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1
Sultana, Sharmin, Shahina Tabassum, and Afzalun Nessa. "Human Leukocyte Antigen: Class I Allele Frequencies and Haplotype Distributionin a Tertiary Care Hospital in Bangladesh." Bangladesh Medical Research Council Bulletin 44, no. 1 (June 6, 2018): 1–8. http://dx.doi.org/10.3329/bmrcb.v44i1.36798.
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Human leukocyte antigen (HLA) are cell surface glycoproteins encoded by Major Histocompatibility Complex (MHC) geneof human genome. HLA antigen frequency and haplotype distribution are useful for determining disease associations, origin, migration and genetic relationships between populations and predicting the outcome of transplantation. Thus, the present study was carried outto identify HLA class I (HLA-A and HLA-B) antigen and haplotype distribution among a selected Bangladeshi population. This retrospective study was conducted among 1070 individuals who were referred by cliniciansfor HLA typing at the Tissue Typing Laboratory of the Department of Virology, Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period 2009 to 2011. For HLA typing, Blood was collected in heparin containing tube and the laboratory tests were performed by the microlymphocytotoxicity technique according to manufacturer’s instructions.Out of 19 HLA-A and 37HLA-B antigens tested, a total of 19/19 and 36/37 antigens were detectedrespectively in this study. The most frequent antigens of HLA-A and HLA-B detected were A11 (25.4%), A24 (16.6%), B75 (18.1%) and B35 (11.3%). The least antigen frequency detected for HLA-A locus were A69 (0.09%), A26 (0.28%), A34 (0.28%), while for HLA-B locus were B81 (0.09%) and B56 (0.09%). Among the HLA-A and HLA-B antigens, some alleles were found to be homozygote such as A11 (4.0%), A2 (2.7%), A24 (2.1%) andB75 (2.4%), B35 (1.8%), and B44 (1.4%) respectively. The most frequent haplotype in the study populationwereA11: B75 (4.9%). The most frequent antigens of HLA-A and HLA-B detected were A11 (25.4%), B75 (18.1%) respectively. The distribution of HLA haplotypes among the study population indicates that it has the influence of Oriental and Asian populations. Thus, this study will be helpful to provide valuable information for population genetics and HLA disease association analysis.Bangladesh Med Res Counc Bull 2018; 44(1):01-08
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Bhowmik, Devolina, Md Ruhul Amin Miah, Shirin Tarafder, Ahmed Abu Saleh, and Manash Chandra Sarker. "Distribution of HLA-B Locus Antigens in Patients with Psoriatic Arthritis in Bangladesh." Bangladesh Journal of Medical Microbiology 12, no. 2 (August 16, 2018): 14–20. http://dx.doi.org/10.3329/bjmm.v12i2.51691.
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This study was designed to investigate the distribution of HLA-B locus antigens in patients with psoriatic arthritis (PsA) in Bangladesh and identify HLA markers related to disease manifestation in PsA. HLA-B typing was carried out by polymerase chain reaction (PCR) with sequence specific primers in a group of 50 consecutive PsA patients. The reports of HLA-B locus antigens typing were collected from 50 ages and sex matched unrelated healthy donors as controls. A total of 17 HLA-B locus antigens were determined in both patients and controls. The most common antigen was B*15 (34%) followed by B*07 (26%), B*27 (24%), B*38 (20%). Human leukocyte antigens B*07, B*27 and B*38 alleles were found to be significantly prevalent in PsA patients compared with healthy controls. We found a statistically significant association between spondylitis pattern and the presence of HLA-B*27. PsA in Bangladeshi patients seems to be associated with the presence of B*07, B*27 and B*38 alleles.
Bangladesh J Med Microbiol 2018; 12 (2): 14-20
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Kao, KJ, DJ Cook, and JC Scornik. "Quantitative analysis of platelet surface HLA by W6/32 anti-HLA monoclonal antibody." Blood 68, no. 3 (September 1, 1986): 627–32. http://dx.doi.org/10.1182/blood.v68.3.627.627.
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Abstract Class I molecules of human major histocompatibility complex (HLA) are the most important antigenic system in determining the survival of transfused platelets in alloimmunized patients. Platelets with reduced expression of a specific type of HLA antigen may escape specific anti- HLA antibody-mediated destruction. By using 125I-labeled Fab fragments of W6/32 anti-HLA monoclonal antibody and competitive protein binding assays, we measured the range of total HLA concentrations on platelets. In 12 individuals examined, the mean number of HLA-A, B, and C molecules per platelet was 81,587 +/- 20,016 (mean +/- SD); its range was between 54,782 to 116,185 molecules per platelet. After treatment with chloroquine, 79.9 +/- 7.0% (mean +/- SD, n = 6) of HLA antigens were removed from platelets as determined by binding of 125I-W6/32 Fab. A similar result was obtained when HLA antigens on chloroquine-treated platelets were evaluated with immunofluorescence flow cytometry. In contrast, chloroquine treatment did not remove integral membrane protein such as P1A1 antigens on platelets. The presence of HLA antigens in the chloroquine eluate of platelets could be demonstrated to contain HLA antigens similar in mol wts to intact class I molecules by an immunoblotting technique. These data suggest that 70% to 80% of platelet HLA antigens are adsorbed and that such HLA antigens are not proteolytic products of integral membrane class I molecules. The origin of the adsorbed platelet HLA-antigens remains to be determined.
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Kao, KJ, DJ Cook, and JC Scornik. "Quantitative analysis of platelet surface HLA by W6/32 anti-HLA monoclonal antibody." Blood 68, no. 3 (September 1, 1986): 627–32. http://dx.doi.org/10.1182/blood.v68.3.627.bloodjournal683627.
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Class I molecules of human major histocompatibility complex (HLA) are the most important antigenic system in determining the survival of transfused platelets in alloimmunized patients. Platelets with reduced expression of a specific type of HLA antigen may escape specific anti- HLA antibody-mediated destruction. By using 125I-labeled Fab fragments of W6/32 anti-HLA monoclonal antibody and competitive protein binding assays, we measured the range of total HLA concentrations on platelets. In 12 individuals examined, the mean number of HLA-A, B, and C molecules per platelet was 81,587 +/- 20,016 (mean +/- SD); its range was between 54,782 to 116,185 molecules per platelet. After treatment with chloroquine, 79.9 +/- 7.0% (mean +/- SD, n = 6) of HLA antigens were removed from platelets as determined by binding of 125I-W6/32 Fab. A similar result was obtained when HLA antigens on chloroquine-treated platelets were evaluated with immunofluorescence flow cytometry. In contrast, chloroquine treatment did not remove integral membrane protein such as P1A1 antigens on platelets. The presence of HLA antigens in the chloroquine eluate of platelets could be demonstrated to contain HLA antigens similar in mol wts to intact class I molecules by an immunoblotting technique. These data suggest that 70% to 80% of platelet HLA antigens are adsorbed and that such HLA antigens are not proteolytic products of integral membrane class I molecules. The origin of the adsorbed platelet HLA-antigens remains to be determined.
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Gingrich, RD, CE Dahle, KF Hoskins, and MJ Senneff. "Identification and characterization of a new surface membrane antigen found predominantly on malignant B lymphocytes." Blood 75, no. 12 (June 15, 1990): 2375–87. http://dx.doi.org/10.1182/blood.v75.12.2375.2375.
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Abstract A monoclonal antibody, 1D10, was derived that identifies a new antigenic epitope on the surface of malignant B lymphocytes. Normal resting and stimulated lymphocytes do not express the antigen. The majority of individuals with acute Epstein-Barr virus infection express the antigen on their lymphocytes, and in these patients, the T lymphocyte may also be antigen positive. The antigen was found on B- lymphoid neoplasia from the early pre-B cell stage through terminally differentiated plasma cells, a characteristic not reported for other B cell-associated antigens. Studies on homozygous typing cells and cells from individuals with known HLA phenotypes indicate that the antigen does not segregate in a pattern characteristic for major histocompatibility antigens. The molecule is a heterodimeric polypeptide with the molecular weight and isoelectric points of the alpha and beta chains being 32,000 d/4 and 28,000 d/6, respectively. Evidence is presented that the 1D10 molecule is not HLA-DR, -DP, or - DQ. By extrapolation, we suggest that this novel molecule may represent HLA D-region gene expression of a gene(s) not normally expressed. Potential candidates are D-region pseudogenes. We conclude that the antigenic epitope identified by the 1D10 monoclonal antibody is unique among previously described B-lymphocyte antigens. Further studies of the factors controlling the expression of this molecule, as well as studies designed to look at the possible cellular function, may provide insights for understanding crucial events in the malignant transformation of lymphocytes.
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Gingrich, RD, CE Dahle, KF Hoskins, and MJ Senneff. "Identification and characterization of a new surface membrane antigen found predominantly on malignant B lymphocytes." Blood 75, no. 12 (June 15, 1990): 2375–87. http://dx.doi.org/10.1182/blood.v75.12.2375.bloodjournal75122375.
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A monoclonal antibody, 1D10, was derived that identifies a new antigenic epitope on the surface of malignant B lymphocytes. Normal resting and stimulated lymphocytes do not express the antigen. The majority of individuals with acute Epstein-Barr virus infection express the antigen on their lymphocytes, and in these patients, the T lymphocyte may also be antigen positive. The antigen was found on B- lymphoid neoplasia from the early pre-B cell stage through terminally differentiated plasma cells, a characteristic not reported for other B cell-associated antigens. Studies on homozygous typing cells and cells from individuals with known HLA phenotypes indicate that the antigen does not segregate in a pattern characteristic for major histocompatibility antigens. The molecule is a heterodimeric polypeptide with the molecular weight and isoelectric points of the alpha and beta chains being 32,000 d/4 and 28,000 d/6, respectively. Evidence is presented that the 1D10 molecule is not HLA-DR, -DP, or - DQ. By extrapolation, we suggest that this novel molecule may represent HLA D-region gene expression of a gene(s) not normally expressed. Potential candidates are D-region pseudogenes. We conclude that the antigenic epitope identified by the 1D10 monoclonal antibody is unique among previously described B-lymphocyte antigens. Further studies of the factors controlling the expression of this molecule, as well as studies designed to look at the possible cellular function, may provide insights for understanding crucial events in the malignant transformation of lymphocytes.
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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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Popovska, Mirjana, Aneta Atanasovska-Stojanovska, Sashka Todoroska, Vera Radojkova-Nikolovska, Lindita Zendeli Bedhxeti, Ana Spasovska-Gjorgovska, Spiro Spasovski, and Marija Ivanovska-Stojanoska. "Oral Lichen Planus – Related Connection with HLA-System Antigens." PRILOZI 41, no. 1 (June 1, 2020): 65–77. http://dx.doi.org/10.2478/prilozi-2020-0024.
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AbstractAim:To determine whether there is an immunogenic connection and antigen difference between the HLA antigens in the erosive (EOLP) and reticular (ROLP) oral lichen planus.Materials and Method: 73 patients with ROLP and EOLP have been tested. Typing of the HLA antigens has been made for locus A and B. The typing of the HLA was conducted with the use of microlymphocyto toxic test by Terasaki. The reading of the findings has been conducted with an inverse microscope. When a reaction has 4 points it is considered to be positive.Results: The most frequently typified antigens in ROLP from locus A are HLA А2 (57.57%) and А3 (33.33)%, and for locus B 21.21%. In EOLP it is А9 (8888%). In locus B a connection has been found with HLA B8 (77.77%). The statistical analysis with the ×2 test has shown that the carriers of HLA A9 display a relative risk (RR) of 3.65 and ×2=20.72. Consequently, there is high static importance for locus A p<0,001. For locus B, In EOLP for HLA B8, RR=6. 7 ×2=37.64 and p<0,001. ROLP has shown association with HLA A3, where RR=2. 31 and ×2 =9.14 and p<0.05.Conclusions: In ROLP A3 antigen and in EOLP A9 and A8 may be considered as carriers with proneness to OLP.
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Rajaei, Elham, Mohammad T. Jalali, Seyed M. Sadegh Pezeshki, Hadi Rezaeeyan, Mahmood Maniati, Milad Elyasi, and Zeinab D. Zayeri. "Dose HLA-B5, 7, 8, 27, and 51 Antigens Associated to Behcet's disease? A Study in Southwestern Iran." Current Rheumatology Reviews 16, no. 2 (May 11, 2020): 120–24. http://dx.doi.org/10.2174/1573397115666190918153721.
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Background: Behcet's disease is a potentially life threatening autoimmune disease with recurrent ulcers and unknown pathogenesis. Gender and human leukocyte antigen-B51 seem to have an effective role in the clinical features of the disease. Objective: The aim of this study is to evaluate the frequency of HLA-B5, 7, 8, 27 and 51 in behçet's disease in southwestern Iranian patients who visited the rheumatology clinic and to find the association between these HLA types and the disease. Methods: 63 patients with behcet's disease participated in this study and peripheral blood samples were collected from them. The expression of each HLA antigen was evaluated by standard lymphocytotoxicity technique. Results: Compared to other studied antigens, the expression of HLA-B5 and HLA-B51 was more prevalent among our patients. According to the results, 25% and 21% of patients were positive for HLA-B5 and HLA-B51, respectively. Conclusions: HLA-B5 and HLA-B51 are dominant positive HLA antigens among behcet's disease patients in the southwest of Iran; however, we cannot conclude that these antigens are valuable diagnostic or prognostic biomarkers due to our study limitations. We suggest studying the association between HLA-B antigens and inflammation severity in patients to determine the possible prognostic value of HLA-B antigens in Iranian population in the southwest and this region needs more studies in HLA subject among BD patients because of the frequency of BD to evaluate the value of HLA typing in BD prognosis.
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Archbold, Julia K., Whitney A. Macdonald, Stephanie Gras, Lauren K. Ely, John J. Miles, Melissa J. Bell, Rebekah M. Brennan, et al. "Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition." Journal of Experimental Medicine 206, no. 1 (January 12, 2009): 209–19. http://dx.doi.org/10.1084/jem.20082136.
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Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.
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GÖNEN, Sevim, Sinan SARI, Yaşar KANDUR, Buket DALGIÇ, and Oğuz SÖYLEMEZOĞLU. "EVALUATION OF HUMAN LEUKOCYTE ANTIGEN CLASS I AND II ANTIGENS IN HELICOBACTER PYLORI-POSITIVE PEDIATRIC PATIENTS WITH ACTIVE GASTRITIS AND DUODENAL ULCER." Arquivos de Gastroenterologia 54, no. 4 (October 2, 2017): 297–99. http://dx.doi.org/10.1590/s0004-2803.201700000-62.
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ABSTRACT BACKGROUND: As being the first bacteria determined to be carcinogenic, Helicobacter pylori (H. pylori) is a pathogen localized in the stomach in more than half of the world population. Some earlier studies have found a relation between tissue histocompatibility antigens and gastric cancers depending on the regions. OBJECTIVE: The present study aimed to determine the distribution of human leukocyte antigen (HLA) class I and class II antigens in H. pylori-positive pediatric patients with active gastritis and duodenal ulcer, excluding cancer cases, in our center. METHODS: The study included 40 patients diagnosed with H. pylori-positive active gastritis and duodenal ulcer and 100 controls consisting of healthy donor candidates. The HLA class I and class II antigens were studied in the isolated DNA samples using the polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS: The frequency of HLA-B*51 antigen was significantly higher in the patient group than in the control group (40% vs 17%; P=0.003). There was no difference between the two groups in terms of the frequencies of HLA-A, HLA-C, HLA-DR, and HLA-DQ antigens. CONCLUSION: It was determined that HLA-B*51 plays a critical role in H. pylori infection.
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Driianska, V., O. Petrina, M. Velychko, F. Haisenyuk, and G. Drannik. "Peculiarities of phenotypes of patients with pyelo- and glomerulonephritis by HLA distribution analysis." Ukrainian Journal of Nephrology and Dialysis, no. 4(60) (December 26, 2018): 11–18. http://dx.doi.org/10.31450/ukrjnd.4(60).2018.02.
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Studies devoted to the role of human leucocyte antigens (HLA) in pathogenesis of chronic kidney disease (CKD) have demonstrated the associative links of the HLA antigens, which stipulate the relative and attributive risks of some autoimmune diseases, with immune disorder and a high production of pro-inflammatory cytokines.
The aim of our study was to determine the peculiarities of phenotypes of CKD patients according to the distribution of HLA-A, B and DR antigens and to conduct their comparative analysis in patients with pyelonephritis (PN) and glomerulonephritis (GN).
Methods: The distribution of HLA-A, B, DR antigens in 384 CKD patients (120 with PN and 264 with GN) was analyzed. HLA antigens were defined using a standard microlymphocytotoxic test on the Terasakiґs planchette with special panels of anti-HLA serums (20 antigens of locus A, 31 – B and 9 – DR). The control group consisted of 350 healthy donors.
The HLA antigen frequencies in normal and diseased subjects were compared taking each antigen separately, using χ2 test. The etiologic fraction (attributive risk s > 0,1) was counted using the formula: s = x - y/I- y, where x is frequency of antigen in patients and y is frequency in healthy. The s reading was considered reliable when it exceeded 0.1.
Results. The causal role (σ > 0,1) was determined for А10, А11; В14, В16 for PN; antigens-protectors - А2, В21, В35, В40.
For CGN, NS the relative risk is high (RR > 2) at the presence of HLA-A23, А24, А28; B8, В38, В41, В44; DR1, DR4, DRw52 in phenotype, the causal role in etiopathology (σ>0.1) is indicated for A24,А28; B8; DR1, DR4, DRw52; the disease protectors are B12 and B16.
Conclusion. Conclusion. The features of the HLA-phenotype of patients with pyelo- and glomerulonephritis were shown. It allowed to establish the interconnectedness of the antigens of the histocompatibility complex with the risk of kidney diseases developing, which could help to personificate of the treatment and predicte of the course of the disease.
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Kojima, Seiji, Hiromasa Yabe, Koji Kato, Hisato Kigasawa, Hisashi Sakamaki, Masahiro Tsuchida, Shunichi Kato, Yasuo Morishima, and Yoshihisa Kodera. "Effects of HLA-C and HLA-DQB1 Mismatching on Outcome of Unrelated Donor Marrow Transplantation for Patients with Severe Aplastic Anemia." Blood 106, no. 11 (November 16, 2005): 563. http://dx.doi.org/10.1182/blood.v106.11.563.563.
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Abstract Prior studies assessing the effects of HLA mismatching on outcomes of unrelated donor marrow transplantation (UBMT) have yielded conflicting results. Our previous study revealed that mismatching of HLA-A and -B antigens, and not of HLA-DRB1 antigen, was the most crucial risk factor for survival for patients with SAA who received UBMT (Kojima S et al, Blood100: 799, 2002). Because only the data of HLA-A, -B, and DRB1 were available, the role of HLA-C and DQB1 mismatching was not clarified in that study. The current study aimed to evaluate the effects of HLA-C and DQB1 mismatching. From Feb 1993 to April 2003, 260 consecutive patients with acquired aplastic anemia (AA) received UBMT through the Japan Marrow Donor Program. We selected 79 recipient-donor pairs in which molecular analysis of HLA-A, -B, -C, -DRB1, and DQB1 were performed. Patient ages ranged from 3 to 46 years (median, 15 years). Various preconditioning regimens were used by individual centers. In 69 patients (87%), cyclosporine and methotrexate were used for the prophylaxis against GVHD. Of the 79 pairs, 26 (33%) were found to be matched at HLA-A, -B, -C, -DRB1, and DQB1; 18 (23%) were mismatched at a single HLA antigen (6 HLA-A or -B, 7 HLA-C, 5 HLA-DRB1 or HLA-DQB1); 31 (39%) were mismatched at two HLA antigens (5 HLA- and HLA-DQB1, 18 HLA-A or -B and HLA-C or -DRB1 or -DQB1, 8 HLA-C and HLA-DRB1 or -DQB1); and 9 (11%) were mismatched at 3 HLA antigens. Transplant-related toxicities such as graft failure, grade 3 to 4 acute GVHD, and chronic GVHD were found in 7/74, 14/70, and 16/59, respectively. In a univariate analysis, any single HLA mismatching including HLA-A, -B, or -C did not increase the incidence of acute GVHD. Of 79 patients, 44 survived. The 5-year survival rate did not differ between recipients transplanted from a full-matched donor (68.5%) and those from any single HLA mismatched donors (66.7 to 80.0%). In addition, the 5-year survival rate was not worse (62.5%) in patients transplanted from HLA-C and HLA-DRB1 or -DQB1 mismatched donors. However, the 5-year survival rate was significantly worse (38.9%) in recipients who transplanted from HLA-A or -B mismatched and -C or -DRB1 or -DQB1 mismatched donors and it was 0% in patients who were mismatched at 3 antigens. In a multivariate analysis, the relative risk for HLA-A or -B and -C or -DRB1 or -DQB1 mismatching was 4.24 (95% CI, 1.6–11.5) and for 3 antigen mismatching, it was 20.0 (95% CI, 5.6–71.6). The current JMDP study showed that mismatching of a single HLA antigen did not result in increased mortality. However, in patients with HLA-A or -B mismatching, additional mismatching at HLA-C, -DRB1, or -DQB1 had a significant adverse effect on survival. Matching of HLA-C and -DQB1 should be incorporated into algorithms for unrelated donor selection.
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Koclega, Anna, Miroslaw Markiewicz, Urszula Siekiera, Alicja Dobrowolska, Sylwia Mizia, Monika Dzierzak-Mietla, Patrycja Zielinska, Malgorzata Sobczyk-Kruszelnicka, and Slawomira Kyrcz-Krzemien. "Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Mismatched Unrelated Donors." Blood 120, no. 21 (November 16, 2012): 4475. http://dx.doi.org/10.1182/blood.v120.21.4475.4475.
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Abstract Abstract 4475 Introduction: Anti-HLA Antibodies (Abs) are considered an important factor in solid organ transplants and transfusion medicine, but role of humoral arm of immunological response to HLA antigens in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unknown. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define presence and profiles of anti-HLA Abs detected before or after allo-HSCT from HLA-mismatched unrelated donors and their impact on allo-HSCT results. Material and methods: 35 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL (7pts), AML(18pts), CML(5pts), SAA(2pts), CLL(1pt), MDS(1pt) and PNH (1pt). Preparative regimen was myeloablative in 33pts (94.3%) and reduced in 2pts (5.7%). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (34pts) or Alemtuzumab (1pt). HLA A, B, C, DR, DQ alleles were PCR-typed. 21(60%) pts had mismatch of single HLA-antigen: A-4(11.4%), B-1(2.8%), C-13(37%), DQ-3(8,5%); 10(28.5%) pts had mismatch of single HLA-allele: A-3(8.5%), B(11.4%), DQ-3(8.5%); 4 pts had double antigenic (A+C and A+DQ) or combined antigenic/allelic (A/B and C/A) HLA mismatches. Anti-HLA A, B, C, DR, DQ, DP Abs were identified in sera collected before start of the conditioning treatment and +30 days, +100 days and 1 year after allo-HSCT with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens. Results: Anti-HLA Abs pre-formed before allo-HSCT were detected in 17(48.5%) pts: against class I, II or both in 6(35%), 4(24%) and 7(41%) pts. Anti-HLA Abs were detected after allo-HSCT in 25(71.4%) pts, against class I, II or both in 9(36%), 3(12%) and 13(52%) pts, respectively. In 7 pts anti-HLA Abs were not detected neither before nor after allo-HSCT. Anti-HLA Abs directed against the mismatched HLA antigens were observed in 4 pts before and in 10 pts after allo-HSCT, no anti-HLA Abs specific against mismatched alleles were detected. Allo-HSCT results obtained in studied subgroups are presented in the Table below: Conclusions: Our preliminary results indicate that anti-HLA Abs are present pre- or post-transplant in mismatched allo-HSCT recipients and may be potentially responsible for the occurrence of complications, what needs to be further investigated and analyzed. Disclosures: No relevant conflicts of interest to declare.
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Chen, Xiaoling, Wenbo Wang, Shufeng Wang, Gang Meng, Mengjun Zhang, Bing Ni, Yuzhang Wu, and Li Wang. "An immunodominant HLA-A*1101-restricted CD8+ T-cell response targeting hepatitis B surface antigen in chronic hepatitis B patients." Journal of General Virology 94, no. 12 (December 1, 2013): 2717–23. http://dx.doi.org/10.1099/vir.0.052167-0.
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Hepatitis B virus (HBV) infection is a worldwide public health problem. HBV-specific CD8+ CTLs are vital for viral clearance. Identification of immunodominant CTL epitopes from HBV-associated antigens is necessary for therapeutic vaccine development. We showed that the HLA-A*1101 allele is one of the most common alleles in both healthy individuals and chronic hepatitis B (CHB) patients in the Chongqing area, China. However, less than 10 % of epitopes of HBV-associated antigens have been identified in an HLA-A*1101 context. Here, we describe an immunodominant CD8+ T-cell response targeting a hepatitis B surface antigen determinant (HBs295–304) restricted by HLA-A*1101 in both healthy individuals and CHB patients. Moreover, HBs295–304 is more immunogenic for CTL induction than a known naturally HLA-A*1101-processed epitope from hepatitis B core antigen (HBc88–96). Therefore, the newly identified epitope, HBs295–304, will benefit the development of immunotherapeutic approaches for HBV infection.
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Ramilyeva, I. R., Zh K. Burkitbaev, S. A. Abdrakhmanova, A. A. Turganbekova, D. K. Baimukasheva, and E. B. Zhiburt. "DISTRIBUTION PATTERN FOR HLA SPECIFICITIES IN THE PATIENTS WITH ACUTE MYELOID LEUKEMIA." Medical Immunology (Russia) 21, no. 5 (December 13, 2019): 965–72. http://dx.doi.org/10.15789/1563-0625-2019-5-965-972.
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The article presents a study on the distribution of gene polymorphisms in the histocompatibility antigens among the patients diagnosed with AML, and healthy donors in the Republic of Kazakhstan, as well as features of the HLA-A*, *B, Cw*, DRB1*, DQB1* distribution among the patients with acute myeloid leukemia (AML). HLA typing and data processing were performed at the Research and Production Center of Transfusiology, Nur-Sultan. A total of 3808 people were examined, including 3621 healthy blood donors and 187 patients diagnosed with AML. Genomic DNA for HLA typing was isolated from peripheral blood leukocytes by proteinase method using columns with silica membrane and using a set of reagents PROTRANS DNA BOX (Protrans, Germany). Typing of HLA-A, B, C, DRB1, DQB1 in the patients and blood donors was performed by polymerase chain reaction using commercial reagent kits from Protrans (PROTRANS HLA- A*/B*/DRB1* Cyclerplate System, PROTRANS HLA-C* Cyclerplate System, PROTRANS HLA-DQB1* Cyclerplate System).HLA-A*31 (OR = 1.8; CI 1.16-2.79; p < 0.01) proved to be more common in the group of patients compared to the control group, which suggesting an association between AML and presence of this antigen. The control group showed an increased frequency of HLA-A*02 antigen (OR = 0.55; CI 0.41-0.75; p < 0.01). This antigen may be, therefore, exert a protective effect in AML development.The studies of major histocompatibility complex which include HLA genes, did significantly expanded the understanding of HLA antigens which may have strong associative links with distinct diseases, and moderately or poorly expressed links in other disorders. Analysis of the literature data showed that myeloid leukemia is characterized by decreased frequency of HLA-B13, B14, B40 antigens, most often determined by antigens B16, Bw 22, B27. In this study, HLA-A*31, B*37 were associated with AML. Phenotypes with antigens HLA-A*02, B*27, C*02, DRB1*01, *04, DQB1*06 have a probable protective effect on the development of this pathology.The study has determined some features of histocompatibility gene distribution in AML patients, detection of HLA-markers that determine the risk or resistance to the occurrence of this disease. We have established characteristic specific markers of HLA system among AML patients in Kazakhstan, which may be associated with higher risk of the disease.
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Versteeg, R., K. M. Krüse-Wolters, A. C. Plomp, A. van Leeuwen, N. J. Stam, H. L. Ploegh, D. J. Ruiter, and P. I. Schrier. "Suppression of class I human histocompatibility leukocyte antigen by c-myc is locus specific." Journal of Experimental Medicine 170, no. 3 (September 1, 1989): 621–35. http://dx.doi.org/10.1084/jem.170.3.621.
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The c-myc oncogene downregulates class I HLA expression in human melanoma. The major class I HLA antigens are encoded by three loci, A, B, and C, and we investigated whether these loci are suppressed equally by c-myc. In three melanoma cell lines with high c-myc expression, we analyzed mRNA, protein, and cell surface expression of the class I HLA antigens. Whereas the HLA-B locus expression was found to be strongly reduced, the HLA-A locus was expressed normally. Analysis of c-myc-transfected clones of two melanoma cell lines confirmed that c-myc preferentially suppresses the class I HLA-B locus. Immunohistochemical analysis of fresh melanoma lesions also showed that in the tumors the HLA-A loci are expressed normally, while on the majority of tumor cells no HLA-B antigen expression was found. This downregulation may have consequences for the recognition of malignant cells by tumor-infiltrating lymphocytes. Our results predict that HLA-B-restricted cytotoxic T cells will be unable to kill high c-myc-expressing melanoma cells.
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Stasiak, Magdalena, Bogusław Tymoniuk, Bartłomiej Stasiak, and Andrzej Lewiński. "The Risk of Recurrence of Subacute Thyroiditis Is HLA-Dependent." International Journal of Molecular Sciences 20, no. 5 (March 3, 2019): 1089. http://dx.doi.org/10.3390/ijms20051089.
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The frequency of recurrence of subacute thyroiditis (SAT) is rather high, reaching 20–30%. The reason for SAT relapse is still unknown. Recently, we have demonstrated the association between SAT and the presence of HLA-B*18:01, DRB1*01, and C*04:01, apart from the previously known HLA-B*35. The aim of the present study was to evaluate the correlation between SAT-associated HLA haplotypes and the risk of SAT recurrence. HLA-A, -B, -C, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method in 49 SAT patients. The patients were divided into the following HLA groups: 1. HLA-B*35 and/or HLA-C*04, but without any other of the analyzed antigens; 2. HLA-DRB1*01, regardless of the co-presence of HLA-B*35 or -C*04:01, but without HLA-B*18:01; 3. HLA-B18 only, without any other antigen; 4. HLA-B*18:01 plus -B*35, regardless of the presence of any other analyzed antigens. The recurrence rate was compared between the groups. The recurrence rate was significantly increased in patients with HLA-B*18:01 plus HLA-B*35. In conclusion, the risk of SAT recurrence was HLA-dependent and the determining factor was the co-presence of HLA-B*18:01 and -B*35. In such high-risk patients, the steroid treatment regimen should be intensified with a slower dose reduction.
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Doyle, A., W. J. Martin, K. Funa, A. Gazdar, D. Carney, S. E. Martin, I. Linnoila, F. Cuttitta, J. Mulshine, and P. Bunn. "Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer." Journal of Experimental Medicine 161, no. 5 (May 1, 1985): 1135–51. http://dx.doi.org/10.1084/jem.161.5.1135.
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We have found markedly deficient expression of the class I major histocompatibility antigens HLA-A,B,C and beta 2m on human small-cell lung cancer (SCLC) lines and fresh tumor samples. The deficit of HLA-A,B,C and beta 2-microglobulin (beta 2m) antigen expression was demonstrated with both radiobinding assays and indirect immunofluorescence assays. Immunoprecipitation of metabolically labeled cells with antibodies to class I antigens showed most SCLC lines to have synthesized almost no beta 2m and HLA-A,B,C proteins. Northern blot analysis, using human HLA-A,B, and beta 2m cDNA probes, showed that almost all SCLC lines tested had markedly decreased amounts of HLA and beta 2m mRNA, but both gene products could be induced with interferon treatment of SCLC lines. We conclude that human SCLC, in contrast to other lung cancer types, is characterized by greatly reduced transcription of HLA-A,B,C and beta 2m genes, which suggests the existence of a mechanism for evading the host immune response to the tumor and of an E1a-like product in this type of tumor cell.
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Jahn, Lorenz, Pleun Hombrink, Chopie Hassan, Michel G. D. Kester, Renate S. Hagedoorn, Dirk M. van der Steen, Marjolein P. Schoonakker, J. H. Frederik Falkenburg, Peter A. van Veelen, and Mirjam H. M. Heemskerk. "High-Affinity CD20-Specific T-Cell Receptors Suitable for Adoptive Immunotherapy in the Treatment of CD20low B-Cell Malignancies." Blood 124, no. 21 (December 6, 2014): 3837. http://dx.doi.org/10.1182/blood.v124.21.3837.3837.
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Abstract Therapeutic monoclonal antibodies (mAb) such as Rituximab and Ofatumumab have demonstrated the clinical efficacy of targeting the B-cell restricted antigen CD20 for the treatment of B-cell lymphomas and leukemia. Although CD20 is also expressed on healthy B-cell cells which are depleted in the course of therapy, long-term B-cell aplasia is well manageable. However, non-responsive or refractory disease to CD20-targeted mAb treatment has been reported with various mechanisms of resistance: downregulation of CD20 expression, internalization of CD20:mAb complex, inhibition of complement-dependent cytotoxicity and absence of an effector cell repertoire in patients treated with chemotherapy prior to mAb infusion. Therefore, additional therapeutic strategies are required. T-cell receptor (TCR) gene transfer is an attractive strategy to equip T-cells with TCRs of defined antigen-specificity. Due to their high sensitivity for cognate antigen presented in HLA, TCRs can induce T-cell activation even when antigen expression is very low. However, the broad application of TCR-based adoptive immunotherapy directed against self-antigens such as CD20 is hampered by lack of an effective immune response against self-antigens. T-cells carrying high-affinity TCRs reactive to such self-antigens are deleted by negative selection during thymic development to prevent auto-reactivity. An attractive strategy to target self-antigens is to exploiting the immunogenicity of such antigens presented in the context of allogeneic HLA (alloHLA). Here, we used the CD20-derived peptide SLFLGILSV (CD20SLF) binding in HLA-A2 to isolate CD20-reactive T-cells carrying high-affinity TCRs. From peripheral blood mononuclear cells of HLA-A*0201 (HLA-A2)-negative healthy individuals CD8+ T-cells binding to peptide-HLA tetramers composed of CD20SLF bound to HLA-A2 were isolated and clonally expanded. Two high-avidity T-cell clones were identified specific for HLA-A2-bound CD20SLF. CD20-dependent recognition was demonstrated for both clones by transducing the CD20 gene in HLA-A2-positive cell lines which otherwise lack CD20 expression. Both CD20-specific T-cell clones efficiently recognized CD20-expressing HLA-A2-positive primary B-cell malignancies including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In addition, the CD20-specific T-cell clones were able to more efficiently recognize ALL cell-lines than CD20-specific mAbs. We demonstrated that on target cells with only very low CD20 surface expression, the CD20-specific T-cell clones could still efficiently recognize endogenously processed CD20-derived peptide in the context of HLA-A2. Furthermore, no recognition of HLA-A2-positive but CD20-negative cell subsets including CD34+hematopoietic progenitor cells, T-cells, immature and mature dendritic cells could be demonstrated. Additionally, recognition of HLA-A2-positive non-hematopoietic cells such as fibroblasts even under simulated inflamed conditions was absent. Transduction of the identified TCRs resulted in efficient expression of the introduced CD20-specific TCRs and conferred CD20-specificity onto recipient cells. In summary, we exploited the immunogenicity of alloHLA to raise high-avidity T-cells against self-antigens such as CD20. The identified CD20-specific T-cell clones efficiently recognized CD20-expressing primary ALL, CLL and MCL. These T-cells clones more efficiently recognized B-cell malignancies than CD20-targeted mAbs while no recognition of CD20-negative hematopoietic and non-hematopoietic cells was observed. Transduction of these CD20-specific TCRs conferred CD20-specificity onto recipient cells. These CD20-specific TCRs can be useful to treat patients with CD20low B-cell malignancies by administering TCR-engineered T cells with potent effector function. Disclosures No relevant conflicts of interest to declare.
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Thurlow, P. J., L. Kerrigan, R. A. Harris, and I. F. McKenzie. "Analysis of human bone marrow with monoclonal antibodies." Journal of Histochemistry & Cytochemistry 33, no. 12 (December 1985): 1183–89. http://dx.doi.org/10.1177/33.12.2415573.
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In order to study the antigenic phenotype of different hemopoietic cells, we used a series of monoclonal antibodies to investigate normal bone marrow in a standard immunofluorescence assay. The antibodies detected the following antigens: HLA-ABC, beta 2-microglobulin (beta 2m), HLA-DR (Ia), a lymphocyte subset and specific antigen (T and B) HuLy-m2, m3, T lymphocyte antigen (HuLy-m1), lymphocyte T200 antigen (HuLy-m4), a viral-associated antigen (HuLy-m5), and platelet-specific glycoproteins IIb-IIIa (HuPl-m1). The following results were obtained: (a) normoblasts were weakly HLA-ABC+, beta 2m+ and Ia-; all other lymphocyte and platelet antigens were not detected. (b) Myeloid cells at all stages of differentiation (promyelocytes, myelocytes, metamyelocytes, and neutrophils) were HLA-ABC+; beta 2m+; HuLy-m1-, m2-, m3+/- (20%), m4+, m5+/- (20%); HuPl-m1-; in addition, promyelocytes and myelocytes were Ia+ but neutrophils and metamyelocytes were Ia-. (c) Lymphocytes were HLA-ABC+, beta 2m+, Ia+/- (20-30%), HuLy-m1+/- (40-50%), m2+/- (60-70%), m3+, m4+, m5+; Pl-m1-. (d) Platelets and megakaryocytes were HLA-ABC+; beta 2m+; Ia-; HuLy-m1+-, m2-, m3-, m4-, m5-, HuPl-m1+, and the putative "megakaryocyte precursors" were HuPl-m1+, Ia-, HuLy-m1-. The different cell types in bone marrow could readily be distinguished, particularly cells of the myeloid series (Ia and HuLy-m4, m5), lymphocytes (Ia and HuLy-m1, m2, m3), and platelets and their precursor cells (HuPl-m1). This simple method of defining cellular phenotypes in bone marrow has demonstrated the practicality of using monoclonal antibodies to identify marrow cells and should be of diagnostic value.
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Duygu, Burcu, Benedict M. Matern, Lotte Wieten, Christina E. M. Voorter, and Marcel G. J. Tilanus. "Specific amino acid patterns define split specificities of HLA-B15 antigens enabling conversion from DNA-based typing to serological equivalents." Immunogenetics 72, no. 6-7 (June 20, 2020): 339–46. http://dx.doi.org/10.1007/s00251-020-01172-8.
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Abstract The HLA-B15 typing by serological approaches defined the serological subgroups (or splits) B62, B63, B75, B76, B77 and B70 (B71 and B72). The scarcity of sera with specific anti-HLA antibodies makes the serological typing method difficult to discriminate a high variety of HLA antigens, especially between the B15 antigen subgroups. Advancements in DNA-based technologies have led to a switch from serological typing to high-resolution DNA typing methods. DNA sequencing techniques assign B15 specificity to all alleles in the HLA-B*15 allele group, without distinction of the serological split equivalents. However, the presence of antibodies in the patient defined as split B15 antigens urges the identification of HLA-B*15 allele subtypes of the donor, since the presence of donor-specific antibodies is an important contraindication for organ transplantation. Although the HLA dictionary comprises information regarding the serological subtypes of HLA alleles, there are currently 394 B15 antigens out of 516 in the IPD-IMGT/HLA database (3.38.0) without any assigned serological subtype. In this regard, we aimed to identify specific amino acid patterns for each B*15 serological split, in order to facilitate the assignment of B*15 alleles to serological equivalents after high-resolution molecular typing. As a result, serological specificities of 372/394 not yet assigned alleles could be predicted based on amino acid motifs. Furthermore, two new serological types were identified and added, B62-Bw4 and B71-Bw4.
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Krangel, M. S. "Secretion of HLA-A and -B antigens via an alternative RNA splicing pathway." Journal of Experimental Medicine 163, no. 5 (May 1, 1986): 1173–90. http://dx.doi.org/10.1084/jem.163.5.1173.
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Human class I major histocompatibility antigens (HLA-A, -B and -C) are integral membrane protein heterodimers, which are anchored in the membrane via a stretch of hydrophobic amino acids near the carboxyl terminus of the heavy chain. It has previously been shown that a mutagenized cell line secretes a water soluble form of the HLA-A2 antigen, due to a pattern of RNA splicing that removes exon 5 (encoding the transmembrane hydrophobic amino acids) from mature, HLA-A2--encoding transcripts. The present study was undertaken to assess whether a similar process might be operative in nonmutagenized cells. It is shown that water soluble class I molecules (primarily HLA-A24) are secreted by the T leukemic cell line HPB-ALL, and that alternative splicing removes exon 5 from a fraction of HLA-A24--encoding transcripts. It is further shown that class I molecules are secreted, possibly in an allele-specific fashion, from a variety of tumor cells and normal cells. The possible relationship between these findings and previous reports of HLA-A and -B antigens in human serum is discussed.
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Litwin, V., J. Gumperz, P. Parham, J. H. Phillips, and L. L. Lanier. "NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 537–43. http://dx.doi.org/10.1084/jem.180.2.537.
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Natural killer (NK) cells kill normal and transformed hematopoietic cells that lack expression of major histocompatibility complex (MHC) class I antigens. Lysis of HLA-negative Epstein Barr virus-transformed B lymphoblastoid cell lines (B-LCL) by human NK cell clones can be inhibited by transfection of the target cells with certain HLA-A, -B, or -C alleles. NK cell clones established from an individual demonstrate clonal heterogeneity in HLA recognition and a single NK clone can recognize multiple alleles. We describe a potential human NK cell receptor (NKB1) for certain HLA-B alleles (e.g., HLA-B*5101 and-B*5801) identified by the mAb DX9. NKB1 is a 70-kD glycoprotein that is expressed on a subset of NK cells and NK cell clones. DX9 monoclonal antibody (mAb) specifically inhibits the interaction between NK cell clones and B-LCL targets transfected with certain HLA-B alleles, but does not affect recognition of HLA-A or HLA-C antigens. An individual NK cell clone can independently recognize B-LCL targets transfected with HLA-B or HLA-C antigens; however, DX9 mAb only affects interaction with transfectants expressing certain HLA-B alleles. These findings demonstrate the existence of NK cell receptors involved in the recognition of HLA-B and imply the presence of multiple receptors for MHC on an individual NK clone.
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Žertová, Miroslava, and Zdenko Procházka. "Synthesis of three peptides from HLA-A and HLA-B antigens." Collection of Czechoslovak Chemical Communications 56, no. 9 (1991): 1971–73. http://dx.doi.org/10.1135/cccc19911971.
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Loken, MR, VO Shah, KL Dattilio, and CI Civin. "Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development." Blood 70, no. 5 (November 1, 1987): 1316–24. http://dx.doi.org/10.1182/blood.v70.5.1316.1316.
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Abstract A panel of B lymphoid-reactive monoclonal antibodies was used to analyze the phenotypic changes that accompany B lymphocyte development in normal human bone marrow. The B lymphoid cells were identified using light scattering and the expression of CD19 on a flow cytometer. Quantitative three-color immunofluorescence was then used to correlate other cell surface antigens on these cells identified as B lymphoid in normal marrow. CD10 and CD20 identified almost exclusive populations and provided a convenient means of discriminating between the less and more mature B lineage cells. The CD10+ cells could be further subdivided using CD34. The population of CD19+, CD10+, CD34+ cells comprised only 0.6% of marrow cells, but these contained the majority of terminal deoxynucleotidyl transferase (TdT+) cells. In the assessment of class II antigens, HLA-DR was expressed on all B lineage cells whereas HLA-DP preceded HLA-DQ in appearance during the developmental process. Among the later antigens expressed on B lineage cells, cell surface IgM, CD20, and HLA-DQ were expressed at essentially the same time. Cell surface CD10 was lost at the time when CD21 and CD22 were acquired on the cell surface. These data illustrate that multiparameter flow cytometry can be used to define a continuous progression of stages of B lymphocyte development based on cell surface antigen expression even though these cells represent a minor fraction of normal marrow cells.
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Loken, MR, VO Shah, KL Dattilio, and CI Civin. "Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development." Blood 70, no. 5 (November 1, 1987): 1316–24. http://dx.doi.org/10.1182/blood.v70.5.1316.bloodjournal7051316.
Full textAbstract:
A panel of B lymphoid-reactive monoclonal antibodies was used to analyze the phenotypic changes that accompany B lymphocyte development in normal human bone marrow. The B lymphoid cells were identified using light scattering and the expression of CD19 on a flow cytometer. Quantitative three-color immunofluorescence was then used to correlate other cell surface antigens on these cells identified as B lymphoid in normal marrow. CD10 and CD20 identified almost exclusive populations and provided a convenient means of discriminating between the less and more mature B lineage cells. The CD10+ cells could be further subdivided using CD34. The population of CD19+, CD10+, CD34+ cells comprised only 0.6% of marrow cells, but these contained the majority of terminal deoxynucleotidyl transferase (TdT+) cells. In the assessment of class II antigens, HLA-DR was expressed on all B lineage cells whereas HLA-DP preceded HLA-DQ in appearance during the developmental process. Among the later antigens expressed on B lineage cells, cell surface IgM, CD20, and HLA-DQ were expressed at essentially the same time. Cell surface CD10 was lost at the time when CD21 and CD22 were acquired on the cell surface. These data illustrate that multiparameter flow cytometry can be used to define a continuous progression of stages of B lymphocyte development based on cell surface antigen expression even though these cells represent a minor fraction of normal marrow cells.
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Rajaei, Elham, Mohammad Taha Jalali, Saeid Shahrabi, Ali Amin Asnafi, and Seyed Mohammad Sadegh Pezeshki. "HLAs in Autoimmune Diseases: Dependable Diagnostic Biomarkers?" Current Rheumatology Reviews 15, no. 4 (November 25, 2019): 269–76. http://dx.doi.org/10.2174/1573397115666190115143226.
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Background: The process of antigen presentation to immune cells is an undeniable contributor to the pathogenesis of autoimmune diseases. Different studies have indicated several factors that are related to autoimmunity. Human Leukocyte Antigens (HLAs) are among such factors, which have a key role in autoimmunity because of their involvement in antigen presentation process. Methods: Relevant English language literature was searched and retrieved from Google Scholar search engine and PubMed database (1996-2018). The following keywords were used: "Human leukocyte antigen", "Behcet’s syndrome", "Rheumatoid arthritis", "Systemic lupus erythematosus", "Type 1 diabetes", "Celiac Disease" and "Autoimmunity". Results: There is a strong association between HLA alleles and autoimmune diseases. For instance, HLA-B alleles and Behcet’s syndrome are strongly correlated, and systemic lupus erythematosus and Type 1 diabetes are related to HLA-DQA1 and HLA-DQB1, respectively. Conclusion: Association between numerous HLA alleles and autoimmune diseases may justify and rationalize their use as biomarkers as well as possible diagnostic laboratory parameters.
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Fasano, Ross M., Harold Cliff Sullivan, Robert A. Bray, Howard M. Gebel, Erin K. Meyer, Annie M. Winkler, Cassandra D. Josephson, Sean R. Stowell, Alexander (Sandy) Duncan, and John D. Roback. "Genotyping Applications for Transplantation and Transfusion Management: The Emory Experience." Archives of Pathology & Laboratory Medicine 141, no. 3 (March 1, 2017): 329–40. http://dx.doi.org/10.5858/arpa.2016-0277-sa.
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Current genotyping methodologies for transplantation and transfusion management employ multiplex systems that allow for simultaneous detection of multiple HLA antigens, human platelet antigens, and red blood cell (RBC) antigens. The development of high-resolution, molecular HLA typing has led to improved outcomes in unrelated hematopoietic stem cell transplants by better identifying compatible alleles of the HLA-A, B, C, DRB1, and DQB1 antigens. In solid organ transplantation, the combination of high-resolution HLA typing with solid-phase antibody identification has proven of value for highly sensitized patients and has significantly reduced incompatible crossmatches at the time of organ allocation. This database-driven, combined HLA antigen/antibody testing has enabled routine implementation of “virtual crossmatching” and may even obviate the need for physical crossmatching. In addition, DNA-based testing for RBC antigens provides an alternative typing method that mitigates many of the limitations of hemagglutination-based phenotyping. Although RBC genotyping has utility in various transfusion settings, it has arguably been most useful for minimizing alloimmunization in the management of transfusion-dependent patients with sickle cell disease or thalassemia. The availability of high-throughput RBC genotyping for both individuals and large populations of donors, along with coordinated informatics systems to compare patients' antigen profiles with available antigen-negative and/or rare blood-typed donors, holds promise for improving the efficiency, reliability, and extent of RBC matching for this population.
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Muller, J. Y., L. Hallé, and G. Jaeger. "HLA-A and B antigens in AKA pygmies." Tissue Antigens 17, no. 4 (December 11, 2008): 372–75. http://dx.doi.org/10.1111/j.1399-0039.1981.tb00718.x.
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Hallé, L., N. Simonney, C. Kaplan, J. Y. Muller, and J. M. Fine. "HLA-A, B antigens and asymptomatic monoclonal gammopathy." Tissue Antigens 22, no. 5 (December 11, 2008): 383–84. http://dx.doi.org/10.1111/j.1399-0039.1983.tb02269.x.
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Anagnostopoulou, U., M. Toumbis, K. Konstantopoulos, V. Kotsovoulou-Fouskaki, and J. Zervas. "HLA-A and -B antigens in chronic bronchitis." Journal of Clinical Epidemiology 46, no. 12 (December 1993): 1413–16. http://dx.doi.org/10.1016/0895-4356(93)90141-m.
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Jahn, Lorenz, Renate S. Hagedoorn, Pleun Hombrink, Michel G. D. Kester, Dirk M. van der Steen, Chopie Hassan, Marjolein P. Schoonakker, et al. "T Cell Receptor Gene Therapy Targeting the Intracellular Transcription Factor Bob1 for the Treatment of Multiple Myeloma and Other B Cell Malignancies." Blood 126, no. 23 (December 3, 2015): 3002. http://dx.doi.org/10.1182/blood.v126.23.3002.3002.
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Abstract Therapeutic reactivity of CD20-specific monoclonal antibodies (mAb) or CD19-specific chimeric antigen receptor (CAR)-transduced T cells is exerted by targeting extracellular antigens. In contrast to mAbs and CARs, T cell receptors (TCRs) recognize antigen-derived peptides that are bound to human leukocyte antigen (HLA) molecules on the cell surface. Since HLA molecules constantly sample the entire endogenous proteome of a cell, extracellular and intracellular antigens are presented and can thus be recognized by a TCR. Here, we identified the intracellular transcription factor Bob1 encoded by gene POU2AF1 as a suitable target for immunotherapy. Bob1 is highly expressed in CD19+ B cells, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and multiple myeloma (MM) and is absent in the non-B lineages including CD34+ hematopoietic progenitor cells (HPCs), T cells, fibroblasts, keratinocytes and gastrointestinal tract. Bob1 is localized intracellularly but HLA-presented Bob1-derived peptides are accessible on the cell surface to TCRs and can thus be recognized by T cells. From the HLA-presented ligandome (Mol Cell Proteomics, 2013;12:1829) we identified naturally processed Bob1-derived peptides displayed in HLA-A*0201 (HLA-A2) and in HLA-B*0702 (HLA-B7). Since auto-reactivity towards self-antigens such as Bob1 is prevented by depleting high-avidity T cells recognizing self-antigens in self-HLA, we exploited the immunogenicity of these peptides presented in allogeneic HLA. From a HLA-A2/B7-negative healthy individual we isolated T cell clone 4G11 demonstrating high sensitivity and specificity for Bob1-derived peptide Bob144 presented in HLA-B7. Bob1-dependent recognition was demonstrated by transduction of Bob1 into cell lines that otherwise lack Bob1 expression. No harmful toxicities of clone 4G11 were observed against a wide panel of Bob1-negative stimulator cells including HLA-B7-positive CD34+ HPCs, T cells, monocytes, immature and mature dendritic cells, and fibroblasts even under simulated inflamed conditions. Furthermore, stringent HLA-B7-restricted recognition was observed for clone 4G11 when tested against a stimulator panel expressing a wide range of common and rare HLA class I and II molecules. Clone 4G11 demonstrated clinical applicability by efficiently recognizing HLA-B7+ primary ALL, CLL and MCL. Furthermore, reproducible strong recognition of purified primary HLA-B7+ MM could be demonstrated. Therefore, the TCR of clone 4G11 may be used for immunotherapy by administering TCR-transduced T cells to patients suffering from B cell malignancies including multiple myeloma. Retroviral gene transfer of TCR 4G11 led to efficient cell surface expression demonstrated by binding of TCR-transduced CD8+ T cells to pMHC-tetramer composed of peptide Bob144 bound to HLA-B7. TCR-modified CD8+ T cells strongly recognized Bob1-expressing HLA-B7+ multiple myeloma cell lines U266 and UM9, and ALL cell lines. TCR-modified T cells efficiently lysed HLA-B7+ primary ALL, CLL and MCL at very low effector-to-target ratios. In addition, highly purified primary multiple myeloma samples were also readily lysed. Furthermore, TCR-transduced T cells strongly proliferated in an antigen-specific manner when stimulated with primary malignant cell samples including ALL, CLL, and MCL or MM cell lines. As expected, TCR-transduced T cells also lysed autologous primary and CD40L-stimulated B cells since these targets cells also express Bob1. In contrast, no lysis of Bob1-negative autologous primary and activated T cells, or monocytes was observed when co-cultured with TCR-transduced T cells. In summary, we identified the intracellular transcription factor Bob1 encoded by gene POU2AF1 as a suitable target for TCR-based immunotherapies of B cell malignancies. Bob1-specific T cell clone 4G11 efficiently recognized primary B cell leukemia and multiple myeloma. Gene transfer of TCR of clone 4G11 installed Bob1-reactivity and specificity onto recipient T cells shown here by cytolytic capacity and proliferation upon antigen encounter. TCR gene transfer approaches using this Bob1-specific TCR can bring novel treatment modalities and possibly curative therapy to patients with B cell malignancies including multiple myeloma. Disclosures No relevant conflicts of interest to declare.
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Roelen, Dave, Simone van Bree, Urs Schanz, Els van Beelen, Jon van Rood, and Frans Claas. "Quantitative and qualitative differences between CTLP against HLA-A antigens and CTLP against HLA-B antigens." Human Immunology 36, no. 1 (January 1993): 64. http://dx.doi.org/10.1016/0198-8859(93)90094-h.
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Mohagheghpour, N., N. K. Damle, S. Takada, and E. G. Engleman. "Generation of antigen receptor-specific suppressor T cell clones in man." Journal of Experimental Medicine 164, no. 3 (September 1, 1986): 950–55. http://dx.doi.org/10.1084/jem.164.3.950.
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We have shown previously that CD8+ T cells proliferate upon exposure to autologous, antigen primed CD4+ T cells, and suppress the response of fresh T cells to the priming antigen but not irrelevant antigens. The stimulus and target of suppression in this system appears to be the antigen receptor on the surface of CD4+ cells, rather than the nominal antigen. In the current study, alloantigen primed CD4+ inducer cells and IL-2-containing medium were used to generate clones of suppressor cells from several individuals. The clones inhibited the response of fresh autologous T cells only to the original allogeneic stimulator cell and to stimulator cells that shared HLA-DR antigens with the priming cell. The clones were also genetically restricted, since they inhibited the response of HLA-A,B-compatible but not HLA-A,B-incompatible individuals. The availability of a method for reproducibly generating antigen receptor-specific suppressor T cell clones in vitro should make it possible to clarify the mechanism, whereby such cells are activated and exert their suppressive effect.
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Nakanishi, Koji, Tetsuro Kobayashi, Toshio Murase, Taeko Naruse, Yoshisuke Nose, and Hidetoshi Inoko. "Human Leukocyte Antigen-A24 and -DQA1*0301 in Japanese Insulin-Dependent Diabetes Mellitus: Independent Contributions to Susceptibility to the Disease and Additive Contributions to Acceleration of β-Cell Destruction*." Journal of Clinical Endocrinology & Metabolism 84, no. 10 (October 1, 1999): 3721–25. http://dx.doi.org/10.1210/jcem.84.10.6045.
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Abstract The aim of this study is to identify insulin-dependent diabetes mellitus (IDDM)-susceptible HLA antigens in IDDM patients who do not have established risk allele, HLA-DQA1*0301, and analyze relationship of these HLA antigens and the degree of β-cell destruction. In 139 Japanese IDDM patients and 158 normal controls, HLA-A, -C, -B, -DR and -DQ antigens were typed. Serum C-peptide immunoreactivity response (ΔCPR) to a 100-g oral glucose load ≤ 0.033 nmol/l was regarded as complete β-cell destruction. All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc = 0.0256 and Pc = 0.0080, respectively). ΔCPR in IDDM patients with both HLA-DQA1*0301 and HLA-A24 (0.097 ± 0.163 nmol/L, mean ± sd, n = 65) were lower than in IDDM patients with HLA-DQA1*0301 only (0.219 ± 0.237 nmol/L, n = 45, P < 0.0001) and in IDDM patients with HLA-A24 only (0.187 ± 0.198 nmol/L, n = 14, P = 0.0395). These results indicate that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate β-cell destruction in an additive manner.
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Litwin, V., J. Gumperz, P. Parham, J. H. Phillips, and L. L. Lanier. "Specificity of HLA class I antigen recognition by human NK clones: evidence for clonal heterogeneity, protection by self and non-self alleles, and influence of the target cell type." Journal of Experimental Medicine 178, no. 4 (October 1, 1993): 1321–36. http://dx.doi.org/10.1084/jem.178.4.1321.
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Prior studies using polyclonal populations of natural killer (NK) cells have revealed that expression of certain major histocompatibility complex (MHC) class I molecules on the membrane of normal and transformed hematopoietic target cells can prevent NK cell-mediated cytotoxicity. However, the extent of clonal heterogeneity within the NK cell population and the effect of self versus non-self MHC alleles has not been clearly established. In the present study, we have generated more than 200 independently derived human NK cell clones from four individuals of known human histocompatibility leukocyte antigens (HLA) type. NK clones were analyzed for cytolytic activity against MHC class I-deficient Epstein Barr virus (EBV) transformed B lymphoblastoid cell lines (B-LCL) stably transfected with several HLA-A, -B, or -C genes representing either self or non-self alleles. All NK clones killed the prototypic HLA-negative erythroleukemia K562 and most lysed the MHC class I-deficient C1R and 721.221 B-LCL. Analysis of the panel of HLA-A, -B, and -C transfectants supported the following general conclusions. (a) Whereas recent studies have suggested that HLA-C antigens may be preferentially recognized by NK cells, our findings indicate that 70% or more of all NK clones are able to recognize certain HLA-B alleles and many also recognize HLA-A alleles. Moreover, a single NK clone has the potential to recognize multiple alleles of HLA-A, HLA-B, and HLA-C antigens. Thus, HLA-C is not unique in conferring protection against NK lysis. (b) No simple patterns of HLA specificity emerged. Examination of a large number of NK clones from a single donor revealed overlapping, yet distinct, patterns of reactivity when a sufficiently broad panel of HLA transfectants was examined. (c) Both autologous and allogeneic HLA antigens were recognized by NK clones. There was neither evidence for deletion of NK clones reactive with self alleles nor any indication for an increased frequency of NK clones recognizing self alleles. (d) With only a few exceptions, protection conferred by transfection of HLA alleles into B-LCL was usually not absolute. Rather a continuum from essentially no protection for certain alleles (HLA-A*0201) to very striking protection for other alleles (HLA-B*5801), with a wide range of intermediate effects, was observed. (e) Whereas most NK clones retained a relatively stable HLA specificity, some NK clones demonstrated variable and heterogeneous activity over time. (f) NK cell recognition and specificity cannot be explained entirely by the presence or absence of HLA class I antigens on the target cell.(ABSTRACT TRUNCATED AT 400 WORDS)
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VANNAS, SALME, ANJA TIILIKAINEN, ANTTI VANNAS, and KARI KARJALAINEN. "HLA-B 12 AND HLA-B 27 ANTIGENS AND SUSCEPTIBILITY TO THE CORNEAL ALLOGRAFT REACTION." Acta Ophthalmologica 56, no. 5 (May 27, 2009): 689–96. http://dx.doi.org/10.1111/j.1755-3768.1978.tb06632.x.
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Spaapen, Robbert M., Henk M. Lokhorst, Kelly van den Oudenalder, Brith E. Otterud, Harry Dolstra, Mark F. Leppert, Monique C. Minnema, Andries C. Bloem, and Tuna Mutis. "Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis." Journal of Experimental Medicine 205, no. 12 (November 10, 2008): 2863–72. http://dx.doi.org/10.1084/jem.20080713.
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Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA)–matched allogeneic stem cell transplantation (allo-SCT). We report the first hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4+ T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19L-encoded antigen was identified using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fine mapping the genetic locus defined by pairwise linkage analysis. This strategy was also applicable for genome-wide identification of a wide range of mHags. CD19L-specific CD4+ T cells provided antigen-specific help for maturation of dendritic cells and for expansion of CD8+ mHag-specific T cells. They also lysed CD19L-positive malignant cells, illustrating the potential therapeutic advantages of targeting this novel CD19L-derived HLA class II–restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings.
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Backert, Linus, Daniel J. Kowalewski, Simon D. Walz, Heiko Schuster, Claudia Berlin, Mirle Schemionek, Tim H. Brümmendorf, et al. "HLA Ligandome Analysis of Different Hematological Malignancies Identifies a Small Panel of "Pan-Leukemia"-Associated Antigens." Blood 128, no. 22 (December 2, 2016): 2169. http://dx.doi.org/10.1182/blood.v128.22.2169.2169.
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Abstract Effective antigen-specific T-cell-based cancer immunotherapy requires exact knowledge of tumor-associated epitopes that can act as rejection antigens. While the current paradigm views mutation-derived neoantigens as the most promising targets, we have recently demonstrated that tumor-specific T-cell responses target panels of non-mutated tumor-associated self antigens in patients with hematological malignancies. Using the approach of direct HLA ligandome analysis by mass spectrometry, we were able to identify and characterize multiple immunogenic and naturally presented tumor-associated antigens for chronic lymphocytic leukemia (CLL, Kowalewski et. al., PNAS 2015), acute myeloid leukemia (AML, Berlin/Kowalewski et. al., Leukemia 2014), multiple myeloma (MM, Walz/Stickel et. al., Blood 2015) and chronic myeloid leukemia (CML, unpublished data). In this project we performed a comprehensive meta-analysis of our HLA ligandome data from different hematological malignancies (HM) to screen for the existence of "pan-leukemia" antigens for the broad application in T-cell based immunotherapy approaches in hematological malignancies. In a first step we performed unsupervised cluster analyses to identify similarities and differences in the HLA ligandome landscape of HM. To avoid skewed clustering due to HLA types of the samples, these analyses were performed specifically for the most common HLA allotypes in our datasets (A*02 (n=46 HM), A*03 (n=28 HM)). Distinct clustering was shown for the different entities (CLL, MM, CML, AML) as well as for the lymphoid versus myeloid malignancies on the HLA ligandome level. To identify leukemia-exclusive HLA ligands we compared the HLA ligandomes of CLL (HLA class I, n=35; HLA class II, n=30), AML (HLA class I, n=19; HLA class II, n=20), MM (HLA class I, n=15; HLA class II n=12) and CML (HLA class I, n=16; HLA class II n=15) with our normal tissue database including 153 HLA class I and 82 HLA class II ligandomes of various normal tissues (including normal blood, bone marrow and spleen). Cluster analysis of the leukemia-exclusive antigens showed identical clustering of the different entities and lymphoid/myeloid malignancies as shown before for the whole HLA ligandome and the respective source proteins. Overlap analysis revealed only 0.6% (16/2,716) and 0.3% (10/3,141) of the identified leukemia-exclusive HLA class I and class II antigens, respectively, to be represented across all analyzed hematological malignancies. These "pan-leukemia" antigens (n=26) include candidate antigens associated with T-cell activation (HSH2D), lymphoid development (IL2RF) and oncogenesis (LYN protooncogene, RAB5A). However, none of these "pan-leukemia" antigens shows frequent representation (>20%) across all 4 entities (CLL, AML, MM, CML). Furthermore, none of the "pan-leukemia" source proteins yielded corresponding peptides represented in all entities. To identify "pan-leukemia" HLA ligands, overlap analyses were performed in an allotype-specific fashion for the most frequent HLA allotypes (HLA-A*01, -A*02, -A*03, -A*24, -B*07, -B*08, -B*18) in our cohort. 0% (0/92) of HLA-A*01-, 1.6% (12/744) of HLA-A*02-, 1.4% (8/561) of HLA-A*03-, 0% (0/331) of HLA-A*24-, 0.1% (1/830) of HLA-B*07-, 0% (0/472) of HLA-B*08- and 0.8% (5/600) of the HLA-B*18-restricted peptides showed representation in all four entities. Out of these 26 "pan-leukemia" HLA ligands, only two (1 HLA-A*02-, 1 HLA-A*03-restricted peptide) showed frequent representation (>20%) in all entities. These peptides represent "pan-leukemia" targets that might be used for immunotherapeutic approaches in patients expressing the respective HLA allotype. Taken together, our approach of direct HLA ligandome analysis of hematological malignancies identified a small panel of "pan-leukemia"- proteins and peptides that show cancer-exclusive representation across all 4 included hematological malignancies. However, due to the low presentation frequencies of the candidate targets within the different entities, target discovery and compound development for the immunotherapy of HM may be more effectively achieved in an entity-specific or even patient-individualized manner. Disclosures Kowalewski: Immatics Biotechnologies GmbH: Employment. Schuster:Immatics Biotechnologies GmbH: Employment. Brümmendorf:Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Niederwieser:Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Onyx: Consultancy; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Honoraria.
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Hülsmeyer, Martin, Maria Teresa Fiorillo, Francesca Bettosini, Rosa Sorrentino, Wolfram Saenger, Andreas Ziegler, and Barbara Uchanska-Ziegler. "Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide." Journal of Experimental Medicine 199, no. 2 (January 19, 2004): 271–81. http://dx.doi.org/10.1084/jem.20031690.
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The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.
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Samuels, Sanne, Vivian M. Spaans, Michelle Osse, Lex A. W. Peters, Gemma G. Kenter, Gertjan J. Fleuren, and Ekaterina S. Jordanova. "Human Leukocyte Antigen-DR Expression is Significantly Related to an Increased Disease-Free and Disease-Specific Survival in Patients With Cervical Adenocarcinoma." International Journal of Gynecologic Cancer 26, no. 8 (October 2016): 1503–9. http://dx.doi.org/10.1097/igc.0000000000000783.
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ObjectivesHuman leukocyte antigen (HLA) class II antigens are expressed on antigen-presenting cells, that is, macrophages, dendritic cells, and B lymphocytes. Under the influence of IFN-γ, HLA class II molecules can also be expressed on T lymphocytes, epithelial and endothelial cells. In addition, HLA class II antigens can be expressed in a variety of malignancies; however, the link with prognosis and ultimately patient survival is controversial.MethodsThe pattern of HLA-DRA expression in cervical carcinoma was studied using immunohistochemistry. In total, 124 cervical carcinomas were examined, of which 60 (48.4%) were squamous cell carcinomas and 64 (51.6%) were adenocarcinomas.ResultsIn squamous cell carcinoma, HLA-DRA was expressed in 41 (68.3%) of 60 tumors, whereas in adenocarcinoma, HLA-DRA was expressed in 60 (93.8%) of 64 tumors (P< 0.001). In adenocarcinoma, HLA-DRA expression was associated with an increased disease-free survival (211.0 ± 13.0 vs 53.3 ± 30.5 months;P= 0.004) and disease-specific survival (226.45 ± 11.5 vs 75.8 ± 27.6 months;P= 0.002).ConclusionsUpregulation of HLA-DRA is significantly related to an increased disease-free and disease-specific survival in cervical adenocarcinoma. These data warrant further analysis of the functional role of HLA-DRA in these tumors.
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Gandhi, Maher K., Rebekah M. Brennan, Leesa Wockner, Pratip K. Chattopadhyay, Mario Roederer, David A. Price, David K. Cole, et al. "HLA-Class I Alleles Impact Susceptibility To EBV+ Classical Hodgkin Lymphoma By Altering EBV Latent Antigen-Specific CD8+ T-Cell Immune Hierarchies." Blood 122, no. 21 (November 15, 2013): 630. http://dx.doi.org/10.1182/blood.v122.21.630.630.
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Abstract In Epstein-Barr virus (EBV) classical Hodgkin lymphoma (EBV+ cHL), Hodgkin-Reed Sternberg cell antigen presentation is intact, with viral expression restricted to sub-dominant latent-antigens including LMP1/2A. Large epidemiological studies have reported differential HLA-class I (HLA-I) susceptibility to EBV+ cHL. The functional basis for these observations is unknown. HLA-I molecules present viral peptides for recognition by CD8+ T-cells, and it may be that the relative risk of developing EBV+ cHL is due to HLA-I alleles influencing the magnitude of CD8+ T-cell immunity against relevant EBV-specific antigens. However this remains speculative, with immunological evidence lacking. Several non-HLA-I linked genetic susceptibility loci have been identified, and HLA-I associations may simply represent markers for genes of diverse functions that are in linkage disequilibrium to the HLA-I region. We undertook an Australasian Leukaemia and Lymphoma Group study to address this fundamental question, utilizing 4 distinct but complimentary experimental approaches. 1. 9 EBV+ cHL and 11 EBV-ve cHL pre-therapy PBMC samples were tested for ex-vivo IFNγ, TNFα and CD107a CD8+ T-cell immunity, using overlapping LMP1 and LMP2A peptide pools. The non-HRS expressed EBV-lytic protein BZLF1 was a control. Highly stringent FACS gating was used to maximize specificity. Results were interrogated using Profile and SPICE analysis. Interestingly IFNγ, TNFα and CD107 CD8+ T-cell responses in HLA-A*02 EBV+ cHL (but not EBV-ve cHL) patients were greater than non-HLA-A*02 (LMP1 p=0.002; LMP2A p=0.03; combined LMP1/LMP2A p=0.005), whereas BZLF1 was equivalent, indicating that HLA-I provides differential CD8+ T-cell immunity against relevant EBV-latent antigens in EBV+ cHL but not EBV-ve cHL. 2. However, up to 4 different HLA-A/B molecules can potentially present relevant EBV-derived epitopes in each individual, adding a confounding layer of complexity to single allele-based effects. To overcome this and enhance sensitivity, we used the mutant HLA-I 721.221 cell-line (pulsed with LMP2A), transfected with either HLA-A*01, HLA-A*02, HLA-A*03 or HLA-B*08 alleles, as antigen presenting cells to in-vitro expand LMP2A-specific CD8+ T-cells from HLA-A*02 heterozygotes. This found ∼90% of the HLA-I LMP2A response was restricted through HLA-A*02. 3. In contrast to EBV+ cHL, in EBV-post-transplant lymphoproliferative disorders (EBV+ PTLD) the immunogenic EBNA3A/3B/3C latent-antigens are expressed. We compared HLA-I associations in 110 cHL (35% EBV+ cHL) to 153 PTLD (63% EBV+ PTLD) patients. Using Bonferoni corrected statistics, we confirmed that HLA-A*02 and HLA-A*01 homozygotes had lower and higher susceptibility to EBV+ cHL respectively, and that HLA-B*37 was positively associated. Notably, no HLA-I associations with EBV+ PTLD were found. 4. To investigate the impact of HLA-I on the hierarchy of CD8+ T-cell immunity to sub-dominant (LMP1/2A) and immune-dominant (EBNA3A/3B/3C) EBV-latent proteins, we analysed the diversity of HLA-class I restricted T-cells in 30 healthy EBV+ participants. To supplement 30 ‘defined' (i.e. validated) HLA-I EBV-latent antigen epitopes and expand HLA-I coverage, we identified 31 ‘SYFPEITHI' bioinformatically ‘predicted' peptide epitopes for HLA-A*01, HLA-A*03 or HLA-B*37 restricted EBV-latent antigens. All SYFPEITHI scores were ≥21, and thermal stability circular dichroism analysis (HLA-A*01) or MHC stabilization assays on T2 cells (HLA-A*03) confirmed peptide binding to HLA-I. Ex-vivo CD107 CD8+ T-cell assays for the 61 peptides, found that sub-dominant LMP1/2A-specific peptide responses were largely confined to HLA-A*02 (Fig 1A), whilst immuno-dominant CD8+ T-cell responses were stimulated by peptides presented by numerous HLA-I alleles (Fig 1B). These data combined illustrate that differential HLA-I-associated susceptibility to EBV+ cHL reflects altered EBV latent antigen-specific CD8+ T-cell immune hierarchies. For lymphomas expressing a restricted set of poorly immunogenic proteins, even modest CD8+ T-cell responses against relevant tumor-associated proteins confer protection, with broad implications for EBV-vaccine design. Studies are required to determine if similar mechanisms are applicable to non-lymphoid EBV+ malignancies with restricted latency such as undifferentiated nasopharngeal carcinoma. Disclosures: No relevant conflicts of interest to declare.
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Hauber, I., H. Gulle, H. M. Wolf, M. Maris, H. Eggenbauer, and M. M. Eibl. "Molecular characterization of major histocompatibility complex class II gene expression and demonstration of antigen-specific T cell response indicate a new phenotype in class II-deficient patients." Journal of Experimental Medicine 181, no. 4 (April 1, 1995): 1411–23. http://dx.doi.org/10.1084/jem.181.4.1411.
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Major histocompatibility complex (MHC) class II deficiency is an inherited autosomal recessive combined immunodeficiency. The disease is known as bare lymphocyte syndrome (BLS). BLS is characterized by a lack of constitutive MHC class II expression on macrophages and B cells as well as a lack of induced MHC class II expression on cells other than professional antigen-presenting cells (APCs) due to the absence of mRNA and protein of the human leukocyte antigen (HLA) class II molecules, designated HLA-DR, -DQ, and -DP. The defect in gene expression is located at the transcriptional level and affects all class II genes simultaneously. Here we have analyzed transcription and protein expression of class II antigens in Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines and mononuclear cells (MNCs) of twin brothers. Whereas flow cytometric analysis failed to detect class II antigens on the cell surface of the patients' EBV-B cells and MNCs, examination of the genes coding for HLA-DR, -DQ, -DP, and the invariant chain (Ii) by reverse transcriptase-polymerase chain reaction amplification resulted in an unusual mRNA pattern in the B cell lines of the patients (HLA-DR alpha +, -DR beta, -DQ alpha +, -DQ beta -, -DP alpha -; -DP beta +, Ii+). In accordance with these findings no HLA-DR beta-specific protein was detected by immunoblotting, whereas low levels of HLA-DR alpha and normal levels of Ii were present. In contrast to EBV-B cells, the MNCs of both patients displayed a residual HLA-DR beta, -DQ beta, and -DP alpha mRNA signal. Furthermore, HLA-DR beta-specific protein was found in addition to HLA-DR alpha by immunoblotting of cell lysates, even though it was clearly decreased as compared with controls. Our results indicate that the defect in class II antigen expression is not necessarily present to the same extent in B cells and cells of other lineages. mRNA levels of HLA-DR beta were found to be enriched in adherent cells within the MNC fraction. Further investigations indicated that the MHC class II expressed is functional in antigen presentation, as the two boys' CD4+ T cells became activated and expressed interleukin-2R after stimulation of peripheral blood mononuclear cell cultures with recall antigen (tetanus toxoid). Furthermore, T cells tested in one of the two patients responded to both MHC class I and II allostimulation, and this response was inhibited by monoclonal antibodies of the respective specificity.(ABSTRACT TRUNCATED AT 400 WORDS)
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Strandhave, Charlotte, Kaj Anker Jørgensen, Knud Bendix, Bente Jespersen, Robert Schou Pedersen, Esben Søndergaard, Leif Spange Mortensen, and Francesco d'Amore. "Posttransplant Lymphoproliferative Disorders (PTLD) After Renal Transplantation: Focus on HLA Antigens." Blood 116, no. 21 (November 19, 2010): 5074. http://dx.doi.org/10.1182/blood.v116.21.5074.5074.
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Abstract Abstract 5074 Background: PTLD is a lymphoid proliferation that develops as a consequence of immunosuppression. It represents monoclonal B-cell, or rarely T-cell, proliferations, occurring in a setting of decreased T-cell immune surveillance. It has been shown that HLA-B mismatching is associated with increased risk of skin cancer in recipients of renal transplants. An association between skin cancer related to human papillomavirus and HLA-A11 has also been established in this group of patients. Bakker et al has shown that HLA-B mismatching is a risk marker of PTLD. More specifically, Subklewe et al found that HLA-B18 and HLA-B21 were associated with increased risk of PTLD, whereas mismatch at HLA-A03 and HLA-DR7 level reduced the risk of PTLD. We therefore hypothesized that mismatch of certain HLA alleles may be risk predictors of PTLD after renal transplantation. Methods: According to the national renal transplantation database of the Danish Society of Nephrology, 872 renal transplantations in 793 patients were performed at Aarhus University Hospital between 1990 and 2005. A total of 11 cases of PTLD were retrospectively identified through the National Danish Pathology database and individually reviewed by an experienced hematopathologist (KB). PTLD patients were investigated according to transplantation procedure, clinicopathological patient characteristics, type of lymphoma, outcome and HLA haplotype of both donor and recipient. Results: Univariate Cox regression analysis showed no positive correlation between risk of PTLD and number of HLA-B mismatches, or with HLA-A or HLA-DR mismatches. Conversely, we found a decreased risk with one/two HLA-B mismatches compared to no mismatches (p<0.01). With regard to specific alleles, HLA-B37 showed a trend towards an association with PTLD (OR = 8.62; 95% CI 1.70–43.6; P<0.04), whereas the same association was significantly stronger for HLA-DR6 (OR= 30.7; 95% CI 4.97–189.8; p<0.005). Unlike earlier reports, no association with HLA-B18 and HLA-B21 mismatches was observed. Conclusions: Our data suggest not only that the risk of developing PTLD is unaffected by an increasing number of HLA-B mismatches, but that a low number of such mismatches may even protect against PTLD developement. In our analysis, we found a moderate correlation between PTLD and HLA-B37, and a stronger one with HLA-DR6. The latter observation has never been previously reported. Further analyses with larger cohorts of renal transplant patients are needed to clarify the role of HLA antigens as risk markers for PTLD in order to establish whether a pre-emptive PTLD monitoring of renal transplant patients expressing certain haplotypes/haplotype mismatches is justified. Disclosures: No relevant conflicts of interest to declare.
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Wölfel, T., E. Klehmann, C. Müller, K. H. Schütt, K. H. Meyer zum Büschenfelde, and A. Knuth. "Lysis of human melanoma cells by autologous cytolytic T cell clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens." Journal of Experimental Medicine 170, no. 3 (September 1, 1989): 797–810. http://dx.doi.org/10.1084/jem.170.3.797.
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From the peripheral blood of the melanoma patient (AV), we derived cytolytic T lymphocyte (CTL) clones that lysed the autologous tumor line SK-MEL-29, but not autologous EBV-B cells, K562, and other tumor targets. By immunoselection experiments it was shown that the CTL clones recognized at least three different antigens on the autologous tumor cells. We demonstrate here that these melanoma antigens are presented to the CTL in association with HLA-A2. First, HLA-A2-reactive pregnancy sera as well as an mAb against HLA-A2 inhibited the CTL lysis. Second, immunoselected melanoma subclones that were resistant to lysis by CTL clones against the three antigens described were found to lack expression of HLA-A2. By sensitizing the patient's lymphocytes against an HLA-A2- melanoma clone, we established a new series of CTL clones recognizing autologous AV melanoma cells. However, efficient lysis was only seen when target cells were pretreated with IFN-gamma. The lytic activity of these CTL was selectively inhibited by an mAb against a common HLA-B determinant. These results indicate that in addition to HLA-A2, other class I antigens are involved in the recognition of AV melanoma cells by autologous CTL.
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Yu, Jieh-Juen, TataReddy Goluguri, M. Neal Guentzel, James P. Chambers, Ashlesh K. Murthy, Karl E. Klose, Thomas G. Forsthuber, and Bernard P. Arulanandam. "Francisella tularensis T-Cell Antigen Identification Using Humanized HLA-DR4 Transgenic Mice." Clinical and Vaccine Immunology 17, no. 2 (December 16, 2009): 215–22. http://dx.doi.org/10.1128/cvi.00361-09.
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ABSTRACT There is no licensed vaccine against the intracellular pathogen Francisella tularensis. The use of conventional mouse strains to screen protective vaccine antigens may be problematic, given the differences in the major histocompatibility complex (MHC) binding properties between murine and human antigen-presenting cells. We used engineered humanized mice that lack endogenous MHC class II alleles but that express a human HLA allele (HLA-DR4 transgenic [tg] mice) to identify potential subunit vaccine candidates. Specifically, we applied a biochemical and immunological screening approach with bioinformatics to select putative F. tularensis subsp. novicida T-cell-reactive antigens using humanized HLA-DR4 tg mice. Cell wall- and membrane-associated proteins were extracted with Triton X-114 detergent and were separated by fractionation with a Rotofor apparatus and whole-gel elution. A series of proteins were identified from fractions that stimulated antigen-specific gamma interferon (IFN-γ) production, and these were further downselected by the use of bioinformatics and HLA-DR4 binding algorithms. We further examined the validity of this combinatorial approach with one of the identified proteins, a 19-kDa Francisella tularensis outer membrane protein (designated Francisella outer membrane protein B [FopB]; FTN_0119). FopB was shown to be a T-cell antigen by a specific IFN-γ recall assay with purified CD4+ T cells from F. tularensis subsp. novicida ΔiglC-primed HLA-DR4 tg mice and cells of a human B-cell line expressing HLA-DR4 (DRB1*0401) functioning as antigen-presenting cells. Intranasal immunization of HLA-DR4 tg mice with the single antigen FopB conferred significant protection against lethal pulmonary challenge with an F. tularensis subsp. holarctica live vaccine strain. These results demonstrate the value of combining functional biochemical and immunological screening with humanized HLA-DR4 tg mice to map HLA-DR4-restricted Francisella CD4+ T-cell epitopes.
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Long, Heather M., Jianmin Zuo, Alison M. Leese, Nancy H. Gudgeon, Hui Jia, Graham S. Taylor, and Alan B. Rickinson. "CD4+ T-cell clones recognizing human lymphoma-associated antigens: generation by in vitro stimulation with autologous Epstein-Barr virus–transformed B cells." Blood 114, no. 4 (July 23, 2009): 807–15. http://dx.doi.org/10.1182/blood-2008-12-194043.
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Abstract Epstein-Barr virus (EBV)–specific T-cell preparations, generated by stimulating immune donor lymphocytes with the autologous virus-transformed B-lymphoblastoid cell line (LCL) in vitro, can be used to target EBV-positive malignancies. Although these preparations are enriched for EBV antigen–specific CD8+ T cells, most also contain a CD4+ T-cell population whose specificity is unknown. Here, we show that, although CD4+ T-cell clones derived from such cultures recognize HLA class II–matched LCLs but not mitogen-activated B lymphoblasts, many (1) do not map to any known EBV antigen, (2) can be raised from EBV-naive as well as EBV-immune persons, and (3) can recognize a broad range of human B lymphoma–derived cell lines irrespective of EBV genome status, providing those lines to express the relevant HLA class II–restricting allele. Importantly, such CD4+ clones not only produce IFNγ but are also cytotoxic and can control the outgrowth of HLA-matched lymphoma cells in cocultivation assays. We infer that such CD4+ T cells recognize cellular antigens that are preferentially up-regulated in EBV-transformed but not mitogen-activated B lymphoblasts and that are also expressed in a range of B-cell malignancies. Such antigens are therefore of potential value as targets for CD4+ T cell–based immunotherapy.
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Bernhardt, Anna Luise, Sascha Kretschmann, Judith Bausenwein, Heidi Balzer, Andreas Mackensen, and Anita Natalie Kremer. "Characterizing the Immunogenicity of DM-Sensitive and DM-Resistant Antigens." Blood 132, Supplement 1 (November 29, 2018): 3310. http://dx.doi.org/10.1182/blood-2018-99-112103.
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Abstract Introduction: The separation of graft-versus-leukemia (GvL) effect from graft-versus-host-disease (GvHD) is a major objective after allogeneic stem cell transplantation. We recently described two types of endogenous HLA class II restricted antigens depending on their behavior towards HLA-DM. While DM-resistant antigens are presented in the presence of HLA-DM, presentation of DM-sensitive antigens rely on co-expression of HLA-DO - the natural inhibitor of HLA-DM. Since the expression of HLA-DO is not upregulated by inflammatory cytokines and restricted to B-cells, dendritic cells and thymic epithelial cells, DM-sensitive antigens cannot be presented on non-hematopoietic tissues. Therefore, usage of CD4 T-cells directed against DM-sensitive antigens might allow separation of GvL from GvHD. However, it remains elusive whether immunogenicity and anti-tumorigenic potential of DM-sensitive and DM-resistant antigens have comparable properties in vivo. Methods: Therefore, we sought to create an in vivo system using a DM-sensitive and a DM-resistant variant of the same model antigen. First, we generated murine cell lines overexpressing either H2-M or H2-O (murine HLA-DM or HLA-DO, respectively) to allocate the two model antigens ovalbumin (OVA) and murine Y-chromosome antigen DBY to their category. Furthermore, we introduced one to three amino acid substitutions within the MHC II restricted T-cell epitopes of the two antigens and tested DM-sensitivity or DM-resistance by T-cell activation using proliferation and IFN-g secretion as read-out in vitro. Finally, we vaccinated B6 mice with the generated epitope variants and measured expansion, phenotype and reactivity of OVA- or DBY-specific CD4 T-cells in vivo. Results: By testing T-cell recognition of OVA or DBY on murine B-cell lines overexpressing H2-M and H2-O, respectively, we could show that OVA leads to a more potent T-cell activation in the presence of H2-O demonstrating its DM-sensitive character. In contrast the wildtype epitope of DBY does not rely on H2-O expression for strong T-cell activation and was therefore assessed as DM-resistant antigen. By introducing one to three amino acid substitutions within the T-cell epitope we could generate one further DM-sensitive variant of OVA but also two DM-resistant counterparts. Likewise, we designed both DM-resistant and DM-sensitive epitope variants of murine DBY. To assess T-cell receptor avidity to our epitope variants presented on natural antigen presenting cells, titration of DM-sensitive and DM-resistant variants of the same antigen on untreated splenocytes from OVA or DBY T-cell receptor transgenic mice, respectively, were performed. We observed comparable activation of the same T-cell clone activated by either variant of the epitope as measured by proliferation and IFN-g secretion. Furthermore, upon vaccination of B6 mice with either variant of the epitope we could measure comparable expansion, phenotype, and reactivity of OVA- and DBY-specific T-cells both invivo and ex vivo. Conclusion: We successfully generated DM-sensitive and DM-resistant variants of the same epitope for the two model antigens OVA and murine DBY. With this tool we could demonstrate that DM-sensitive antigens are not inferior to their DM-resistant counterpart. Therefore, targeting DM-sensitive antigens after allogenic stem cell transplantation might be an interesting tool to improve the GvL effect with only limited GvHD. Disclosures Bernhardt: DFG TRR221/project A1 (German Research Foundation): Research Funding.
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Robson, Neil C., Tristan McAlpine, Ashley J. Knights, Max Schnurr, Amanda Shin, Weisan Chen, Eugene Maraskovsky, and Jonathan Cebon. "Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery." Blood 116, no. 2 (July 15, 2010): 218–25. http://dx.doi.org/10.1182/blood-2009-10-249458.
Full textAbstract:
Abstract The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)–A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c+ blood DCs cross-presented NY-ESO-1–specific HLA-A2157-165–, HLA-B760-72–, and HLA-Cw392-100–restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1157-165/HLA-A2, NY-ESO-160-72/HLA-B7, and NY-ESO-192-100/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-160-72/HLA-B7–restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A–, B–, and C–restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.