. Inhibitory blockade promoted rituximab-mediated cytotoxicity by peripheral blood mononuclear cells in three separate HLABw4+, KIR3DL1+ volunteers. These results suggest that manipulating the balance between inhibitory and activating receptors on NK cells might be applied to improve ADCC and ultimately lead to an improvement in response rates to rituximab and related lymphoma-directed antibodies that mediate ADCC. Supported by R01CA50633.
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Majorczyk, Edyta, Aleksandra Zoń-Giebel, Arkadiusz Chlebicki, Izabela Nowak, Piotr Wiland, and Piotr Kuśnierczyk. "Do KIR genes impact the susceptibility to ankylosing spondylitis in Polish patients?" Postępy Higieny i Medycyny Doświadczalnej 73 (June 18, 2019): 310–15. http://dx.doi.org/10.5604/01.3001.0013.2523.
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Aim: Ankylosing spondylitis (AS), a chronic inflammatory arthritis, is strongly associated with HLA-B27 gene worldwide. Among immunocyte receptors reacting with HLA-B27 are killer cell immunoglobulin-like receptors (KIRs ), particularly KIR3DL1 and KIR3DL2. The KIR family includes both activating and inhibitory receptors. These may be expressed on NK cells and subtypes of T cells, which via activating/inhibitory signals regulate the activity of immunocompetent cells and potentially have an impact on inflammation and autoimmunity occurrence. However, reports on the role of KIRs in AS are controversial. Material/Methods: We examined the possible associations of KIR genes in 192 patients diagnosed with AS compared with 191 control individuals. KIR genes were typed using PCR-SSP method. Results: No single KIR gene frequency was found to differ between patients and controls. Nevertheless, the genotypes containing three genes encoding activating KIRs, as well as those characterized by ratios of activating to inhibitory KIRs close to 1:2 (0.5–0.6) were significantly less frequent in AS than in controls. On the contrary, higher ratios (0.67–1.67) were more frequent in AS in comparison to controls. Conclusions: Our results suggest a protective effect of the presence of 3 (but not more) genes encoding activating KIRs, and of a ratio of activating to inhibitory KIRs close to 1:2 (0.5–0.6) but not higher. On the other hand, higher activating to inhibitory KIR ratios seem to predispose to AS. This suggests a very narrow window for optimal ratio of activating to inhibitory KIRs.
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Ayello, Janet, Prakash Satwani, Carmella van de Ven, Elizabeth Roman, Allison O’Neill, Max Shutran, Matthew Greenhawt, et al. "Prolonged Ex Vivo Expansion (7–10 Days) of Cord Blood (CB) Recryopreserved and Rethawed Aliquots with Anti-CD3, IL-2, IL-12 Significantly Expands NKT Cells, NKT KIR Substes and NK Cytotoxicity Compared to Short-Term Expansion: Potential for CB Adoptive Cellular Immunotherapy (ACI)." Blood 104, no. 11 (November 16, 2004): 2845. http://dx.doi.org/10.1182/blood.v104.11.2845.2845.
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Abstract CD56+ NK subsets exhibit differential receptor profiles including killer-Ig-like receptors (KIR), C-lectin (NKG2) and natural cytotoxicity receptors involved with tumor target recognition which may play a role in ACI for malignancies (Farag et al, Blood 2002). UCB is limited by the absence of available donor effector cells (NK, CTL, LAK and NKT cells) for infusion after transplantation for the treatment of minimal residual resistant hematological relapse and/or PTLD (Barker et al, Blood 2001; Locatelli, et al Blood 1999). We have demonstrated the ability to ex-vivo expand (EVE) CB in short term culture (48hrs) with IL-2, IL-7, IL-12 and anti-CD3 (AB/CY) cryopreserved, thawed, recryopreserved, rethawed and ex vivo expanded (CTCTE) with a significant increase in CD3−/16+/56+ bright/dim subsets expressing KIR3DL1, KIR2DL1/S1, KIR2/DL2, CD94/NKG2A (Ayello/Cairo et al, BBMT 25a 2004). Timeus et al (Hematologica 2003) demonstrated the ability to sequentially freeze-thaw UCB twice without a detrimental effect on UCB clonogenic potential or viability (Hematologica 2003). In this study we compared previous short term (48hr) cultures with prolonged cultures (48–240hrs) on expansion, maturation, NK and LAK cytolytic ability, KIR inhibitory and C-lectin NK subsets in CTCTE UCB utilizing the same AB/CY cocktail. UCB were cryopreserevd and thawed by the NHBLI/COBLT method (Fraser/Cairo et al, J Hemat 1998). After rethawing, nonadherent UCB cells were cultured in serum-free media alone or with anti-CD3 (50 ng/ml), IL-2 (5 ng/ml), IL-7 (10 ng/ml) and IL-12 (10 ng/ml) [ABCY] for 4 time periods: 48, 96, 168 and 240 hrs. NK subsets (CD94+, CD16+, CD56+) and NK receptor (KIR3DL1, KIR2DL1/S1, KIR2DL2 and NKG2a) expression were analyzed by flow cytometry using CD3, CD16, CD56, NKBL1, CD158a, CD158b, CD94 and NKG2a mAbs. Additionally, NK and LAK cytotoxicity was measured by europium release assay. There was a significant increase in NKT (CD3+/16+/56+) UCB with AB/CY from 48–240 hrs vs media (2.97±.3 vs 66.7±7.1 vs 35.8±5.9%, p<.001; p<.01), NKT KIR2DL1/S1 from 48–168 hrs vs media (2.76±.4 vs 33.6±8.5 vs 12.1±0.9%, p<.001, p<.05), NKT KIR3DL1 at 48 vs 240 hrs (1.27±0.5 vs 22.2±4.6%, p<.05) and NK (CD3−/16+/56+) KIR3DL1 48 vs 240 hrs vs media (18.8±2.8 vs 38.3±6.3 vs 12.1±4.2%, p<.05, p<.001). A significant increase was shown in UCB NK cytotoxicity on Day 7 (168hrs) [48 vs 96 vs168 hrs] AB/CY vs media alone (168hrs): 53.8±3.9 vs 56±1.6 vs 71.5±.8 vs 40.7±2.0%, p<.001). Similarly, there was a significant maximal increase in UCB LAK cytotoxicity at 168 hrs [48 vs 96 vs 168 hrs] AB/CY vs media: 31.8±1.8 vs 5.47±1.4 vs 63.95±.74 vs 41.6±1.1%, p<.001. We observed a significant enhancement in proliferation at 48 vs 96 vs 168 vs 240 hrs in ABCY vs media (p<.001) and maximal proliferation in ABCY vs media at 240 hrs:.41±.098 vs 3.93±.014, p<.001. This data suggests that UCB cryopreserved cells may be thawed at the time of UCBT, recryopreserved, rethawed at a later date, EVE and activated to yield viable NK and NKT KIR subsets with enhanced cytolytic ability for ACI to induce GVHM effects after UCBT.
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Huang, He, Gongqiang Wu, Xiaoyu Lai, Yamin Tan, Yi Luo, and Faming Zhu. "The Distribution of KIR Gene in Chinese Population and the Effect of Donor KIR and Patient HLA Genotypes on Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation." Blood 112, no. 11 (November 16, 2008): 2236. http://dx.doi.org/10.1182/blood.v112.11.2236.2236.
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Abstract Killer cell immunoglobulin-like receptors (KIR) are a family of inhibitory and activatory receptors and are expressed by most NK cells. The interaction between KIR and human leukocyte antigen (HLA) molecules expressed on target cells is known to modulate the cytolytic activity of NK cells. At present, seventeen KIR genes have been identified, and the number of KIR gene loci has been reported to vary among individuals, resulting in a heterogeneous array of KIR genes in different populations. KIR haplotypes are divided into two distinctive groups based on their gene contents. Ruggeri, et al, first reported that KIR-ligand mismatch can alleviate aGVHD, reduce relapse and improve disease-free survival in mismatched hematopoietic stem cell transplants, while some studies show that this kind of mismatch is deleterious. Now the effect of NK cells alloreactivity on outcome of hematopoietic stem cell transplantation remains controversial. Our study is to analyze the KIR gene contents and investigate the impact of KIR-ligand mismatch on outcome following hematopoietic stem cell transplantation in Chinese population. METHODS: 203 cases of allogeneic hematopoietic stem cell transplantation between Jan. 2001 to May. 2008 were involved in the study. KIR genes were typed by using PCR-SSP, and HLA-A, -B and -C loci genes were used by PCR-SSP or PCR-SSO technology. KIR-ligand incompatibility were assessed based on HLA-Cw (divided into C1 and C2 group) and three major inhibiting KIR genotypes (KIR2DL1, KIR2DL2 and KIR2DL3) of 203 donor/recipient pairs. These patients received myeloablative (n=180) or nonmyeloablative (n=23, with ATG) conditioning followed by hematopoietic stem cell transplantation from HLA matched (n=164) or mismatched (n=39) donors. All patients received mycophenolate mofetil (MMF) combined with CsA and short course MTX regimen as prophylaxis for aGVHD. RESULTS: All seventeen KIR genes were observed in the Chinese population. Framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2 were present in all individuals. The most frequent non-framework KIR genes were: KIR2DL1 (99.5%), KIR3DL1 (97.0%), KIR 2DS4 (97.5%), KIR2DL3 (99.5%) and KIR2DP1 (99.5%). The other gene frequencies were KIR2DS2 (25.1%), KIR2DL2 (25.6%), KIR2DL5A (32.5%), KIR2DL5B (30.0%), KIR2DS5 (23.6%), KIR2DS1 (43.8%), KIR2DS3 (21.2%) and KIR3DS1 (34.0%). The most prevalent haplotype group found in the population was A haplotype. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 48.8% (99/203). HLA genotyping showed that 156 out of 203 (76.8%) donor-recipient pairs could be characterized by lack of recipient HLA-Cw ligand for donor KIR2DL1, KIR2DL2/2DL3. KIR-ligand mismatch was not associated with any deleterious or beneficial influence on relapse or overall survival (OS) in Chinese population with hematopoietic stem cell transplantation. But KIR-ligand mismatch could lead to a decreased incidence of aGVHD (36.1% vs 56.3%, P=0.018). When donor NK cells had KIR2DS2 gene, the recipient acquired a decreased incidence of aGVHD (13.2% vs 49.3%, P<0.001), and had better OS (20.8% vs 34.7%, P=0.041). We also found that the presence of donor KIR2DS5 have a positive effect on aGVHD (25.0% vs 44.5%, P=0.011), however, it didn’t improve OS (27.1% vs 32.9%, P=0.197). There was almost no effect on relapse rate even if donor expressed KIR2DS2 or KIR2DS5. CONCLUSION: Our data demonstrated that Chinese population was distinct in KIR gene frequencies and putative KIR haplotypes in comparison to some other populations. KIR-HLA mismatch was not any better effect on relapse, OS, but it had a better effect on aGVHD. Donors with gene KIR2DS2 or KIR2DS5 were associated with lower incidence of aGVHD in allogeneic hematopoietic stem cell transplantation.
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Miller, Jeffrey S., and Valarie McCullar. "Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2." Blood 98, no. 3 (August 1, 2001): 705–13. http://dx.doi.org/10.1182/blood.v98.3.705.
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Abstract The stage of progenitor maturation and factors that determine the fate and clonal acquisition of human natural killer (NK) cell receptors during development are unknown. To study human NK cell receptor ontogeny, umbilical cord blood CD34+/Lin−/CD38− cells were cultured with a murine fetal liver line (AFT024) and defined cytokines. In the absence of lymphocyte-stimulating cytokines or when contact with AFT024 was prohibited, NK cell progeny were killer immunoglobulinlike receptor (KIR) and CD94 lectin receptor negative. In contrast, efficient NK cell differentiation and receptor acquisition was dependent on direct contact of progenitors with AFT024 and the addition of interleukin-15 (IL-15) or IL-2 but not IL-7. To address the question of whether receptor acquisition was determined at the stem cell level, single CD34+/Lin−/CD38−progenitors were studied. More than 400 single cell progeny were analyzed from cultures containing IL-15 or IL-2 and NK cells were always polyclonal, suggesting that receptor fate is determined beyond an uncommitted progenitor and that receptor-negative NK cells acquire class I-recognizing receptors after lineage commitment. KIR2DL2/L3/S2 was expressed more than KIR2DL1/S1 or KIR3DL1, and NKG2A was the dominant CD94 receptor, independent of whether the stem cell source contained the respective major histocompatibility complex class I ligand, suggesting a nonrandom sequence of receptor acquisition. The conclusion is that NK receptor fate is determined after NK cell commitment, does not require stromal presentation of human class I alleles, and is clonally stable after expression but dynamic because new receptors are acquired over time.
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Zhen, Jian Xin, Si Qi Cai, Yuan Tao Chen, Zhi Chao Yang, Jia Cai Zhuo, and Zhi Hui Deng. "KIR3DL1 and HLA-Bw4 Interaction Showed a Favorable Role in Patients with Myelodysplastic Syndromes in Chinese Southern Han." BioMed Research International 2020 (April 30, 2020): 1–6. http://dx.doi.org/10.1155/2020/6215435.
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Background. The association studies of killer cell immunoglobulin-like receptors (KIRs) with the occurrence of myelodysplastic syndromes (MDS) are limited worldwide; this study investigated the genetic risk/protective factors of MDS in KIR and human leucocyte antigen (HLA) systems to gain a better understanding of the role played by KIR and their cognate HLA ligands in MDS pathogenesis. Methods. We genotyped a total number of 77 patients with MDS from Chinese Southern Han and 745 healthy controls for the KIR loci and HLA class I. The carrier frequencies of KIR genes, KIR genotypes, class I HLA ligands, and KIR-HLA combinations were calculated by direct counting. The effect of individual KIR genes and HLA ligands on MDS risk was evaluated by logistic regression analyses using SAS 9.2 software. Results. We found that neither the KIR genes nor the KIR genotypes were associated with the occurrence of MDS. However, we observed that the frequencies for the strong inhibitory ligand HLA-Bw4 as well as KIR3DL1-HLA-Bw4 combination were significantly higher in healthy controls than those in the MDS patient group, respectively (73.42% vs. 62.34%, P=0.038; 70.87% vs. 59.74%, P=0.043). Conclusion. Our results showed that HLA-Bw4 ligand and KIR3DL1-HLA-Bw4 combination could confer a protective effect against MDS in Chinese Southern Han.
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Schenk, Alexander, Walter Pulverer, Christine Koliamitra, Claus Bauer, Suzana Ilic, Rudolf Heer, Robert Schier, et al. "Acute Exercise Increases the Expression of KIR2DS4 by Promoter Demethylation in NK Cells." International Journal of Sports Medicine 40, no. 01 (December 3, 2018): 62–70. http://dx.doi.org/10.1055/a-0741-7001.
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AbstractPositive effects of exercise on cancer prevention and progression have been proposed to be mediated by stimulating natural killer (NK) cells. Because NK cell receptors are regulated by epigenetic modifications, we investigated whether acute aerobic exercise and training change promoter DNA methylation and gene expression of the activating KIR2DS4 and the inhibiting KIR3DL1 gene. Sixteen healthy women (50–60 years) performed a graded exercise test (GXT) and were randomized into either a passive control group or an intervention group performing a four-week endurance exercise intervention. Blood samples (pre-, post-GXT and post-training) were used for isolation of DNA/RNA of NK cells to assess DNA promoter methylation by targeted deep-amplicon sequencing and gene expression by qRT-PCR. Potential changes in NK cell subsets were determined by flow cytometry. Acute and chronic exercise did not provoke significant alterations of NK cell proportions. Promoter methylation decreased and gene expression increased for KIR2DS4 after acute exercise. A high gene expression correlated with a low methylation of CpGs that were altered by acute exercise. Chronic exercise resulted in a minor decrease of DNA methylation and did not alter gene expression. Acute exercise provokes epigenetic modifications, affecting the balance between the activating KIR2DS4 and the inhibiting KIR3DL1, with potential benefits on NK cell function.
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Gonzalez, Betsy A., Guadalupe Sanchez, Andrea Munguia, Felicitas Manzanares, Miriam Valencia, Aida Delgado, Hilario Flores-A, and Clara Gorodezky. "P255 Distribution of KIR3DL1-3DS1 NK receptors and their ligands in Mexican Mestizos from Mexico city." Human Immunology 78 (September 2017): 241. http://dx.doi.org/10.1016/j.humimm.2017.06.315.
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Gabriel, Ian H., Ruhena Sergeant, Richard Szydlo, Jane F. Apperley, Hugues deLavallade, Abdullah Alsuliman, Ahmad Khoder, et al. "Interaction between KIR3DS1 and HLA-Bw4 predicts for progression-free survival after autologous stem cell transplantation in patients with multiple myeloma." Blood 116, no. 12 (September 23, 2010): 2033–39. http://dx.doi.org/10.1182/blood-2010-03-273706.
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Abstract Natural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1+ (P = .01). This was most evident for patients in complete or partial remission (good risk; GR) at ASCT. The relative risk (RR) of progression or death for patients with KIR3DS1+ compared with KIR3DS1− was 1.9 (95% CI, 1.3-3.1; P = .002). The most significant difference in PFS was observed in patients with GR KIR3DS1+ in whom HLA-Bw4, the ligand for the corresponding inhibitory receptor KIR3DL1, was missing. Patients with KIR3DS1+KIR3DL1+HLA-Bw4− had a significantly shorter PFS than patients who were KIR3DS1−, translating to a difference in median PFS of 12 months (12.2 vs 24 months; P = .002). Our data show that KIR–human leukocyte antigen immunogenetics represent a novel prognostic tool for patients with myeloma, shown here in the context of ASCT, and that KIR3DS1 positivity may identify patients at greater risk of progression.
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Psaila, Bethan, Nayla Boulad, Emily Leven, Naznin Haq, Christina Soo Lee, Shehzad Ahmad, Ruhena Sargent, et al. "The Influence Of KIR Haplotype In ITP Incidence, Treatment Response and Bleeding Symptoms." Blood 122, no. 21 (November 15, 2013): 2316. http://dx.doi.org/10.1182/blood.v122.21.2316.2316.
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Abstract The pathogenesis of immune thrombocytopenia (ITP) is multifactorial, with both cellular and humoural immune dysfunction. The role of NK cells has not been well defined in ITP but in other diseases NK cells have a role in rejecting “foreign” eg transplanted organ or tumor, and also acting against self as occurs in autoimmunity. NK cell activity is orchestrated by the balance of activating vs. inhibitory signalling, in particular via the killer cell immunoglobulin-like receptor (KIR) family of receptors. Significant variation exists in KIR allelic subtype and copy number for the KIR between individuals, and associations have been made with certain haplotypes and a number of autoimmune disorders including rheumatoid arthritis, scleroderma and diabetes. Previous reports have demonstrated a reduction in natural killer (NK) cell number and function in ITP and expression of inhibitory KIR genes is increased in patients in remission vs. active ITP. Methods To explore whether a particular KIR haplotype might predispose to ITP, and also affect response to ITP treatment, we performed KIR genotyping using the Invitrogen SSP kit on 92 patients attending a haematology centre in New York and compared the results to data from 213 controls taken from the USA Eastern Database. Genomic DNA was typed for the inhibitory KIR genes KIR2DL1, KIR2DL2, KIR2DL5A (alleles 001 and 002), KIR2DL5B (alleles 002-004, 06, and 007), KIR3DL1, KIR3DL3; the activating KIR genes KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DS1; the framework genes KIR2DL3, KIR2DL4, KIR3DL2, KIR3DP1; and the pseudogene KIR2DP1. The patients with ITP had been or were receiving treatment with IVIG (n=64), corticosteroids (72) and rituximab (37). Bleeding symptoms were recorded. Response to treatment was defined as complete - platelet count increase to > 100 x 109/mL; partial - platelet count increase to > 50 x 109/mL; or no response. For the purpose of analysis, PRs and CRs were combined. A comprehensive database allowed a logistic regression, assessing both responses to treatments, platelet counts, neutrophil counts, CRP, lymphocyte subsets and bleeding symptoms. Results The expression of two inhibitory KIR genes, 2DL1 and 3DL1, was significantly lower in the patients with ITP as compared to controls (87% 2DL1 and 87% 3DL1 compared to 99% in controls - P < 0.02). Response to rituximab was strongly related to KIR haplotype expression. 2DL1 expression was higher among nonresponders to Rituximab (100% of non responders compared to 82% of responders), whereas 2DL3 expression was significantly lower (79% compared to 90%) (P < 0.05, Figure 1B). Separately, patients with the 2DS3 allele, an activatory KIR, were 5.5 times more likely to have experienced significant bleeding. Conclusions Although these findings are preliminary and require further investigation, these data suggest that increased cytotoxic autoimmunity due to reduced KIR inhibition may be associated with the development of ITP and possibly contribute importantly to the pathogenesis. Anti-CD20 targeting therapy directed at B cells was strongly influenced by 2 different KIRs (1 upregulated and one down-regulated) emphasizing the potential role of NK cells in elimination of tissue-based (nodal) B cells. Finally a more pronounced clinical phenotype with a markedly higher incidence of severe bleeding associated with an increased activatory KIR expression demonstrates the role of NK cells in bleeding presumably via their effects on either endothelial cells or platelet function. These exciting findings will be pursued for confirmation in a larger number of patients. Disclosures: Bussel: Amgen: Family owns stock Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Family owns stock, Family owns stock Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.
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Giebel, Sebastian, Joanna Dziaczkowska, Tomasz Czerw, Jerzy Wojnar, Malgorzata Krawczyk-Kulis, Izabela Nowak, Aleksandra Holowiecka, et al. "Sequential Acquisition of Inhibitory NK Cell Receptors After Allogeneic Hematopoietic Stem Cell Transplantation: The Role of Steroids and Other Transplantation-Related Factors." Blood 114, no. 22 (November 20, 2009): 3543. http://dx.doi.org/10.1182/blood.v114.22.3543.3543.
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Abstract Abstract 3543 Poster Board III-480 Donor-recipient incompatibility for ligands of killer immunoglobulin-like receptors (KIRs) was shown to result in NK cell alloractivity and graft-vs.-leukemia reaction after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, clinical data are inconsistent suggesting the impact of various procedure-related factors on NK cell maturation and their possibility to display alloreactivity. In particular, only NK cells expressing KIRs but not CD94:NKG2A receptor are able to kill leukemic targets. Our goal was to prospectively evaluate reconstitution of NK cell inhibitory receptors after alloHSCT and to identify factors affecting this process. Eighty-three adults with hematological malignancies treated with myeloablative T-replete alloHSCT from either HLA-matched sibling (n=32) or unrelated donor (n=51), were included. The expression of inhibitory receptors (KIR2DL1, KIR2DL2/DL3, KIR3DL1, NKG2A) on NK cells was analyzed by flow cytometry in donors as well as on days +28,+56,+100,+180,+365 after alloHSCT. In parallel, reconstitution of lymphocyte subpopulations (CD3+, CD3+CD4+, CD3+CD8+, CD19+) in peripheral blood was studied. The median frequencies of KIR2DL1+ NK cells on days +28,+56,+100,+180,+365 equaled 4.7%, 5.6%, 5.9%, 9.1%, and 12.6%, respectively, and were significantly lower compared to 20.1% in donors. On day +28, frequency of KIR2DL1+ NK cells was higher for patients receiving peripheral blood compared to bone marrow transplants (p=0.02). Expression of KIR2DL1 correlated positively with the CD34+ cell dose on days +28, +56, +100 and +180 (p<0.05). Expression of KIR2DL2DL3 in subsequent study time-points was 14.4%, 20%, 19.6%, 20.9%, and 25.4%, compared to 24.5% in donors (p<0,05 up to day +100). On day +28 the frequency of KIR2DL2/DL3+ NK cells correlated positively with the absolute number of circulating CD3+ cells (p=0.007) and CD3+CD8+ cells (p=0.003). The frequencies of KIR3DL1 in subsequent time-points were 16.8%,13.8%,10.9%,10.1%, and 9.2% vs. 18.1% in donors. The expression of NKG2A on day +28 equaled 89.9% and decreased to 79%, 68.9%,64% and 51.9% on days +56, +100, +180, and +365, respectively (up to day +180, p<0.05 compared to 46.8% in donors). The frequency of NKG2A+ NK cells was lower for patients receiving PB compared to BM transplants on days +56, +100, and +180 (p<0.05). On day +365, median expression of NKG2A by NK cells was 60.5% for patients who were treated with steroids at any time after alloHSCT compared to 48.1% for the remaining subjects (p=0.04). On day +28, the frequency of NKG2A+ NK cells correlated negatively with the absolute number of circulating CD3+ cells (p=0.004) and CD3+CD8+ cells (p=0.04). We conclude that: 1) the acquisition of KIRs by NK cells after alloHSCT is sequential and starts with KIR3DL1, followed by KIR2DL2/DL3 and KIR2DL1; 2) NKG2A is overexpressed within 6 months after transplantation and the expression remains elevated in case of the use of steroids; 4) T-cell recovery occurs in parallel to NK cell maturation. Our observations should be taken into account when trying to predict potential benefit from NK cell alloreactivity. Disclosures: No relevant conflicts of interest to declare.
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Gooneratne, Shayarana L., Jonathan Richard, Wen Shi Lee, Andrés Finzi, Stephen J. Kent, and Matthew S. Parsons. "Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells." Journal of Virology 89, no. 1 (October 15, 2014): 97–109. http://dx.doi.org/10.1128/jvi.02461-14.
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ABSTRACTMany attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus bothin vitroandin vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1+NK cell subset from HLA-Bw4+individuals exhibits an activation advantage over the KIR3DL1−subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines.IMPORTANCENK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.
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Pende, Daniela, Stefania Marcenaro, Michela Falco, Stefania Martini, Maria Ester Bernardo, Daniela Montagna, Elisa Romeo, et al. "Anti-Leukemia Activity of Alloreactive NK Cells in Haploidentical HSCT in Pediatric Patients: Re-Defining the Role of Activating and Inhibitory KIR." Blood 112, no. 11 (November 16, 2008): 3002. http://dx.doi.org/10.1182/blood.v112.11.3002.3002.
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Abstract T-cell depleted hematopoietic stem cell transplantation from haploidentical donors (haplo-HSCT) has been reported to benefit from the graft-versus-leukemia effect mediated by natural killer (NK) cells when donor displays NK alloreactivity versus the recipient. NK alloreactivity is mediated by NK receptors, namely Killer Ig-like receptors (KIR) which are specific for allotypic determinants that are shared by different HLA-class I alleles (referred to as KIR ligands). It is known that KIR2DL1 recognizes HLA-C alleles characterized by Lys at position 80 (C2 group), KIR2DL2/3 recognize HLA-C alleles characterized by Asn at position 80 (C1 group), KIR3DL1 recognizes HLA-B alleles sharing the Bw4 supertypic specificity (Bw4 group) and KIR3DL2 recognizes HLA-A3 and –A11 alleles. KIR2D/3DL are inhibitory receptors that, upon engagement with the cognate ligand, inhibit lysis. Activating KIRs, highly homologous in the extracellular domain to the inhibitory counterparts, are KIR2DS1, KIR2DS2 and KIR3DS1, but only KIR2DS1 has been shown to specifically recognize C2 group of alleles expressed on B-EBV cells. We analyzed 21 children with leukemia receiving haplo-HSCT from a relative after a myeloablative conditioning regimen; in all pairs, the expression of a given KIR ligand (HLA class I allele) of the donor was missing in the patient (i.e. KIR ligand-mismatched haplo-HSCT). T-cell depletion was performed through positive selection of CD34+ cells; no pharmacological immune suppression was employed after HSCT. KIR genotype of all donors was evaluated to detect the presence of the various inhibitory and activating KIR genes. Phenotypic analyses were performed on NK cells derived from the donor and the patient at different time points after HSCT. Thanks to the availability of new mAbs able to discriminate between the inhibitory and the activating forms of a certain KIR, we could identify the alloreactive NK cell subset at the population level. These alloreactive NK cells express the KIR specific for the KIR ligand-mismatch (permissive inhibitory KIR) and the activating KIR (if present), while they do not express all inhibitory KIR specific for the patient HLA alleles and NKG2A. Thus, in most instances, we could precisely identify the size of the alloreactive NK cell subset in the donor and in the reconstituted repertoire of the recipient. Functional assays were performed to assess alloreactivity, using appropriate B-EBV cell lines and, if available, patient’s leukemia blasts. In some cases, also NK cell clones were extensively studied, for phenotype and receptor involvement in killing activity. We found that, in most transplanted patients, variable proportions of donor-derived alloreactive NK cells displaying anti-leukemia activity were generated and maintained even at late time-points after transplantation. Donor-derived KIR2DL1+ NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3+ NK cells displayed poor alloreactivity against leukemia cells carrying HLA alleles belonging to the C2 specificity. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3+ (or by NKG2A+) NK cells that co-expressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role for the KIR2DS2 activating receptor in leukemia cell lysis could not be established. Taken together, these findings provide new information on NK alloreactivity in haplo-HSCT that may greatly impact on the selection of the optimal donor.
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Hochberg, Jessica, Janet Ayello, Carmella VandeVen, Jeremy Gold, Evan Cairo, Frances Zhao, and Mitchell S. Cairo. "Significant Ex-Vivo Expansion and Functional Activation of Cord Blood (CB) Natural Killer (NK) Cells with A Concomittant Significant Decrease in CB T Cells Following Stimulation with Genetically Engineered K562 Cells (K562-mb15-41BBL)." Blood 114, no. 22 (November 20, 2009): 499. http://dx.doi.org/10.1182/blood.v114.22.499.499.
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Abstract Abstract 499 Introduction: CD56+ NK subsets exhibit differential NK receptors (NKR) such as cytotoxicity profiles including killer-Ig-like receptors (KIR), C-lectin (NKG2) and natural cytotoxicity receptors (NCR) involved with tumor target recognition, which, in part, may play a role in adoptive cellular immunotherapy (ACI) for malignancies (Farag et al Blood, 2002). NK cell activation and NK mediated cytolysis is induced by triggering receptors such as NCR (i.e. NKp46), and NKG2 surface receptors like NKG2D (Moretta et al, Curr Opin in Immunol, 2004, Marcenaro et al, Eur J Immunol, 2003). The major limitations of the use of NK cells in ACI include lack of tumor recognition and/or limited numbers of viable and functionally active NK cells (Shereck/Cairo et al. PBC, 2007). To circumvent these limitations, methods to expand and activate PB NK cells by genetic reengineering have been developed (Imai/Campana et al. Blood, 2005). It has been demonstrated that PB NK cells expanded with modified K562 cells expressing membrane bound IL-15 and 4-1BBL (K562-mb15-41BBL; Imai et al Blood, 2005) are significantly increased in number and maintain heterogeneous KIR expression (Fusaki/Campana et al, BJH, 2009) .We have previously reported the ex-vivo expansion, activation and cytolytic activity of CB NK cells with a cocktail of antibody and cytokines (Ayello/Cairo et al, BBMT, 2006; Ayello/Cairo, Exp Hem, 2009, In Press). Objective: In this study, we compared CB NK expansion and activation following stimulation with genetically engineered K562 cells (K562-mb15-41BBL, generously supplied by D.Campana, St Jude's Children's Hospital, Memphis, TN) with wild-type (WT) K562 cells and NK cell characterization expressing inhibiting and activating KIRs, c-lectin, NCRs and NK cytolytic activation. Methods: Following irradiation with 100Gy, K562-mb15-41BBL or WTK562 were incubated at a 1:1 ratio with fresh CB MNCs at 37C, 5% CO2 for 7 days in RPMI-1640+10IU IL-2. NKR expression (KIR2DS4, NKG2D, NKG2A, CD94, KIR3DL1, KIR2DL2, Nkp46) and LAMP-1 (CD107a) receptor expression and NK cell phenotype (CD56 dim and bright subsets) were determined by flow cytometry. Results: On Day 0, NK cells population was 3.9±1.3%. After 7 days in culture, CB NK cells were significantly increased compared to WTK562 and media alone (72±3.9 vs 43±5.9 vs 9±2.4%, p<0.01). This represented a 35-fold or 3374±385% increase of the input NK cell number. This was significantly increased compared to WTK562 (1771±300%, p<0.05). Concomitantly, there was a significant decrease in CB T cells vs WTK562 or media alone (15±2 vs 36±2 vs 51±7%, p<0.001),respectively. There was a significant increase in CD56bright vs CD56dim populations (67 vs 33%, p<0.01) following stimulation with K562-mb15-41BBL. Also, there was a 10-fold increase in CB NK cells expressing KIR3DL1 following stimulation with K562-mb15-41BBL vs WTK562 (p<0.01) and a 5-fold increase in NK KIR2DS4 expression (p<0.05), respectively. There was a significant increase in the expression of NK activation marker, CD107a, compared to WTK562 (51±0.7 vs 32±1.1,p<0.05). There was no change in CB NK cell expression of the c-lectin receptor, CD94/NKG2A and CD94/NKG2D after stimulation with K562-mb15-41BBL. A standard cryopreserved CB unit (25 ml) contains approximately 750×106 MNC. By using the smaller 5-ml aliquot (20%) of a two-aliquot bag (150×106 MNCs × 3.9%=5.8×106 NK cells), this expansion method would hypothetically yield 200×106 CB NK cells after 7 days stimulation with K562-mb15-41BBL. Conclusion: These results suggest that CB MNC can be ex-vivo expanded with K562-mb15-41BBL resulting in specific expansion of CB NK cells with increased NK KIR expression (KIR2DS4 and KIR3DL1) and NK activation (CD107a), along with a significant decrease in CB T cells. This expansion provides a means to enhance specific CB NK cell expansion for possible use for adoptive cellular immunotherapy in the post UCBT setting Disclosures: No relevant conflicts of interest to declare.
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Shang, Qiannan, Xingxing Yu, Xunhong Cao, Xuefei Liu, Zhengli Xu, Yingjun Chang, Xiaosu Zhao, et al. "Costimulatory Molecule DNAM-1 Is Essential for Optimal NK Education Post Allogeneic Hematopoietic Stem Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 3291. http://dx.doi.org/10.1182/blood-2019-130593.
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Background: DNAM-1 (DNAX accessory molecule-1, CD226) is a costimulatory molecule that is constitutively expressed by NK cells and CD8+ T cells. Interaction between DNAM-1 on NK cells and CD8+ T cells with its ligands on target cells triggers cell-mediated cytotoxicity and cytokine production. Previous mouse model had showed that the expression of DNAM-1 is associated with NK education. Moreover, Monika's group found that DNAM-1 serves as an intrinsic, readout-independent marker for NK cell education in health donor. Our previous study had demonstrated that when both donors and hosts present all the KIR ligands for donor KIRs, reconstituted NK cells would achieve better functional education and contribute to least relapse for the patients post allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the roles of DNAM-1 in NK education post allo-HSCT were unknown. Aims: In this study, we have investigated the contribution of DNAM-1 expression to NK education post transplantation. Methods :We prospectively enrolled 114 patients undergoing haplo-SCT between May 2016 and April 2017 to explore the NK cell dynamic education at days 30, 90 and 180 post-transplant. Peripheral blood mononuclear cells of each sample were analyzed by 15-colors flow cytometry to evaluate of the phenotype as well as functional recovery of NK cells with different maturation expression levels of NKG2A, KIR, and CD57, as well as of activating receptors (NKp30, NKp46, NKG2D, DNAM-1) and CD25, CD122 as well as CD107a and IFN-gamma on NK cells. To study the correlation between the expression of DNAM-1 and effect of donor and host HLA on NK cell education, the expression of DNAM-1 on single-KIR+ NK cells (exhibiting NKG2A, KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor) was compared based on the combination between donor/host HLA and donor inhibitory KIR. Results: The DNAM-1 expression on single-KIR+ NK cell ligated by sole donor HLA, or sole host HLA, or both donor and host HLA is higher compared to those single-KIR+ NK cells lacking ligands from donor or host or both. From the donor point of view, when donor only presented C1C1 ligand for KIR2DL2/L3, the MFI of DNAM-1 on single KIR2DL2/L3+ NK cells was significantly higher than KIR2DL1+ NK cells and KIR3DL1+ NK cells at 90day (P<0.0001, P=0.046) and 180day (P<0.0001, P=0.034) post transplantation. However, when donor presented C1C1 ligand for KIR2DL2/L3 and Bw4 ligand for KIR3DL1, the MFI of DNAM-1 on single KIR2DL1+ NK cells was significantly lower than KIR2DL2/l3+ NK cells and KIR3DL1+ NK cells at 90day (P<0.0001, P=0.0002) and 180day (P<0.0001, P<0.0001) post transplantation. There was no difference between single KIR2DL1+ NK cells and single KIR3DL1+ NK cells. When donor expressed all HLA(Bw4C1C2) for KIR2DL2/L3, KIR2DL1, KIR3DL1, there was no difference in the expression of DNAM-1 among three single KIR+ NK cells. No matter from the host point or from the combination of donor and host point of view, the DNAM-1 expression differences were same to from donor point of view. There was a clear hierarchy of DNAM-1 expression among NK populations when both of donors and hosts presenting all HLA (Bw4C1C2) for donor KIRs. NK cells with sole KIR or sole NKG2A exhibited higher DNAM-1 expression compared with NKG2A-KIR- NK cells. NK cells with two or three inhibitory KIRs exhibited higher DNAM-1 expression compared with NKG2A+KIR- NK cells. NK cells with 3 inhibitory KIRs and NKG2A expression exhibited maximum DNAM-1 expression at day 30, 90, 180 post transplantation. Meanwhile, the expression of DNAM-1 on NK cells correlated with different ways of education through NKG2A and KIR. There were two fundamental forms of HLA haplotype -21 HLA-B dimorphism: one preferentially supplying CD94:NKG2A ligands (-21M HLA-B), the other preferentially supplying KIR ligands (-21T HLA-B). The expression of DNAM-1 on NKG2A-KIR2DL1+ NK cells was significantly lower when donor or patient was Bw6C1C1 (M/M) compared with when donor or patient was Bw4C2Cx (T/T). However, the expression of DNAM-1 on NKG2A+KIR- NK cells showed no significant difference when donor or patient was Bw6C1C1 (M/M) compared with when donor or patient was Bw4C2C2 (T/T). Summary: This study demonstrated that no matter from donor or/and host point of view, DNAM-1 expression contributes to optimal NK cells education post allo-HSCT. Disclosures No relevant conflicts of interest to declare.
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Zhao, Xiang-Yu, Xing-Xing Yu, Zheng-Li Xu, Xun-Hong Cao, Ming-Rui Huo, Xiao-Su Zhao, Ying-Jun Chang, et al. "Donor and host coexpressing KIR ligands promote NK education after allogeneic hematopoietic stem cell transplantation." Blood Advances 3, no. 24 (December 23, 2019): 4312–25. http://dx.doi.org/10.1182/bloodadvances.2019000242.
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Abstract The rate and extent of natural killer (NK)–cell education after hematopoietic cell transplantation correlates with leukemia control. To study the effect of donor and host HLA on NK-cell reconstitution, single killer-cell immunoglobulin-like receptor (KIR)+ NK cells (exhibiting KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor) were grouped into 4 groups based on the interaction between donor/host HLA and donor inhibitory KIR in 2 cohorts (n = 114 and n = 276, respectively). On days 90 to 180 after transplantation, the absolute number and responsiveness against K562 cells (CD107a or interferon-γ expression) of single-KIR+ NK cells were higher in pairs where donor and host HLA both expressed ligands for donor inhibitory KIRs than in pairs where 1 or both of the donor and recipient HLA lacked at least 1 KIR ligand. NK-cell responsiveness was tuned commensurate with the number of inhibitory receptors from the donor. When both donor and host expressed the 3 major KIR ligands (HLA-C1, HLA-C2, and HLA-Bw4), NK cells expressing 3 inhibitory receptors (KIR2DL1/2DL3/3DL1) reached the maximum responsiveness against K562 cells compared with those NK cells expressing only 1 or 2 inhibitory receptors. When donor and host HLA both expressed all ligands for donor inhibitory KIRs, patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) showed the lowest recurrence rate after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In conclusion, this study demonstrates that when both donors and hosts present all the KIR ligands for donor KIRs, reconstituted NK cells achieve better functional education and contribute to least relapse among patients. This observation study was registered at www.clinicaltrials.gov as #NCT02978274.
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Juárez-Reyes, A., D. E. Noyola, A. Monsiváis-Urenda, C. Alvarez-Quiroga, and R. González-Amaro. "Influenza Virus Infection but Not H1N1 Influenza Virus Immunization Is Associated with Changes in Peripheral Blood NK Cell Subset Levels." Clinical and Vaccine Immunology 20, no. 8 (June 19, 2013): 1291–97. http://dx.doi.org/10.1128/cvi.00194-13.
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ABSTRACTThe innate immune system constitutes the first line of defense against viral agents, and NK cells seem to have an important protective role during the early phases of influenza virus infections. We decided to assess the levels of NK and NKT lymphocytes and the expression levels of different membrane receptors (NKp44, NKp46, NKG2A, killer cell immune-like receptor [KIR] 3DL1/DS1, KIR2DL1/DS1, and CD161) in peripheral blood samples of patients with influenza (n= 17) and healthy individuals immunized against this virus (seasonal and [H1N1]pdm2009 influenza vaccines;n= 15 and 12, respectively). Blood samples were obtained from all individuals, and NK and NKT cell subsets were analyzed by multiparametric flow cytometry. We found that the patients with severe influenza (n= 9) showed significant increases in the percentages of NKp46+NKp44+NK cells and the proportions of NK and NKT lymphocytes expressing KIR2DL1 and KIR3DL1 and reductions in the percentages of NKp46+NKp44−NK cells compared to those in the healthy controls (n= 27). In contrast, influenza immunization, against either the seasonal or the pandemic H1N1 virus, was not associated with important changes in the levels of NK and NKT lymphocytes or the expression levels of the different receptors by these cells. Our data suggest that severe influenza is associated with important and complex alterations on NK cells, which might contribute to the pathogenesis of this condition.
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Schetelig, Johannes, Henning Baldauf, Falk Heidenreich, Carolin Massalski, Sandra Frank, Jürgen Sauter, Matthias Stelljes, et al. "External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails." Blood 135, no. 16 (April 16, 2020): 1386–95. http://dx.doi.org/10.1182/blood.2019002887.
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Abstract Several studies suggest that harnessing natural killer (NK) cell reactivity mediated through killer cell immunoglobulin-like receptors (KIRs) could reduce the risk of relapse after allogeneic hematopoietic cell transplantation. Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or KIR-disadvantageous. This study was aimed at externally validating this model in unrelated donor hematopoietic cell transplantation. The impact of the predictor on overall survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, Karnofsky performance status, donor age, HLA match, sex match, cytomegalovirus match, conditioning intensity, type of T-cell depletion, and graft type. Data from 2222 patients with acute myeloid leukemia or myelodysplastic syndrome were analyzed. KIR genes were typed by using high-resolution amplicon-based next-generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald test, P = .93) for OS and 1.04 (Wald test, P = .78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately but found no significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus-leukemia reactions and to eventually use KIR genotype information for donor selection.
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Ayello, Janet, Prakash Satwani, Carmella Van de Ven, Elizabeth Roman, Laxmi Baxi, Joanne Kurtzburg, and Mitchell S. Cairo. "Optimal Ex-Vivo Expansion (EvE) of Cord Blood (CB) Natural Killer (NK) Cells, NK Cytotoxicity and NK Receptor (NKR) Expression: Potential for CB Adoptive Cellular Immunotherapy (ACI)." Blood 106, no. 11 (November 16, 2005): 34. http://dx.doi.org/10.1182/blood.v106.11.34.34.
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Abstract CD56+ NK subsets exhibit differential receptor profiles including killer-Ig-like receptors (KIR), C-lectin (NKG2) and natural cytotoxicity receptors (NCR) involved with tumor target recognition which may play a role in ACI for malignancies (Farag et al Blood, 2002). NK cell activation and NK mediated cytolysis is induced by several triggering receptors such as NCR (i.e. NKp44, NKp46) and NKG2 surface receptors like NKG2D (Moretta, et al, Curr Opinion in Immunol, 2004; Marcenaro et al, Eur J Immunol, 2003). UCB is limited by the absence of available donor effector cells (NK, CTL, LAK and NKT cells) for infusion after transplantation for the treatment of minimal residual resistant hematological relapse and/or PTLD (Barker et al, Blood, 2001; Locatelli, et al Blood,1999). We demonstrated the ability to EvE CB in short term culture (48 hrs) with IL-2, IL-7, IL-12 and anti-CD3 (ABCY) cryopreserved, thawed, recryopreserved, rethawed and ex vivo expanded (CTCTE) with significant increase in CD3−/16+/56+ bright/dim subsets expressing KIR3DL1, KIR2DL1/S1, KIR2DL2 and CD94/NKG2A (Ayello/Cairo et al, BBMT, 25a, 2004). In this study, we compared short-term cultures (48 hrs) with prolonged cultures (4 to 10 days) on expansion, maturation and expression of NCR, NKG2, KIR and cytolytic mechanisms in previously cryopreserved CB that were TCTE. CB was cryopreserved and thawed by the NHLBI/COBLT method. (Kurtzberg/Cairo, Transfuison, 2005). Rethawed nonadherent CB cells were cultured (2–10 days) in serum-free medium alone or with anti-CD3 (50 ng/ml, IL-2 (5 ng/ml), IL-7 (10 ng/ml) and IL-12 (10 ng/ml) (ABCY). NK receptor expression (CD94, NKG2C, NKG2D, NKp44, NKp46, KIR2DS4) and intracellular perforin and granzyme B activity were determined by flow cytometry. NK and LAK cytotoxicity was measured by europium release assay. Significant increases were seen in NK activating KIR2DS4 at day 10 vs 2 in ABCY both in CD3−/16+/56+ dim and bright subsets (16.9±0.4 vs 2.1±0.2% and 22.3±0.3 vs 0.9±0.2%, p<0.001, respectively). C-lectin activating receptor CD94/NKG2D was increased at day 7 vs 2 following ABCY EvE (41.4 ±0.43 vs 23.7±2.0 %, p<0.001). A significant increase was seen in NK (CD3−/16+/56+dim) KIR3DL1 subset at day 10 vs 2 (38.3±2.8 vs 18.9±6.3 7%, p<0.05). In contrast, NCR expression in CD3−/16+/56+ dim NKp44 subset was significantly decreasedat day 10 vs 2 of EvE with ABCY (15.2±0.7 vs 27.2±0.7%, p<0.001). A significant decrease was seen in CD3−/16+/56+ dim NKp46 expression following day 10 vs 2 (8.5±0.2 vs 23.5±1.2 %, p<0.001). Perforin expression demonstrated a significant decrease in ABCY at day 10 vs 2 (55.7±1.8 vs 84.3±1.3%, p<0.001) yet increasing levels of granzyme B from day 2 to 10 (25.8±1.8 vs 45.1±1.7%, p<0.0001). A significant increase in CB NK and LAK cytotoxicity was seen in ABCY on day 10 vs 2 (NK: 71.5 ±1.6 vs 53.8±10.3%, p<0.001; LAK: 63.2±0.24 vs 31.8±1.8%, p<0.001). In summary, CB MNC may be thawed at time of CB transplantation, recryopreserved, rethawed and at a later date EvE and activated for 7–10 days to yield viable NK subsets. EvE in ABCY at 10 days yielded increased expression of NK KAR (CD56+dim and bright) and granzyme B expression but decreased NK C-lectin CD94/NKG2D, NCR NKp46 and NKp48 and perforin expression.
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O'Connell, Karen A., Yefei Han, Thomas M. Williams, Robert F. Siliciano, and Joel N. Blankson. "Role of Natural Killer Cells in a Cohort of Elite Suppressors: Low Frequency of the Protective KIR3DS1 Allele and Limited Inhibition of Human Immunodeficiency Virus Type 1 Replication In Vitro." Journal of Virology 83, no. 10 (February 11, 2009): 5028–34. http://dx.doi.org/10.1128/jvi.02551-08.
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ABSTRACT Natural killer (NK) cells are associated with the innate immune response and are important in many viral infections. Recent studies indicate that NK cells can control human immunodeficiency virus type 1 (HIV-1) replication. We studied the effect of NK cells on HIV-1 replication in a subpopulation of HIV-1-infected individuals termed elite suppressors (ES) or elite controllers. These patients maintain a clinically undetectable viral load without treatment and thus provide a fascinating cohort in which to study the immunological response to HIV-1. Using an autologous system, we analyzed the effects of NK cells and CD8+ T cells on viral replication in CD4+ T lymphoblasts. Although we had postulated that NK cells of ES would be highly effective at controlling viral replication, we found that NK cells from some, but not all, ES were capable of inhibiting replication in the presence of interleukin-2, and the inhibition was less robust than that mediated by CD8+ T cells. Additionally, we examined whether particular alleles of the KIR receptors, specifically KIR3DS1 and KIR3DL1, or allele-ligand combinations correlated with the control of HIV-1 replication by NK cells and whether any specific KIR alleles were overrepresented in ES. Our ES cohort did not differ from the general population with respect to the frequency of individual KIR. However, of the eight ES studied, the four exhibiting the most NK cell-mediated control of viral replication also had the fewest activating KIR and were haplotype A. Thus, the strong NK cell-mediated inhibition of viral replication is not necessary for the immunological control of HIV-1 in all ES.
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Gabriel, Ian H., Ruhena Sargent, Hugues de Lavallade, Richard Szydlo, Jane Apperley, Ahmad Khoder, Abdullah Alsuliman, et al. "Presence of the Killer Immunoglobulin-Like Gene KIR3DS1 Is Associated with Poor Progression Free and Overall Survival Following Autologous Stem Cell Transplantation in Patients with Myeloma." Blood 114, no. 22 (November 20, 2009): 2840. http://dx.doi.org/10.1182/blood.v114.22.2840.2840.
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Abstract Abstract 2840 Poster Board II-816 Multiple myeloma (MM) remains incurable with a median survival of 3–4 years. Despite high dose therapy and autologous stem cell transplant (ASCT) most patients relapse with median progression-free survival (PFS) of 2.5–4 years and overall survival (OS) of 4–5 years. Although allogeneic SCT (allo-SCT) is potentially curative due to a graft-versus-myeloma effect, its applicability is significantly limited by high transplant related mortality (TRM). Therefore, the identification of additional independent biological predictors of outcome is required in order to tailor therapy to disease. Natural killer (NK) cells provide first line defence against tumors. NK cells have been shown to recognize and kill myeloma cells both in the allogeneic and autologous settings and donor NK genotype has been shown to influence leukemia free survival following allo-SCT. The aim of this study was to investigate the impact of KIR genotype on event-free (EFS) and OS following ASCT for MM. We performed KIR genotyping on 190 patients with MM receiving a first autologous transplant. KIR genotype and haplotype frequencies were comparable to those published for normal controls. Factors found on univariate analysis to be associated with a shorter EFS included haplotype Bx (containing at least 1 of the KIR B haplotype-defining loci- KIR2DL5, 2DS1, 2DS2, 2DS3, 2DS5, or 3DS1) (median 547 vs 656 days, P = 0.036), ≥3 activating KIR genes (median 547 vs 615 days, P = 0.046), the presence of activating KIR genes KIR2DS1 and KIR3DS1 (median 456 vs 589 days, and 464 vs 619 days, P=0.045 and 0.01 respectively). Disease status at ASCT was the most highly predictive factor for EFS. In patients with good risk disease (CR or PR at ASCT) KIR3DS1 status was highly predictive for EFS 464 days (341–586) vs 731 days (599–862) (P = 0.003) and OS 807days (713-901) vs 967 (925-1009) (P=0.023). KIR3DS1 was not predictive in patients with poor risk disease (P=0.36). Of note KIR3DS1+ve patients were equally represented in good risk (CR and PR) and poor risk (refractory or relapsed) groups at ASCT (around 30% in both groups). Notably the median EFS for KIR3DS1+ good risk patients was not significantly different to poor risk disease patients (P = 0.061). ASCT outcome was then determined according to 3 main groups based on disease status and KIR3DS1 status; A: Good Risk, KIR3DS1-ve; B: Good Risk, KIRDS1+ ve; and C Poor risk (KIR3DS1+ve or -ve). The RR of relapse or death was 1.0, 1.9 (P=0.002, 95% CI 1.3-3.1), and 3.0 (P=0.0001, 95% CI 1.9-4.8) respectively. By multivariate analysis, after adjusting for the presence of adverse cytogenetics and serum albumin and β2m, the KIR3DS1 status and grouping remained highly predictive of poor EFS, RR of 1.0, 2.7 (P= 0.021, 95%CI 1.2-6.2) and 5.3 (P= < 0.0001, 95%CI 2.4-11.7) respectively. The prognostic value of KIR3DS1 however, was greatest in patients in whom the ligand for the corresponding inhibitory KIR3DL1, Bw4 was missing. KIR3DS1+ KIR3DL1+ HLA-Bw4 negative patients had significantly reduced median EFS of 400d (315-495) vs 615 (545-684) for all other patients (P=0.048). Again this was most striking in good risk patients. Patients who had the genotype KIR3DS1+ KIR3DL1+ HLA-Bw4 –ve had a significantly shorter EFS survival of 372 days compared to 509 days in KIR3DS1+KIR3DL1+HLA-Bw4+ patients and 793 days for KIR3DS1 negative individuals (P=0.004). In conclusion: Our data from 190 patients with MM suggests that KIR3DS1, a gene previously linked to an increase risk of progression to invasive cervical carcinoma, independently predicts for poor EFS and OS following ASCT. A significant proportion (30%) of patients who are defined as good risk at ASCT (CR and PR) are KIR3DS1+ve and have an EFS which is not significantly different from patients who have refractory/relapsed disease at ASCT. This effect of KIR3DS1 is more significant in the absence of HLA-Bw4, the ligand for the inhibitory receptor KIR3DL1. The mechanism for this is effect is unclear and we are currently performing functional studies to further understand these findings. Disclosures: Apperley: Novartis: Consultancy, Honoraria. Marin:Novartis: Consultancy, Research Funding.
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Lisovsky, Irene, Gamze Isitman, Rujun Song, Sandrina DaFonseca, Alexandra Tremblay-McLean, Bertrand Lebouché, Jean-Pierre Routy, Julie Bruneau, and Nicole F. Bernard. "A Higher Frequency of NKG2A+than of NKG2A−NK Cells Responds to Autologous HIV-Infected CD4 Cells irrespective of Whether or Not They Coexpress KIR3DL1." Journal of Virology 89, no. 19 (July 22, 2015): 9909–19. http://dx.doi.org/10.1128/jvi.01546-15.
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ABSTRACTEpidemiological and functional studies implicate NK cells in HIV control. However, there is little information available on which NK cell populations, as defined by the inhibitory NK cell receptors (iNKRs) they express, respond to autologous HIV-infected CD4+(iCD4) T cells. NK cells acquire antiviral functions through education, which requires signals received from iNKRs, such as NKG2A and KIR3DL1 (here, 3DL1), engaging their ligands. NKG2A interacts with HLA-E, and 3DL1 interacts with HLA-A/B antigens expressing the Bw4 epitope. HIV-infected cells downregulate HLA-A/B, which should interrupt negative signaling through 3DL1, leading to NK cell activation, provided there is sufficient engagement of activating NKRs. We examined the functionality of NK cells expressing or not NKG2A and 3DL1 stimulated by HLA-null and autologous iCD4 cells. Flow cytometry was used to gate on each NKG2A+/NKG2A−3DL1+/3DL1−(NKG2A+/−3DL1+/−) population and to measure the frequency of all possible combinations of CD107a expression and gamma interferon (IFN-γ) and CCL4 secretion. The highest frequency of functional NK cells responding to HLA-null cell stimulation was the NKG2A+3DL1+NK cell population. The highest frequencies of functional NK cells responding to autologous iCD4 cells were those expressing NKG2A; coexpression of 3DL1 did not further modulate responsiveness. This was the case for the functional subsets characterized by the sum of all functions tested (total responsiveness), as well as by the trifunctional CD107a+IFN-γ+CCL4+, CD107a+IFN-γ+, total CD107a+, and total IFN-γ+functional subsets. These results indicate that the NKG2A receptor has a role in NK cell-mediated anti-HIV responses.IMPORTANCEHIV-infected CD4 (iCD4) cells activate NK cells, which then control HIV replication. However, little is known regarding which NK cell populations iCD4 cells stimulate to develop antiviral activity. Here, we examine the frequency of NK cell populations, defined by the presence/absence of the NK cell receptors (NKRs) NKG2A and 3DL1, that respond to iCD4 cells. NKG2A and 3DL1 are involved in priming NK cells for antiviral functions upon encountering virus-infected cells. A higher frequency of NKG2A+than NKG2A−NK cells responded to iCD4 cells by developing antiviral functions such as CD107a expression, which correlates with NK cell killing, and secretion of gamma interferon and CCL4. Coexpression of 3DL1 on the NKG2A+and NKG2A−NK cells did not modulate responses to iCD4 cells. Understanding the mechanisms underlying the interaction of NK cells with iCD4 cells that lead to HIV control may contribute to developing strategies that harness NK cells for preventing or controlling HIV infection.
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Kim, Hyung Jin, In Kyu Lee, Won-Kyung Kang, Jung Hyun Kwon, and Seong-Taek Oh. "HLA-cw polypmorphism and killer cell immunoglobulin-like receptor (KIR) gene analysis in Korean patients with colorectal cancer." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 525. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.525.
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525 Background: Many kinds of genetic and environment factors are involved in colorectal cancer development. Natural killer cells (NK cells) play important roles to protect from viral infections and the early development of cancers, and it is activated or inhibited by killer cell immunoglobulin-like receptors (KIR) which bind to HLA class I. KIR genes are encoded on chromosome 19q13.4. And there are 7 kinds of activating KIRs, and another 7 kinds of inhibiting KIRs. The genetic polymorphisms of KIR genes effect the expression of KIR on NK cells, and there are ethnic differences. In this study, we were trying to investigate the KIR genotype of Korean colorectal cancer patients. Methods: DNAs were extracted from the peripheral bloods from normal populations and Korean colorectal cancer patients. KIR genes were amplified using PCR-SSP methods, and HLA-Cw genes were characterized using PCR methods. The results were analyzed between cancer patients and normal control group. Results: KIR2DL2 and KIR2DS2 were found at low rate and KIR2DL3 were found at high rate compare to the Eastern studies, but the rates were similar with Japan study. In this study, KIR2DS5 (33.2% vs. 20.8%, p-value<0.007) was increased in colorectal cancer group, and in rectal cancer subgroup, KIR3DL1 (93.2%, vs. 98.1%, p-value<0.05), KIR2DS2 (7.8% vs. 19.5%, p-value<0.01), KIR2DS4 (93.2% vs. 98.1%, p-value<0.05) were decreased significantly. HLA-Cw6 (9.1% vs. 15.7%, p-value<0.05) and HLA-Cw7 (17.4% vs. 27.7%, p-value<0.02) were decreased in colorectal cancer group, but no difference was found when they were classified to HLA-C1 and HLA-C2 group. Among the patients with HLA-C1 homozygote, KIR2DS2 was decreased significantly (5.8% vs. 14.5%, p-value<0.004). Conclusions: There are ethnic differences of KIR genotypes. KIR2DS5 is increased in Korean colorectal cancer patients, and in rectal cancer subgroup, KIR3DL1, KIR2DS2 and KIR2DS4 are decreased, so there are immunologic differences between colon and rectal cancers. And among the patients with HLA-C1 homozygote, KIR2DS2 is decreased. Therefore KIR2DS2 in presence of their ligand (HLA-C1 group) may have protective effect against colorectal cancer.
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Chewning, Joseph H., Charlotte N. Gudme, Glenn Heller, and Bo Dupont. "The Activating KIR2DS2 Gene Influences NK Alloreactivity and NK Repertoire." Blood 110, no. 11 (November 16, 2007): 313. http://dx.doi.org/10.1182/blood.v110.11.313.313.
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Abstract The hematopoietic stem cell transplant (HCT) donor KIR genotype has been correlated with disease-free survival in patients with acute myelogenous leukemia. The Killer Cell Immunoglobulin-like Receptor (KIR) gene family encodes highly homologous pairs of activating and inhibiting receptors, 2DL1–2DS1; 2DL2/3–2DS2; and 3DL1–3DS1. Inhibitory members are known to regulate NK cell function through interactions with HLA Class I antigens. The role of activating KIRs and their ligand specificity is, however, not well defined. The activating receptor, KIR2DS1, is known to bind the HLA-Cw C2 group antigens and we have recently demonstrated a role for this receptor in NK cell allorecognition. In contrast, KIR2DS2 does not bind HLA-Cw C1 group antigens, and a functional role of this receptor even in NK allorecognition has not been established. We now demonstrate, that presence of the activating KIR2DS2 gene in NK donors homozygous for the HLA-KIR ligand group C2 is associated with significant alloreactivity against C1 homozygous target cells (polyclonal NK cells, p=0.006; NK clones, p=0.001). This alloreactivity is mediated by “missing self” on the target and is dominated by “lack of C2 group on target”. The “missing C2” effect was absent, however, in C2 homozygous donors lacking 2DS2 (p=0.99). Only very rare cytotoxic NK clones expressing GL183 (2DL2/3, 2DS2) and with alloreactivity against C1 targets could be generated in vitro from 2DS2-positive, C2 homozygous donors. A majority of these rare GL183-positive clones did not demonstrate inhibitory function against the HLA class I deficient 721.221 transfected with Cw3 (C1-group), and GL183 cross-linking of the clones resulted in increased cytokine production. Thus, KIR2DS2 is an activating receptor in NK clones from C2 homozygous donors, but does not appear to recognize C1 ligand. We next investigated 2DS2 function in donors heterozygous for the C groups (i.e. C1/C2). Analysis of NK cell function in a 2DS2-positive, C1/C2 donor revealed a “missing HLA-KIR ligand” effect for the C2 group. Cytotoxicity by IL2-propagated, polyclonal NK cells and NK clones revealed allocytotoxicity against targets lacking the C2 group (p<0.001). In addition, a repertoire analysis on 138 NK clones generated from this donor revealed a marked increase in the number of EB6 (KIR2DL1/S1)-expressing NK clones (95%) compared to both the fresh (10%–50%) and the IL-2-expanded polyclonal NK repertoire (12%–60%). Additionally, all EB6-expressing clones from this donor were inhibited by the C2 ligand. Subsequent studies in freshly isolated NK cells following activating receptor cross-linking (NKp46, NKG2C, and CD16) or by alloantigen activation demonstrated that the functioning subset of NK cells in this donor predominantly expressed the EB6 receptor. Other inhibitory receptors (e.g. NKG2A, KIR3DL1, and KIR3DL2) did not contribute significantly to the functional subset of NK cells. Presence of 2DS2 in this donor was therefore associated with a “skewing” of the NK repertoire towards EB6 positivity, and dominated by functional NK cells that were inhibited by the “self” C2 ligand. Collectively, these studies provide the first evidence that activating KIR can influence the NK cell repertoire. Furthermore, our studies would indicate that presence of activating KIRs in HCT donors for recipients homozygous HLA-KIR ligands might induce post-transplantation graft versus host NK alloreactivity.
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Holderried, Tobias A. W., Hye-Jung Kim, Philipp A. Lang, and Harvey Cantor. "CD8+ Treg - From Mouse To Man." Blood 122, no. 21 (November 15, 2013): 3474. http://dx.doi.org/10.1182/blood.v122.21.3474.3474.
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Abstract T cell-mediated regulation of the immune response to self and foreign antigens is essential to maintain immune homeostasis and prevent autoimmune tissue destruction. The majority of studies addressing this issue, both in mice and humans, have focused on the contribution of CD4+CD25+FOXP3+ regulatory T cells. The contribution of regulatory CD8+ T cells has not been appreciated until recently. Recent studies have identified a small subset of IL-15 dependent CD8+ regulatory T cells (Treg) that is essential for maintenance of self- tolerance and prevention of autoimmune disease in mice. Expression of a triad of cell surface markers – CD44+CD122+Ly49+ – has been used to distinguish and purify CD8+Treg (Kim et al., Nature 2010; Kim et al., PNAS 2011). Here we have defined the human homologue of CD8+ Treg. The Ly49 receptor, identified as a stable surface marker on CD8+ Treg, is a member of a multigenic/multiallelic receptor family recognizing classical MHC class I molecules. The functional homologue of murine Ly49 is the killer cell immunoglobulin-like receptor (KIR). Our analysis has revealed that, while expression of KIR subtype combinations appears to be stochastic and co-expression of these KIR receptors is random, the inhibitory KIR2DL2/3 and KIR3DL1 subtypes are dominantly expressed by human CD3+CD8+ T cells. Similar to murine CD8+ Treg, CD8+ T cells that express KIR2DL2/3 or KIR3DL1 also express CD44 and CD122. Moreover, consistent with murine CD8+ Treg, incubation with IL-15 results in activation and proliferation of KIR+CD8+ T cells that maintain a stable surface phenotype. Gene array analyses in mice has indicated that Helios, a highly conserved zinc finger transcription factor and member of the Ikaros family of transcription factors, is expressed by CD44+CD122+Ly49+ CD8+ Treg. Helios is involved in T cell development and expressed by ∼70% of FoxP3+CD4+ Treg but not by mature B cells, dendritic cells or myeloid cells. Our analyses identified a Helios+ subset in the CD8+ Treg population, which (compared to the Helios- subset) embodies many of the functional characteristics of CD8+ Treg in mice. Co-expression of Helios is also apparent in some KIR+CD8+ T cells in human samples. In mice, we have shown that CD8+ Treg target CD4 TFH cells and thus maintain self-tolerance. In vitro suppression assays revealed that KIR+CD8+ cells but not KIR–CD8+ cells confer inhibitory activity on CD4+CXCR5+ TFHtarget cells in humans. Taken together, our findings implicate KIR+CD8+ cells as the human homologue of murine CD8+ Treg, including expression of transcription factor Helios, responsiveness to IL-15 and suppression of CD4+ TFH cells. Understanding the genetic and biological features of this CD8+ T cell subset in humans opens the possibility of exploiting their regulatory activity for the development of immunotherapy in the context of autoimmune disease and cancer. Disclosures: No relevant conflicts of interest to declare.
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González-Quezada, B. A., M. G. J. Sánchez-Fernández, A. J. Munguía-Saldaña, M. E. Valencia-Macedo, H. Flores-Aguilar, E. Bonilla-Galán, A. Rodríguez-Gómez, A. Díaz-Rivera, and C. Gorodezky. "Allele diversity of the killer cell immunoglobulin-like receptors KIR3DL1/S1 and the combination with their HLA ligands in Mexican Mestizos from Mexico City." Human Immunology 79, no. 12 (December 2018): 834–38. http://dx.doi.org/10.1016/j.humimm.2018.10.011.
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Sobecks, Ronald, Medhat Askar, Dawn Thomas, Lisa Rybicki, Matt Kalaycio, Randall Davis, Robert Dean, et al. "Cytomegalovirus (CMV) Reactivation after T-Cell Replete Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) Correlates with Donor KIR Genotype." Blood 110, no. 11 (November 16, 2007): 2974. http://dx.doi.org/10.1182/blood.v110.11.2974.2974.
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Abstract CMV remains the most common viral infection after AHSCT. NK and T cells provide protection against CMV reactivation. The interaction of inhibitory killer immunoglobulin-like receptors (KIRs) with target cell HLA class I molecules regulates NK cells and some T cell populations. Donor activating KIR genotype has been suggested to influence CMV reactivation after myeloablative AHSCT (Cook et al, Blood2006;107:1230–1232). However, the effect of donor activating or inhibitory KIR genotype on CMV reactivation after T-cell replete RIC AHSCT has not been reported. We analyzed 64 consecutive patients (pts) who underwent T-cell replete matched sibling donor RIC AHSCT at our institution from 1/16/00-4/24/07 with fludarabine and low-dose total body irradiation (200 cGy: 36 pts; 400 cGy: 28 pts). All pts received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. CMV monitoring was performed by polymerase chain reaction testing. 49 (77%) pts were CMV seropositive or had a CMV seropositive donor; 25/49 (51%) had CMV reactivation post-AHSCT. 15 (23%) pts were CMV seronegative along with their donors and 1 (7%) of them had CMV reactivation. Donor activating KIR genotypes (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DS1) and inhibitory genotypes (KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, KIR3DL2) were determined by PCR-SSOP and/or PCR-SSP. Patient HLA KIR ligands including HLA-Cw groups C1 or C2, HLA-Bw4 and HLA-A3/11 (reviewed in Farag et al Blood2002; 100:1935–1947) and donor inhibitory KIR genotypes were analyzed. Missing patient KIR ligand was observed in 15 (23%) of the C1 group, 27 (42%) of the C2 group, 25 (39%) of the HLA-Bw4+ pts and 43 (67%) of the HLA-A3/11+ pts. There were no differences observed for CMV reactivation between any of these groups when comparing those with or without missing ligands. However, when the number of donor activating KIRs were considered a difference in CMV reactivation patterns was appreciated. Pts whose donor KIR genotype contained 5 or 6 activating KIR genes (N=16) had less CMV reactivation compared to those with only 1 to 4 activating KIR genes (N=48) (19% vs. 48%). This finding remained significant on multivariable analysis (p=0.038). No specific activating KIR was found to be associated with CMV reactivation. There were no differences between the groups (5–6 vs. 1–4 activating KIR genes) with regards to patient/donor CMV seropositivity, age, diagnoses, gender, race, number of prior chemotherapy regimens, prior radiation, time from diagnosis to RIC AHSCT, TBI dose, donor to patient gender, CD34+ and CD3+ cell doses. We conclude that donor activating KIR genotype influences CMV reactivation after matched sibling donor T-cell replete RIC AHSCT. These results may guide the selection of donors as well as identify patients who may benefit from closer CMV monitoring and additional strategies to prevent CMV reactivation post transplant. Figure Figure