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1
Fast, LD, CR Valeri, and JP Crowley. "Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease." Blood 86, no. 8 (1995): 3090–96. http://dx.doi.org/10.1182/blood.v86.8.3090.3090.
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Abstract Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.
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Fast, LD, CR Valeri, and JP Crowley. "Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease." Blood 86, no. 8 (1995): 3090–96. http://dx.doi.org/10.1182/blood.v86.8.3090.bloodjournal8683090.
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Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.
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Prokopchuk-Gauk, Oksana, Nicole L. Prokopishyn, Joanna McCarthy, and Meer-Taher Shabani-Rad. "Red Cell Alloimmunization Rates in Allogeneic Hematopoietic Stem Cell Transplant Recipients." Blood 128, no. 22 (2016): 3402. http://dx.doi.org/10.1182/blood.v128.22.3402.3402.
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Abstract Introduction: Donor selection for allogeneic hematopoietic stem cell transplant (allo-HSCT) is dependent on matching with the intended recipient HLA allele profile, but not blood group compatibility. Red blood cell (RBC) phenotype matching is not considered, even if recipient alloantibodies are present pre-HSCT. Historically, up to 3.7% of allo-HSCT recipients have been found to develop new RBC alloantibodies following allo-HSCT. We completed an audit of all adult and pediatric allo-HSCT recipients of the Alberta Bone Marrow and Blood Cell Transplant Program to define the rate of RBC alloimmunization, and evaluate the impact of this RBC alloantibody presence on donor marrow engraftment in our allo-HSCT recipient population. Methods:A retrospective review was completed including all allogeneic pediatric and adult HSCT recipients between January 1, 2007 and January 1, 2015. Data was obtained from review of cellular therapy laboratory electronic records with red cell alloantibody information extracted manually from the transfusion medicine laboratory information system. Results: A total of 674 patients, including 104 pediatric recipients (<18 years old), underwent 697 allo-HSCT procedures (591 peripheral blood, 45 marrow, 61 cord blood). The mean HSCT recipient age was 40 (range 0-66) and most common HSCT indication was acute myeloid leukemia. Myeloablative conditioning was given to all adults and 86% of pediatric recipients. Fully HLA matched grafts were provided to 77% of recipients. ABO compatibility status of allo-HSCT procedures included the following: 362 (52%) ABO identical grafts, 154 (22%) grafts with a minor incompatibility, 143 (21%) grafts with a major incompatibility, and 38 (5.0%) grafts with bidirectional incompatibility. Rh mismatches were present in 165 (24%) of donor-recipient pairs. A total of 47 allo-HSCT recipients, including 3 pediatric and 44 adult patients, were found to have RBC alloantibodies before or after allo-HSCT. A total of 45 (6.4%) of allo-HSCT recipients had detectable RBC alloantibodies pre-HSCT, with 69 individual alloantibodies identified. The most common RBC alloantibody was anti-E (30%). Antibody screen results available on the day of or following HSCT in 43 allo-HSCT recipients found: 12 (28%) with antibody disappearance pre-HSCT and a negative screen on the date of allo-HSCT, 15 (35%) with antibody waning to disappearance after allo-HSCT, and 11 (26%) with persistence of pre-HSCT antibodies following allo-HSCT. New post-HSCT RBC alloantibodies were detected in 3 adult recipients of peripheral blood collected stem cell grafts (anti-D; anti-Kpa; anti-K plus anti-E), with an overall rate of 0.4%. These patients all received myeloablative conditioning and grafts which were ABO identical or had a minor ABO incompatibility. The anti-D antibody developed post-transplant in an Rh positive recipient of an Rh negative graft. Thus, the calculated overall rate of anti-D development in Rh mismatched HSCT recipients was 0.6%. There was no observed impact on neutrophil and platelet engraftment comparing adult allo-HSCT recipients who did and did not have pre-HSCT RBC alloantibodies. Conclusion: The risk of post-HSCT RBC alloantibody development is very low, even in Rh mismatched donor-recipient pairs. ABO incompatibility does not affect the risk of post-HSCT alloantibody development. Allo-HSCT recipients infrequently have pre-HSCT RBC alloantibodies, which may disappear after myeloablative conditioning. The presence of RBC alloantibodies pre-HSCT does not appear to impact donor marrow engraftment. The results of our retrospective study are limited by the availability, timing and frequency of post-HSCT antibody screen investigations. The decision to perform an antibody screen post-HSCT is a clinical one, typically dependent on recipient transfusion needs. Further prospective research is required to more accurately determine the rate of new post-HSCT alloantibody development and duration of alloantibody persistence or disappearance in allo-HSCT recipients. Results of these studies may also help guide RBC transfusion decisions in HSCT recipients known to have pre-HSCT RBC alloantibodies with proven engraftment and a negative post-HSCT antibody screen. Disclosures No relevant conflicts of interest to declare.
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Yahata, Takashi, Shizu Yumino, Yin Sheng, et al. "Clonal Evidence of Human Hematopoietic Stem Cell Hierarchy: Distinct SCID-Repopulating Cell Subsets Contribute to Various Phases of Hematopoiesis." Blood 108, no. 11 (2006): 1655. http://dx.doi.org/10.1182/blood.v108.11.1655.1655.
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Abstract The SCID-repopulating cell (SRC) pool is shown to be heterogeneous and is composed of at least two distinct subsets; short-term and long-term repopulating cells (STRCs and LTRCs), which appear in different time points following transplantation. However, the precise characteristics and their relationships regarding the stem cell function remain elusive. To clarify the specific stem cell activity of each SRC clones that contribute to various stages of hematopoietic reconstitution, we examined the functional aspects of individual SRCs. To determine the repopulating dynamics of individual SRC clones in vivo, we traced the kinetics of individual SRC clones by LAM-PCR based virus integration site analysis. Individual SRC clones which repopulate in each NOG mouse that received EGFP-transduced fractionated CD34+ populations were analyzed at two time points. At 3 weeks after transplantation, BM cells were aspirated from tibia of each recipient, and at 18 weeks recipients were sacrificed and BM cells were recovered from 4 long bones. At each time point, EGFP-expressing human hematopoietic lineage cells were sorted for integration site analysis by LAM-PCR, and the fate of individual SRC clones in the same recipient was examined by clone-tracking analysis. Using primers that were designated based on the genomic sequence information of the CD33+ myeloid cell integration site, we clonally traced distribution of each clone in lineage cells; CD34+ stem/progenitor, T-, and B-lymphoid cells. We found that the early phase of hematopoietic reconstitution was attributed to transient myeloid-restricted clones which rapidly exhausted from the CD34+ stem cell pool. Interestingly, the multilineage cell-producing clones that were responsible for the later phase of hematopoiesis were distinct from the transient myeloid-restricted clones, and these clones continuously self-replicated in the CD34+ stem cell pool. Next, CD34+ cells from the primary recipients were divided into two secondary recipients, and the fate of individual SRC clones in different phases was traced using the paired secondary mice. One recipient was sacrificed at 3 weeks, and the other recipient was sacrificed at 18 weeks after secondary transplantation. First, clones that were detected at the early phase in one recipient were also detected at the later phase in the other recipient (80%). This is clonal evidence that LTRC in the primary recipient produces STRC as well as self-replicating secondary transplantable LTRC. Second, all clones in the secondary recipients were also detected in the primary donor; however, most of clones (68.3%) found in the primary recipients did not contribute to the secondary recipient. In addition, LTRC clones detected in the CD34+ stem cell pool of secondary recipient demonstrated much larger clone size compared to primary recipient. These indicated that the quiescent LTRC clones in the primary recipients were stimulated by transplantation, there by expanded clonally in the secondary recipient and contributed to the later phase of hematopoiesis. Our clonal tracking study clearly demonstrated that the hierarchical structure of the human HSC pool composed of distinct clonal subsets which were heterogeneous in the self-renewal capacity and differentiation ability.
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Zheng, Pingping, John Tamaresis, Govindarajan Thangavelu, et al. "Recipient-specific T-cell repertoire reconstitution in the gut following murine hematopoietic cell transplant." Blood Advances 4, no. 17 (2020): 4232–43. http://dx.doi.org/10.1182/bloodadvances.2019000977.
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Abstract Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation (HCT) caused by alloreactive T cells. Murine models of HCT are used to understand GVHD and T-cell reconstitution in GVHD target organs, most notably the gastrointestinal (GI) tract where the disease contributes most to patient mortality. T-cell receptor (TCR) repertoire sequencing was used to measure T-cell reconstitution from the same donor graft (C57BL/6 H-2b) in the GI tract of different recipients across a spectrum of matching, from syngeneic (C57BL/6), to minor histocompatibility (MHC) antigen mismatch BALB.B (H-2b), to major MHC mismatched B10.BR (H-2k) and BALB/c (H-2d). Although the donor T-cell pools had highly similar TCR, the TCR repertoire after HCT was very specific to recipients in each experiment independent of geography. A single invariant natural killer T clone was identifiable in every recipient group and was enriched in syngeneic recipients according to clonal count and confirmatory flow cytometry. Using a novel cluster analysis of the TCR repertoire, we could classify recipient groups based only on their CDR3 size distribution or TCR repertoire relatedness. Using a method for evaluating the contribution of common TCR motifs to relatedness, we found that reproducible sets of clones were associated with specific recipient groups within each experiment and that relatedness did not necessarily depend on the most common clones in allogeneic recipients. This finding suggests that TCR reconstitution is highly stochastic and likely does not depend on the evaluation of the most expanded TCR clones in any individual recipient but instead depends on a complex polyclonal architecture.
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Ruggeri, Loredana, Marusca Capanni, Myriam Casucci, et al. "Role of Natural Killer Cell Alloreactivity in HLA-Mismatched Hematopoietic Stem Cell Transplantation." Blood 94, no. 1 (1999): 333–39. http://dx.doi.org/10.1182/blood.v94.1.333.413a31_333_339.
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Because of the expression of inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I allotypes, a person’s natural killer (NK) cells will not recognize and will, therefore, kill cells from individuals lacking his/her KIR epitopes. This study investigated the role of NK cell alloreactivity in human HLA haplotype-mismatched hematopoietic stem cell transplantation and, specifically, the role of the three major NK specificities, ie, those for HLA-C group 1, HLA-C group 2, and HLA-Bw4 alleles. In 20 of 60 donor-recipient pairs, KIR epitope incompatibility and functional analyses of donor NK cell clones predicted donor NK cells could cause graft-versus-host (GVH)/graft-versus-leukemia (GVL) reactions. NK cell clones of donor origin were obtained from transplanted recipients and tested for lysis of recipient’s cryopreserved pretransplant lymphocytes. Despite the absence of GVH disease, we detected high frequencies of NK clones which killed recipient’s target cells. Lysis followed the rules of NK cell alloreactivity, being blocked only by the MHC class I KIR epitope which was missing in the recipient. The alloreactive NK clones also killed the allogeneic leukemia. Transplants from these KIR epitope incompatible donors had higher engraftment rates. Therefore, a GVL effector and engraftment facilitating mechanism, which is independent of T-cell–mediated GVH reactions, may be operational in HLA mismatched hematopoietic cell transplants.
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Stockwell, Sally, Muren Herrid, Rhonda Davey, Alan Brownlee, Keryn Hutton, and Jonathan R. Hill. "Microsatellite detection of donor-derived sperm DNA following germ cell transplantation in cattle." Reproduction, Fertility and Development 21, no. 3 (2009): 462. http://dx.doi.org/10.1071/rd08130.
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Although autologous and heterologous transplantation has resulted in colonisation of recipient testes in cattle, the ability of the transplanted spermatogonial stem cells to complete spermatogenesis has not yet been determined. The objective of the present study was to identify and validate microsatellite markers that can distinguish the genotype of different individuals and therefore can be used to detect the presence of donor DNA in recipient semen samples. In a previous study by this group, successful colonisation of recipient testes by heterologous transfer using a fluorescent dye was shown. In the present work, some of the same recipient animals were investigated further to monitor donor-derived sperm production. The bovine microsatellite detection method was developed specifically to test the ejaculates of the recipients and can also be used to pre-match individuals before germ cell transplantation. Semen was collected from the recipients 52–98 weeks after transfer and the presence of donor DNA in the samples was determined using microsatellite markers. In one of the recipients, all collected semen samples were shown to be positive for donor-derived cells; however, the percentage of donor spermatozoa in the recipient ejaculate declined with time. The donor DNA was also detected in both single cell suspensions and testis tissue from this recipient. These results demonstrate for the first time that testicular germ cell transplantation between different breeds of cattle is feasible and the recipients thereof are able to produce spermatozoa of donor origin. This technology has potential applications in livestock breeding systems and may provide an alternative to artificial insemination.
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Steele, D. J., T. M. Laufer, S. T. Smiley, et al. "Two levels of help for B cell alloantibody production." Journal of Experimental Medicine 183, no. 2 (1996): 699–703. http://dx.doi.org/10.1084/jem.183.2.699.
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We have examined whether T cell stimulation by direct or indirect pathways contributes to alloantibody production by B cells after major histocompatibility complex (MHC)-disparate skin graft rejection in mice. Experiments were performed using normal mice, MHC class II-deficient mice, MHC class II-deficient mice with an intact peripheral CD4+ cell population (due to expression of class II antigens only on thymic epithelium), mice lacking the cytoplasmic tail of their MHC class II antigens, and mice depleted of CD4+ cells by anti-CD4 monoclonal antibody treatment. Depletion of recipient CD4+ cells reduced alloantibody production to barely detectable levels. Absence of donor MHC class II antigens did not affect the production of either immunoglobulin (Ig)M or IgG antibodies directed at class I alloantigens. Absence of recipient MHC class II antigens, however, led to production of only IgM but not IgG antibodies, even if the recipients had an intact CD4+ cell population. Absence of the cytoplasmic tail of the recipient's MHC class II antigens led to the production of slightly reduced amounts of IgG antibody. These findings indicate that (a) CD4+ cells are essential helper cells for B cell alloantibody production; (b) production of IgM alloantibody can occur with help from CD4+ cells, which recognize either donor class II antigens or modified recipient class II antigens; (c) isotype switching from IgM to IgG alloantibody requires help from CD4+ cells activated by antigens presented by recipient MHC class II molecules; and (d) the cytoplasmic domain of the recipient MHC class II molecules may be involved in the mechanism that leads to isotype switching by B cells. Thus, there are two levels of CD4-mediated help available for B cells responding to alloantigens: one (involving a noncognate interaction) can produce B cell activation, and a second (involving a cognate interaction) is required for differentiation and IgG alloantibody production.
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Ueda, Masumi, Lan Beppu, Judy Campbell, Mary E. D. Flowers, Jerald P. Radich, and Rainer Storb. "Clonal Hematopoiesis in Donor-Recipient Pairs after Allogeneic Hematopoietic Cell Transplantation." Blood 134, Supplement_1 (2019): 702. http://dx.doi.org/10.1182/blood-2019-126979.
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After allogeneic hematopoietic cell transplantation (HCT), a relatively small number of donor hematopoietic cells must reconstitute the entire recipient hematopoietic system, while the donor is left with a near normal pool of hematopoietic cells. We hypothesized that the increased replicative demand on donor cells in the recipient after allogeneic HCT will accelerate telomere shortening and magnify the genetic alterations that are associated with normal aging, including clonal hematopoiesis. We aimed to compare mutation frequency in genes associated with clonal hematopoiesis of indeterminant potential (CHIP) and myeloid diseases between donors and recipients, with a focus on transplant pairs with older donors. We obtained contemporary blood samples from 10 related donor-recipient pairs surviving a median of 36.6 years (range 6.6-45.7 years) after HCT. Information on donor-recipient pairs is summarized in Table 1. Variant libraries were prepared from bulk peripheral blood mononuclear cells (PBMCs) using Archer Dx VariantPlex Myeloid panel of 75 myeloid disease-associated genes (ArcherDx, Boulder, CO). Sequencing was completed on the Illumina HiSeq system. Variants with allelic frequency (AF) ≥2% were detected in donors (median number of variants 50.5, range 35-107) and recipients (median number of variants 50, range 32-109). In all pairs, there was significant overlap in the variants detected, although some were unique to donors or recipients (Figure 1). Two of the 3 donor-recipient pairs with &gt;25 years difference in donor age (84 and 71 years) and recipient age (47 and 42 years) showed an increase in the shared variant AF in the recipient in DNMT3A (nonsense and frameshift mutations) of 5 to 18% and 5 to 16%, respectively. All other shared variants in CHIP-associated genes (DNMT3A, ASXL1, TET2) detected in 6 pairs did not show significant difference in AF (Table 2). Among other shared variants of non-CHIP genes, 7 pairs showed mutations with ≥5% difference in AF, but the difference was small (mean difference 5.3%, range 4.5-7.4%) (Table 3). In conclusion, our results suggest that even decades after transplantation and high replicative demand, most donor variants, at the level of detection of this assay, do not preferentially expand in the recipient. Donor-recipient pairs with older donors and ~30-year difference in age with the recipient showed a modest expansion in DNMT3A clones. Future studies will compare contemporary samples to historical samples from the time of transplant. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding.
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Storek, Jan, Federico Viganego, Monja A. Dawson, et al. "Factors affecting antibody levels after allogeneic hematopoietic cell transplantation." Blood 101, no. 8 (2003): 3319–24. http://dx.doi.org/10.1182/blood-2002-05-1376.
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AbstractTo obtain insight into the mechanism(s) of posttransplantation humoral immunodeficiency, we evaluated factors affecting serum antibody levels against polio, tetanus, Haemophilus influenzae, andStreptococcus pneumoniae in 87 patients. Patients with hematologic malignancies were randomized to receive marrow versus blood stem cells, which contain approximately 10 times more lymphocytes than marrow. Blood stem cell recipients did not have higher antibody levels than marrow recipients. Recipient pretransplantation antibody levels were correlated with the posttransplantation levels, especially in the first 6 months after transplantation when the correlation coefficients typically exceeded 0.6. Donor pretransplantation antibody levels had less of a correlation with posttransplantation levels in the recipient. Patient or donor age, total body irradiation, and graft-versus-host disease or its treatment appeared to have no effect. In conclusion, antibody levels in the first year after transplantation are affected primarily by pretransplantation antibody levels in the recipient and, to a lesser degree, in the donor. These findings suggest that immunization of the recipient and the donor before transplantation may be more effective in improving antibody immunity after transplantation than manipulating graft-versus-host disease, changing conditioning, or increasing the number of lymphocytes in the graft.
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Teipel, Raphael, Johannes Schetelig, Michael Kramer, et al. "Prediction of Hematopoietic Stem Cell Yield after Mobilization with GCSF in Healthy Unrelated Donors." Blood 124, no. 21 (2014): 1128. http://dx.doi.org/10.1182/blood.v124.21.1128.1128.
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Abstract Introduction: The collection of hematopoietic stem cells from the peripheral blood in healthy donors has been established as a highly efficient method in clinical practice. Nevertheless, there are some donors who mobilize poorly despite adequate mobilization regimes. Several factors influencing the process of stem cell mobilization have previously been discussed in the literature. Methods: In total, the data of 7.216 unrelated donors who underwent GCSF-induced stem cell mobilization and collection in two German apheresis centers between July 1997 and August 2012 were retrospectively reviewed. We systematically analyzed more than 30 factors with potential influence on the mobilization process and established a statistically stable model in order to predict the mobilization efficacy and the harvest success in unrelated stem cell donors. Based on empirical data and standard values, we created three model donors of each gender with different donor profiles (favorable/average/unfavorable). In those model donors we calculated the corresponding likelihood of a successful stem cell harvest dependent on the recipient’s weight. Results: Overall, ten variables with high statistical significance were included in the prediction model. Body mass index, platelet count, absolute lymphocyte count and the relative monocyte count correlated positively with the CD34+ count in the peripheral blood after five days of GCSF use (p < 0.0001 in a multivariate analysis). In contrast, female sex, age, smoking, lactate dehydrogenase (ldh), relative monocyte count, and the relative large unstained cell count were associated negatively with the CD34+ count on day five (p < 0.0001 in a multivariate analysis). In order to predict the harvest success (collection of > 2 x 10^6 CD34+ cells/kg recipient weight after first apheresis) three different models were compared in a ROC-analysis. The first model was purely based on female sex and recipient weight. The second model additionally contained the predicted CD34+ counts. Finally, in the third model the actual observed CD34+ counts were included. By adding the predicted CD34+ counts to the simple model, a significant improvement of the predictability of a harvest success could be viewed although a considerable difference comparing these results to the model with the observed CD34+ counts remained (figure 1). Furthermore, the prediction of harvest success in model donors (figure 2) revealed that donors with a favorable donor profile (covariates set to the most favorable values within the normal range) showed a particular high likelihood for a successful harvest (100 % likelihood, irrespective to donor’s gender or recipient’s weight). The likelihood for a successful harvest in male donors with an average distribution of covariates (covariates set to the empirical mean value) was nearly 100% as well even in donations for heavy recipients. Contrary, the likelihood for an average female donor was high in normal weight recipients (97 %; 60 kg recipient) but decreased with rising recipient weight (78 %; 140 kg recipient). In donors with an unfavorable profile (covariates set to the worst values within the normal range), especially in females, the chance for a successful stem cell collection was poor even when donating for light recipients (54 % in males, 10 % in females; 60 kg recipient). Conclusions: In conclusion, multiple factors with influence on the CD34+ count after GCSF mobilization in healthy donors have been identified. With the prediction model a significant gain in the predictability of a harvest success could be achieved though a certain amount of unexplained variance still remains. Model donors with a favorable or average donor profile had a high likelihood for a successful stem cell collection. In donors with an unfavorable profile, especially in females, the chance for a harvest success was very low. Figure 1: Prediction of harvest success (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Figure 1:. Prediction of harvest success (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Abb.: AUC – area under the curve Figure 2: Probability of harvest success in model donors (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Figure 2:. Probability of harvest success in model donors (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Disclosures Schmidt: Cellex GmbH: Employment. Ehninger:Cellex GmbH: Equity Ownership. Off Label Use: G-CSF.
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Hows, J., K. Beddow, E. Gordon-Smith, et al. "Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation." Blood 67, no. 1 (1986): 177–81. http://dx.doi.org/10.1182/blood.v67.1.177.177.
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Abstract Six cases of immune hemolytic anemia attributed to donor-derived red cell antibodies after allogeneic bone marrow transplantation (BMT) are reported. In 2/6 cases, severe intravascular hemolysis was seen, 6/6 required increased red cell transfusion, and 1/6 was treated by plasma exchange. All recipients were receiving cyclosporine to prevent graft-v- host disease. Investigations showed that in each case, the donor lacked ABO or Rho(D) red cell antigens present in the recipient. The direct antiglobulin test was positive in 6/6. Relevant serum antibody (anti-A, four cases; anti-B, one case; anti-D, one case) was first detected one to three weeks after BMT. Eluates made from recipient red cells showed the same specificity as serum antibody. Maximum hemolysis occurred nine to 16 days after BMT, suggesting that active production of antibody by “passenger” donor lymphocytes was the likely mechanism of hemolysis, rather than passive transfer of antibody in the marrow infusion. Retrospective analysis of 21 consecutive cyclosporine-treated BMT patients receiving marrow lacking ABO or D antigens present in the recipient showed that (1) 15/18 patients tested had red cell antibody production against recipient red cell antigens; (2) despite the frequent presence of antibody specific for recipient red cell antigens, only 3/21 patients developed clinically significant hemolysis; (3) clinical hemolysis could not be predicted by donor or recipient red cell antibody titers. We conclude that although red cell antibody against recipient antigens is frequently produced after minor ABO and D mismatched BMT in cyclosporine-treated recipients, only 10% to 15% of cases develop clinically significant immune hemolysis. The data presented show that the most likely source of antibody is “passenger” donor lymphoid cells.
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Hows, J., K. Beddow, E. Gordon-Smith, et al. "Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation." Blood 67, no. 1 (1986): 177–81. http://dx.doi.org/10.1182/blood.v67.1.177.bloodjournal671177.
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Six cases of immune hemolytic anemia attributed to donor-derived red cell antibodies after allogeneic bone marrow transplantation (BMT) are reported. In 2/6 cases, severe intravascular hemolysis was seen, 6/6 required increased red cell transfusion, and 1/6 was treated by plasma exchange. All recipients were receiving cyclosporine to prevent graft-v- host disease. Investigations showed that in each case, the donor lacked ABO or Rho(D) red cell antigens present in the recipient. The direct antiglobulin test was positive in 6/6. Relevant serum antibody (anti-A, four cases; anti-B, one case; anti-D, one case) was first detected one to three weeks after BMT. Eluates made from recipient red cells showed the same specificity as serum antibody. Maximum hemolysis occurred nine to 16 days after BMT, suggesting that active production of antibody by “passenger” donor lymphocytes was the likely mechanism of hemolysis, rather than passive transfer of antibody in the marrow infusion. Retrospective analysis of 21 consecutive cyclosporine-treated BMT patients receiving marrow lacking ABO or D antigens present in the recipient showed that (1) 15/18 patients tested had red cell antibody production against recipient red cell antigens; (2) despite the frequent presence of antibody specific for recipient red cell antigens, only 3/21 patients developed clinically significant hemolysis; (3) clinical hemolysis could not be predicted by donor or recipient red cell antibody titers. We conclude that although red cell antibody against recipient antigens is frequently produced after minor ABO and D mismatched BMT in cyclosporine-treated recipients, only 10% to 15% of cases develop clinically significant immune hemolysis. The data presented show that the most likely source of antibody is “passenger” donor lymphoid cells.
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Scheinberg, Phillip, Jan J. Melenhorst, Jason M. Brenchley, et al. "The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor." Blood 114, no. 24 (2009): 5071–80. http://dx.doi.org/10.1182/blood-2009-04-214684.
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Abstract The successful reconstitution of adaptive immunity to human cytomegalovirus (CMV) in hematopoietic stem cell transplantation (HSCT) recipients is central to the reduction of viral reactivation-related morbidity and mortality. Here, we characterized the magnitude, specificity, phenotype, function, and clonotypic composition of CMV-specific T-cell responses in 18 donor-recipient pairs both before and after HSCT. The principal findings were: (1) the specificity of CMV-specific T-cell responses in the recipient after HSCT mirrors that in the donor; (2) the maintenance of these targeting patterns reflects the transfer of epitope-specific T-cell clonotypes from donor to recipient; (3) less differentiated CD27+CD57− CMV-specific memory T cells are more likely to persist in the recipient after HSCT compared with more terminally differentiated CD27− CD57+ CMV-specific memory T cells; (4) the presence of greater numbers of less differentiated CD8+ CMV-specific T cells in the donor appears to confer protection against viral reactivation in the recipient after HSCT; and (5) CMV-specific T cells acquire a more differentiated phenotype and a restricted functional profile after HSCT. Overall, these findings define the immunologic factors that influence the successful adoptive transfer of antigen-specific T-cell immunity during HSCT, which enables the identification of recipients at particular risk of CMV reactivation after HSCT.
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Gandhi, Maher K., Mark R. Wills, Georgina Okecha, et al. "Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation." Blood 102, no. 9 (2003): 3427–38. http://dx.doi.org/10.1182/blood-2002-12-3689.
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Abstract To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.
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Onishchenko, N. A., A. O. Nikolskaya, Z. Z. Gonikova, L. A. Kirsanova, M. Yu Shagidulin, and V. I. Sevastianov. "Regenerative and hepatospecific activity of total RNA from xenogenic bone marrow cells." Russian Journal of Transplantology and Artificial Organs 23, no. 1 (2021): 43–48. http://dx.doi.org/10.15825/1995-1191-2021-1-43-48.
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Objective: to study the peculiarities of the induction effect of total RNA (tRNA) from xenogenic bone marrow cells (BMCs) on regeneration processes in the recipient's native liver with extensive liver resection using an adoptive transfer model. Materials and methods. The study was carried out on an adoptive transfer model using male Wistar rats (n = 20) and guinea pigs (n = 17). The donors were rats (n = 10). 12 hours after extensive liver resection (70-75%), tRNA was isolated from BMCs and injected into intact (non-operated) recipients intraperitoneally at a dose of 30 μg/100 g of weight. The induction effect of the tRNA on operated rats was studied in 3 groups of recipients: Group 1 (control, n = 5) - administration of saline to guinea pigs; Group 2 (control, n = 10) - administration of tRNA from a donor rat to a recipient rat (allogeneic transfer); Group 3 (experiment, n = 12) - administration of tRNA from a donor rat to a recipient guinea pig (xenogeneic transfer). In histological preparations of recipient livers, after 48, 72 hours and 7 days, we studied the mitotic activity of hepatocytes and the features of the microscopic picture of the liver. The significance of differences in the compared groups was assessed using the parametric Student's t-test. Results. The ability of BMC tRNA to tissue-specifically activate regenerative and immune responses in the liver after extensive resection was found to depend on the donor and recipient species identity. Introduction of allogeneic donor tRNA in the recipient's liver resulted in predominant enhancement in hepatocyte mitotic activity (p < 0.05). The use of xenogeneic donor tRNA leads to enhanced activity of only immuno-inflammatory reactions in the recipient's liver, such as sinusoidal cell activation, lymphocytic infiltration into sinusoids, and portal tract infiltration by inflammatory cells. Conclusion. To induce regenerative processes in the liver, tRNA obtained from allogeneic BMCs should be used.
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Saito, Yoriko, Naoyuki Uchida, Satoshi Tanaka, et al. "Cell Cycle Entry Potentiates Elimination of Chemotherapy-Resistant Human AML Stem Cells." Blood 114, no. 22 (2009): 1422. http://dx.doi.org/10.1182/blood.v114.22.1422.1422.
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Abstract Abstract 1422 Poster Board I-445 Acute myeloid leukemia (AML) is associated with poor long-term prognosis despite advances in therapeutic modalities over the past few decades. As leukemia stem cells (LSCs) capable of AML initiation may contribute to recurrent disease, LSC-targeted therapies are required to overcome disease relapse and to improve long-term patient outcomes. We previously reported that human AML CD34+CD38- cells self-renew, generate non-stem leukemic cells, and possess potential to initiate leukemia following engraftment of newborn NOD/SCID/IL2rgKO mice. In the recipient bone marrow (BM), AML LSCs were found to reside preferentially within the endosteal region and exhibited chemotherapy resistance. In addition, we observed that AML cells abutting the BM endosteum were cell cycle quiescent while AML cells in the center of the BM were cycling. Based on these findings, we hypothesized that induction of cell cycle entry in quiescent AML LSCs may increase their susceptibility to chemotherapeutic agents, leading to enhanced elimination of LSCs. To test this hypothesis, we assessed the effect of granulocyte colony-stimulating factor (G-CSF) on cell cycle status and chemotherapy susceptibility of primary human AML LSCs in vivo using the NOD/SCID/IL2rgKO xenotransplantation model. In AML-engrafted recipient mice transplanted with LSCs from seven AML patients, flow cytometric analyses demonstrated a significant reduction of quiescent LSCs following 300μg/kg G-CSF sc daily for 5 days (%G0 within hCD34+CD38- BM cells (mean+/-s.e.m): 49.2+/-2.6 (n=47) and 20.5+/-2.0 (n=36), control and G-CSF treated recipients, respectively, p<0.0001 by two-tailed t test). Direct examination of recipient BM in situ revealed cell cycle entry of human AML cells abutting the BM endosteum as evidenced by increased Ki67 expression. Next we developed an in vivo treatment model evaluating the effect of cell cycle induction on chemotherapy-responsiveness of human primary AML LSCs. Human AML-engrafted recipients received AraC alone (1g/kg ip daily for 2 days) or G-CSF followed by AraC (300μg/kg G-CSF sc daily for 5 days with 1g/kg AraC ip daily on days 4 and 5). The proportion of viable active caspase 3-negative human LSCs decreased significantly with pre-chemotherapy cell cycle induction (% active caspase 3-negative hCD34+CD38- BM cell (mean+/-s.e.m.): 82.7+/-1.3% (n=33) and 40.4+/- 3.1% (n=30), AraC alone- and G-CSF followed by AraC-treated recipients, respectively, p<0.0001 by two-tailed t test). TUNEL staining of the recipient BM showed increased apoptosis of AML cells abutting the BM endosteum in recipients receiving AraC following cell cycle induction. Limiting dilution serial transplantation of residual viable human AML cells in the BM of treated recipients showed 100-fold reduction in the frequency of LSCs capable of initiating AML in secondary recipients (BM LSC frequency: 1/560 (n=125) and 1/55,076 (n=109), AraC alone- and G-CSF then AraC-treated recipients, respectively, p=0.0001 by two-tailed t test). At 24 weeks post-transplantation, 89.4% of secondary recipients of G-CSF followed by AraC-treated mice survived compared with only 2.0% survival in secondary recipients of AraC alone-treated mice (p<0.0001, survival estimated by Kaplan-Meier method). These findings indicate that cell cycle status is a key determinant of LSC chemo-responsiveness and that therapeutic strategies promoting LSC cell cycle entry may improve outcomes in AML. Disclosures: No relevant conflicts of interest to declare.
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Kato, S., H. Yabe, M. Yabe, et al. "Studies on transfer of varicella-zoster-virus specific T-cell immunity from bone marrow donor to recipient." Blood 75, no. 3 (1990): 806–9. http://dx.doi.org/10.1182/blood.v75.3.806.806.
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Abstract The transfer of antigen-specific cellular immunity in human bone marrow transplantation (BMT) was studied in 49 donor-recipient pairs, using a varicella-zoster-virus (VZV) specific lymphoproliferative response (LPR) assay. Posttransplant VZV-LPR could be serially measured in 31 long-term surviving recipients. VZV-specific T-cell immunity was detected in the early posttransplant period in 4 of 16 recipients who were, and whose donors were, immune to VZV before BMT, but two of those positive responses diminished in the first 100 days posttransplant. No positive response was detected in the immediate posttransplant period when either only the recipient or the donor was immune to VZV pretransplant. Herpes zoster or chickenpox developed in the recipients depending on a history of pretransplant VZV infection when the VZV-LPR became negative, and recovery from VZV infection was always followed by quick conversion of VZV-LPR. Long-lasting positive VZV-LPR was observed in the two recipients who experienced VZV infection in the immediate pretransplant period and received marrow graft from an immune donor. Our results indicate that a simple or direct transfer of VZV-specific cellular immunity from a marrow donor to a recipient cannot be expected in usual clinical bone marrow transplantation and that there might be a collaboration or recruitment of immune responses involving both donor and recipient that permits the VZV-LPR to remain positive posttransplant.
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Kato, S., H. Yabe, M. Yabe, et al. "Studies on transfer of varicella-zoster-virus specific T-cell immunity from bone marrow donor to recipient." Blood 75, no. 3 (1990): 806–9. http://dx.doi.org/10.1182/blood.v75.3.806.bloodjournal753806.
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The transfer of antigen-specific cellular immunity in human bone marrow transplantation (BMT) was studied in 49 donor-recipient pairs, using a varicella-zoster-virus (VZV) specific lymphoproliferative response (LPR) assay. Posttransplant VZV-LPR could be serially measured in 31 long-term surviving recipients. VZV-specific T-cell immunity was detected in the early posttransplant period in 4 of 16 recipients who were, and whose donors were, immune to VZV before BMT, but two of those positive responses diminished in the first 100 days posttransplant. No positive response was detected in the immediate posttransplant period when either only the recipient or the donor was immune to VZV pretransplant. Herpes zoster or chickenpox developed in the recipients depending on a history of pretransplant VZV infection when the VZV-LPR became negative, and recovery from VZV infection was always followed by quick conversion of VZV-LPR. Long-lasting positive VZV-LPR was observed in the two recipients who experienced VZV infection in the immediate pretransplant period and received marrow graft from an immune donor. Our results indicate that a simple or direct transfer of VZV-specific cellular immunity from a marrow donor to a recipient cannot be expected in usual clinical bone marrow transplantation and that there might be a collaboration or recruitment of immune responses involving both donor and recipient that permits the VZV-LPR to remain positive posttransplant.
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Chen, Benny J., Xiuyu Cui, Jessica Son, and Nelson J. Chao. "Promotion of Stem Cell-Derived New T Cell Generation by CD62L− Memory T Cells Requires Alloantigen Recognition." Blood 104, no. 11 (2004): 3041. http://dx.doi.org/10.1182/blood.v104.11.3041.3041.
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Abstract We recently demonstrated that non-GVHD-inducing CD62L− memory T cells promote T cell regeneration from hematopoietic stem/progenitor cells in the C57BL/6 (H2b) to BALB/c (H2d) bone marrow transplantation model (BLOOD 2004,103:1534). In this model, 1×107 T cell depleted bone marrow from C57BL/6, CD45.2, Thy1.2 mice and 1×106 CD62L− T cells from C57BL/6, CD45.1, Thy1.1 mice are used and the recipient mice are lethally irradiated. This animal model allows us to differentiate the T cells of different origin by flow cytometry. In the current study, we further investigated how CD62L− T cells promote new T cell generation and whether there is any functional relevance using the same model. Previous data suggest that the promoting effect of CD62L− T cells on stem cell-derived new T cell generation is associated with the facilitation of engraftment because host radioresisdant T cells were depleted in CD62L− T cell recipients but not in the T cell-depleted bone marrow control mice. To determine whether CD62L− T cells promote new T cell generation by overcoming T cell-mediated host resistance, we performed the experiment using SCID mice as recipients. SCID mice lack both T and B cells. In consistent with the previous results, serial peripheral blood T cell counts following bone marrow transplantation demonstrated that the promoting effect of CD62L− T cells were dramatically decreased in the SCID recipients, indicating that CD62L− T cell promote new T cell regeneration by overcoming host resistance. To examine whether CD62L− T cells overcome host resistance by “veto effect”, we performed the experiment using CD62L− T cells from (BALB/cxC57BL/6)F1 mice. T cells from F1 mice do not recognize the parental recipient as non-self and can not initiate classical T cell response against the parental antigens. It was previously reported by other investigators that T cells from F1 mice preserve “veto effect”. However, no promoting effect was observed in the recipients of CD62L− T cells from the F1 mice, demonstrating that “veto effect” is not involved. Rather, alloantigen recognition by donor CD62L− T cells is required for the promoting effect. In agreement with the hypothesis that CD62L− T cells promote new T cell generation by enhancing engraftment through overcoming host resistance, both white cell and platelet recovery in peripheral blood was accelerated in CD62L− T cell recipients comparing with that in the control T cell-depleted bone marrow recipients. Finally, we sought to determine whether these findings have any functional relevance in vivo. We evaluated the functional immune recovery by measuring the ability to inhibit the growth of a recipient-type leukemia/lymphoma cell line called BCL1 cells injected intravenously into the transplantation recipients on day +7. While six out of eight T cell-depleted bone marrow control mice developed tumor and died within 30 days after bone marrow transplantation, none of the CD62L− T cell recipients (n=12) developed tumor and all survived more than 60 days after transplantation. As expected, none of the CD62L− T cell recipients developed graft-versus-host disease. Our data indicate that CD62L− T cells promote new T cell generation by enhancing engraftment through overcoming host resistance. This promoting effect requires alloantigen recognition and is not mediated by “veto effect”. Our current focus is trying to determine how allogeneic CD62L− T cells overcome host resistance without causing graft-versus-host disease.
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Yoder, Mervin C., and Kelly Hiatt. "Engraftment of Embryonic Hematopoietic Cells in Conditioned Newborn Recipients." Blood 89, no. 6 (1997): 2176–83. http://dx.doi.org/10.1182/blood.v89.6.2176.
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Abstract Yolk sac hematopoiesis is characterized by restricted hematopoietic cell differentiation. Although multipotent hematopoietic progenitor cells have been identified in the early yolk sac, long-term multilineage repopulating (LTMR) hematopoietic stem cell (HSC) activity has not been demonstrable before day 11 postcoitus (PC) using standard transplantation assays. In the present study, day-10 PC yolk sac hematopoietic cells were infused into myeloablated congenic newborn pups and donor cell engraftment and multilineage reconstitution of peripheral blood cells for at least 11 months in primary recipients was observed. In contrast, transplantation of day-10 PC yolk sac cells into congenic adult recipients did not result in engraftment despite pretransplant conditioning of the recipients or use of recipients that were genetically deficient in stem cells. Although fresh yolk sac cells were incapable of reconstitution when injected into adult recipient mice, yolk sac donor-derived cells residing in the bone marrow of primary newborn transplant recipients were capable of efficient reconstitution of conditioned secondary recipient adult mice. Primary newborn and secondary adult recipient animals engrafted with yolk sac cells were observed to have normal peripheral blood white blood cell counts. Lymphocyte subsets in peripheral blood, thymus, and spleen were also similar to control animals. The distribution and frequency of lineage-restricted progenitors derived from bone marrow of secondary transplant recipients were normal. These results indicate that day-10 PC yolk sac HSCs are capable of engrafting and reconstituting the hematopoietic system of conditioned newborn but not adult recipient animals. Furthermore, the ability of the yolk sac HSCs to differentiate into all hematopoietic lineages in these recipients strongly suggests that the local cellular microenvironment plays a prominent role in regulating yolk sac HSC differentiation.
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Markey, Kate A., Rachel D. Kuns, Renee J. Robb, et al. "Recipient CD8+ DC Delete Alloreactive Donor CTL and Promote Leukemic Relapse after Allogeneic BMT." Blood 126, no. 23 (2015): 4279. http://dx.doi.org/10.1182/blood.v126.23.4279.4279.
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Abstract Allogeneic bone marrow transplantation (BMT) remains the therapy of choice for many haematological malignancies, but despite the curative benefit of the immunological graft-versus-leukemia (GVL) effect, relapse remains a key cause of death. We have investigated the role of recipient dendritic cells (DC) in antigen presentation to donor CD8 cytotoxic T cells (CTL) in a model of BMT where GVHD and GVL are directed to multiple minor histocompatibility antigens (mHA) and survival reflects GVL activity. C3H.Sw bone marrow and purified CD8 T cell grafts were transplanted with B6-derived MLL-AF9 induced primary acute myeloid leukemia (AML) into lethally irradiated B6.CD11c.DOG recipients (diphtheria toxin receptor (DTR), ovalbumin and GFP expression driven off the CD11c promoter) such that recipient DC can be deleted by DT administration. Surprisingly, depletion of recipient DC resulted in improved leukemic control (median survival 43 vs 31 days, P <0.001). The use of IRF8-/- BMT recipients (in which the CD8+ DC subset is absent) confirmed that recipient CD8+ DC were critical for regulating these GVL effects (median survival 43 vs 34 days, P = 0.0005). Conversely, when recipient CD8+ DC were expanded in a B6 to B6D2F1 model with bcr-abl/Nup98-HoxA9 induced primary AML, by using Flt3-L treatment for 10 days prior to BMT, GVL effects were completely eliminated, rendering relapse rate equivalent to that seen in the recipients of T cell depleted (TCD) grafts (median survival 11 days in BM+T and TCD groups where recipients were pre-treated with Flt3-L, vs. >45 days in the saline treated BM+T group). The use of B6.CD11c-Rac1 transgenic BMT recipients (who cannot process and present exogenously acquired antigen) confirmed that this effect was the result of endogenous alloantigen presentation by recipient DC and independent of cross-presentation.Using the same depletion strategies in an antigen-specific model (with donor OT-I T cells and B6.CD11c.DOG x DBA/2 F1 recipients) we confirmed that recipient DC invoked effector donor CTL activation, differentiation (CD25+ CD69+ CD62L-) and subsequent apoptosis (as measured by Annexin V; 52.4% vs. 23.9% in DC replete vs. depleted recipients, P = 0.01). There was a consequent profound contraction of the donor CTL compartment by day 10 in DC replete recipients. This contraction of the CTL compartment was associated with reduced expression of the cytolytic molecule granzyme B (MFI 1922 vs 1097, P = 0.02). Antigen presentation has a critical role in the initiation of donor T cell alloreactivity and GVL after BMT. Here we demonstrate that endogenous alloantigen presentation by recipient CD8+ DC to donor T cells leads to activation induced death of donor CTL early after BMT, which in turn facilitates leukemic relapse. This concept has critical implications for the design of therapies that target DC in the peri-transplant period and confirms that recipient DC regulate GVL effects. Disclosures No relevant conflicts of interest to declare.
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Prokopchuk-Gauk, Oksana, Joanna McCarthy, Peter Duggan, Meer-Taher Shabani-Rad, and Nicole L. Prokopishyn. "Impact of ABO Incompatibility on Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation." Blood 128, no. 22 (2016): 3394. http://dx.doi.org/10.1182/blood.v128.22.3394.3394.
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Abstract Introduction: The selection of an allogeneic hematopoietic stem cell transplant (allo-HSCT) donor is highly dependent on human leukocyte antigen (HLA) allele profile matching with that of the intended recipient to minimize graft-related complications and improve post-transplant outcomes. Although ABO compatibility simplifies recipient transfusion needs, transplantation of an ABO incompatible graft has been identified not to have a significant impact on marrow engraftment or recipient survival. We completed an audit of adult allo-HSCT recipients of the Alberta Bone Marrow and Blood Cell Transplant Program to evaluate the impact of ABO incompatibility on engraftment in our allo-HSCT recipient population. Methods: A retrospective review including all adult allo-HSCT recipients between January 1, 2008 and January 1, 2015 was performed. Data was obtained from review of cellular therapy laboratory electronic records, with blood group confirmation by the transfusion medicine laboratory information system. Statistical calculations were completed using the unpaired t test. Results:A total of 513 adult patients underwent 528 allo-HSCT procedures (493 peripheral blood, 12 marrow, 23 cord blood). The mean HSCT recipient age was 46 (range 17-66) with 291 (57%) male recipients. The most common HSCT indication was acute myeloid leukemia. All allo-HSCT recipients received myeloablative conditioning. A total of 91% of recipients were conditioned with a regimen of Fludarabine-Busulfan-ATG, with or without total body irradiation. ABO compatibility status for allo-HSCT procedures included the following: 264 (50%) ABO identical grafts, 125 (24%) grafts with a minor incompatibility, 113 (21%) grafts with a major incompatibility, and 26 (5%) grafts with bidirectional incompatibility. HLA matching data was available for 447 allo-HSCT procedures. A total of 350 (78%) patients were recipients of fully HLA matched grafts (340 peripheral blood, 9 marrow, 1 cord blood). Taking into consideration ABO compatibility status, 10/10 HLA matched peripheral blood or marrow grafts were provided to 89% of ABO identical graft recipients, 77% of recipients each with a minor or major incompatibility, and 65% of recipients with a bidirectional incompatibility. Cellular engraftment including the number of days until absolute neutrophil count (ANC) > 1.0 x 106/L and platelet count > 20 x 109/L was available for 496 (94%) of all transplant procedures. A total of 34 transplant recipients did not successfully engraft one or both cell lines. A summary of recipient engraftment data for each category of ABO matching according to stem cell source appears in Table 1. Conclusion:In our study population, the risk of non-engraftment is lowest in recipients of ABO identical peripheral blood or marrow source donor stem cells. Time to cellular engraftment following allo-HSCT transplant with peripheral blood or marrow source stem cells of minor or major ABO incompatibility is similar to that of an ABO identical donor, while platelet engraftment appears to be prolonged in the setting of a bidirectional incompatibility. However, the small number of recipients of grafts with a bidirectional incompatibility and the large standard deviation affects our confidence in this result. The impact of ABO matching on engraftment appears to be the greatest in cord blood transplants. The risk of cellular non-engraftment is variable among all ABO compatibility categories, though the time to platelet engraftment is significantly prolonged in recipients of grafts with major ABO or bidirectional incompatibility. These findings are limited by our small cord blood recipient population and the presence of some degree of HLA mismatching in nearly all recipients of cord blood transplants evaluated. Further study is required in larger populations of cord blood transplant recipients to better understand the impact of ABO compatibility status on marrow engraftment, together with variables including the cellular composition of the cord blood graft and host immune factors. Table 1 Rate of non-engraftment and days to neutrophil and platelet engraftment following allo-HSCT according to ABO compatibility, including standard deviation and statistical calculation (*indicates statistically significant value). Table 1. Rate of non-engraftment and days to neutrophil and platelet engraftment following allo-HSCT according to ABO compatibility, including standard deviation and statistical calculation (*indicates statistically significant value). Disclosures No relevant conflicts of interest to declare.
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Seo, Sachiko, Michael Boeckh, Barry E. Storer, et al. "The Effect Of Donor and Recipient Statin Treatment On Infections After Allogeneic Hematopoietic Cell Transplantation." Blood 122, no. 21 (2013): 4548. http://dx.doi.org/10.1182/blood.v122.21.4548.4548.
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Background Recent studies have reported that statin use is associated with improved outcomes in immunocompetent patients with bacterial sepsis and respiratory virus disease. We have reported previously that statin use in donors or recipients was associated with reduced risks of severe acute graft-versus-host disease (GVHD) or chronic GVHD, respectively, after allogeneic hematopoietic cell transplantation (HCT). In the present study, we analyzed the influence of donor and recipient statin use on the incidence of infections and infection-outcomes after allogeneic HCT. Patients and Methods A previously reported cohort of HCT recipients (BBMT 16:1463-6, 2010) was used for the analyses. The cohort included 1206 allogeneic HCT recipients (no statin treatment: n=1130; statin treatment: n=76) transplanted between 2001 and 2008 at the Fred Hutchinson Cancer Research Center. Recipients were considered “statin-treated” when a statin was used to treat hyperlipidemia before and after HCT-conditioning. In addition, for all 567 sibling donors in the same cohort, the statin treatment status at the time of stem cell donation was assessed by review of medical records (no statin treatment: n=480, statin treatment: n=87; Blood 115:1288-95, 2010). The associations between statin use and risks of incident infections or infection-related mortality were evaluated using Cox proportional hazards models. Results Among 1206 HCT recipients, the following proportions experienced first infectious events within 100 days after HCT: bacteremia, 23% (n=275); CMV reactivation, 23% (n=277); respiratory viral infection with upper and/or lower respiratory tract involvement, 8.0% (n=97), and with only lower respiratory tract involvement (LRI), 1.8% (n=22). Within 1 year after HCT, 13% (n=153) developed invasive fungal infections and 3.7% (n=45) developed CMV disease. The overall incidences of bacteremia, invasive fungal infection, CMV reactivation, CMV disease, and LRI were not impacted by recipient or donor statin use. Recipient statin-use, however, was associated with a significantly increased cumulative incidence of gram-negative bacteremia (adjusted HR 2.15 [95% CI, 1.1-4.1], p=0.02), an association not observed with donor statin use. The risk of 30-day mortality attributable to gram-negative bacteremia was not significantly affected by recipient or donor statin use. Finally, the risk of respiratory viral infections was increased in recipients transplanted from statin-treated donors compared with those transplanted from donors not treated with a statin (adjusted HR 2.7 [95% CI, 1.3-5.6], p=0.01). There were no progressions to LRI among recipients transplanted from statin-treated donors (0% vs. 15%, p=0.15). Conclusions Recipient or donor statin use did not alter incidence of most infections after allogeneic HCT. However, while recipient statin use was associated with an increased risk of gram-negative bacteremia, donor statin use was associated with an increased risk of recipient respiratory viral infections without affecting mortality or progression to LRI. The mechanisms underlying these associations remain unknown. Validation of the findings in other large cohorts and, ultimately, randomized trials are needed. Disclosures: Boeckh: Merck: Consultancy, Research Funding.
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Chakraverty, Ronjon, Jennifer Buchli, Guiling Zhao, Richard Hsu, and Megan Sykes. "Host Environment Dictates the Outcome Following Transfer of Graft-Versus-Host Reactive Effector/Memory T Cells." Blood 104, no. 11 (2004): 3046. http://dx.doi.org/10.1182/blood.v104.11.3046.3046.
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Abstract Donor leucocyte infusions (DLI) given to established mixed chimeras (MC) can eliminate normal and malignant hematopoietic cells without causing graft-versus-host disease (GVHD). Identical DLI transferred immediately following lethal irradiation lead to severe GVHD. In contrast to freshly irradiated mice developing GVHD, established MC receiving DLI show delayed kinetics of effector/memory T cell (TE/M) expansion and a distinct distribution with no accumulation of cells in the gut. Lethal irradiation is associated with tissue injury, altered chemokine expression and cytokine dysregulation, and resolution of these changes is important in limiting GVHD following delayed DLI. In an attempt to define the respective roles of ‘intrinsic’ T cell versus ‘extrinsic’ environmental factors in shaping the character of the GVH response elicited, TE/M developing following GVHD induction were transferred to established MC. Conversely, TE/M developing following delayed DLI to MC were transferred to lethally-irradiated 2° recipients. In the first series of experiments, we transferred 1 x 107 C57BL/6 (B6) splenocytes and 5 x 106 B6 T-cell depleted bone marrow (TCD BM) to lethally-irradiated BALB/c recipients. On day 4 following BMT, when GVH-reactive T cell activation and expansion was maximal, 3 x 106 nylon wool-passaged TE/M derived from recipient spleens (equivalent to 1 recipient spleen to 1 secondary recipient) were transferred to established B6 → BALB/c MC or to lethally irradiated BALB/c 2° recipients. The latter mice received B6 TCD BM to prevent death from aplasia. Secondary established MC recipients were resistant to GVHD whereas the lethally-irradiated 2° recipients developed severe, lethal GVHD (median survival time-MST- mixed chimeras &gt;100d versus irradiated mice 52d, p&lt;0.0001). Histological studies confirmed that 4/5 lethally-irradiated 2° recipients developed colitis versus 0/4 MC. TE/M derived from GVHD mice did not increase donor chimerism in 2° MC recipients. In reciprocal experiments, we transferred 2.5 x 107 B6 CD45.1 splenocytes to established B6 CD45.2 → B6D2F1 MC. This number of splenocytes represents the dose required to convert 100% of MC to full donor chimerism without induction of lethal GVHD. On day 12 post-DLI, when GVH-reactive T-cell expansion was maximal, a cohort of recipient mice was sacrificed and splenocytes harvested. On the basis of 1 recipient spleen to 1 secondary recipient, 2.7 x 107 nylon wool-passaged lymphocytes were transferred to 2° freshly-irradiated B6D2F1 recipients together with B6 TCD BM. In parallel, we depleted host-derived cells by sorting for DLI-derived CD45.1+ lymphocytes and transferred these cells on the basis of 1 recipient to 1 2° recipient (7 x 106 lymphocytes) to a second cohort of lethally-irradiated recipients. After a lag-period of about 20 days, 2° recipients of non-fractionated cells lost &gt;10% weight and developed clinical signs of mild GVHD, but then showed almost complete recovery by day 60 post-BMT. In sharp contrast, after a similar lag period, 2° recipients of CD45.1+-selected lymphocytes developed severe lethal GVHD (MST CD45.1+ cells 55d vs &gt;100d non-fractionated cells, p&lt;0.0005). In conclusion, these findings suggest that the host environment strongly influences the capacity of TE/M to induce GVHD. Furthermore, host-derived cells pre-existing in or developing following delayed DLI, reduce the potential of TE/M to induce GVHD.
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Zhu, Kanger, Jun-ping Li, and Tao Zhang. "Clinical Features and Risk Factors of Pure Red Cell Aplasia Following Major ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation." Blood 108, no. 11 (2006): 5238. http://dx.doi.org/10.1182/blood.v108.11.5238.5238.
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Abstract Objective:To study the incidence, risk factors, clinical outcome, management and prevention of pure red cell aplasia (PRCA) following major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HSCT). Method:We retrospectively analyzed 11 cases of PRCA from a series of 42 patients undergoing major ABO-incompatible allo-HSCT from April, 1997 to December, 2005. Results:1. 11 out of the 42 patients developed PRCA (26.1%); 2. All the 11 cases of PRCA were in blood group O recipients of grafts from blood group A donor (n=9) or blood group B donor (n=2). 3. The following factors were associated with an increased risk of PRCA:(1) blood group O recipient;(2) blood group A donor;(3) blood group O/A in recipient/donor pair;4. Only blood group O/A in recipient/donor pair was identified as being significantly associated with the occurrence of PRCA by multivariate analysis (P=0.006); 5. 6 patients who received donor-type plasma exchange did not develop PRCA, and among them, 5 cases were the O blood group recipients. 8 patients obtained spontaneous remission and in the remaining 3 patients, 2 patients with long-lasting PRCA were successfully treated with plasma exchange with donor-type plasma replacement and the other one who was also complicated by EBV-associated lymphoproliferative disorder (EBV-PTLD) responded rapidly to anti-CD20 monoclonal antibody and achieved complete resolution of clinical finding and symptom of both EBV-PTLD and PRCA. Conclusions:The incidence of PRCA in this series of patients was 26.1%. Only blood group A/O in donor/recipient pair is identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Donor-type plasma exchange is an effective approach for the treatment and prophylaxis of PRCA. Anti-CD20 monoclonal antibody is indicated for patients who are not response to conventional therapy.
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Kim, Yeunhee, Danielle Turner, Jacquelyn Nelson, Ina Dobrinski, Margaret McEntee, and Alexander J. Travis. "Production of donor-derived sperm after spermatogonial stem cell transplantation in the dog." REPRODUCTION 136, no. 6 (2008): 823–31. http://dx.doi.org/10.1530/rep-08-0226.
Full textAbstract:
Spermatogonial stem cell transplantation (SSCT) offers unique approaches to investigate SSC and to manipulate the male germline. We report here the first successful performance of this technique in the dog, which is an important model of human diseases. First, we investigated an irradiation protocol to deplete endogenous male germ cells in recipient testes. Histologic examination confirmed >95% depletion of endogenous spermatogenesis, but retention of normal testis architecture. Then, 5-month-old recipient dogs (n=5) were focally irradiated on their testes prior to transplantation with mixed seminiferous tubule cells (fresh (n=2) or after 2 weeks of culture (n=3)). The dogs receiving cultured cells showed an immediate allergic response, which subsided quickly with palliative treatment. No such response was seen in the dogs receiving fresh cells, for which a different injection medium was used. Twelve months post-injection recipients were castrated and sperm was collected from epididymides. We performed microsatellite analysis comparing DNA from the epididymal sperm with genomic DNA from both the recipients and the donors. We used six markers to demonstrate the presence of donor alleles in the sperm from one recipient of fresh mixed tubule cells. No evidence of donor alleles was detected in sperm from the other recipients. Using quantitative PCR based on single nucleotide polymorphisms (SNPs), about 19.5% of sperm were shown to be donor derived in the recipient. Our results demonstrate the first successful completion of SSCT in the dog, an important step toward transgenesis through the male germline in this valuable biomedical model.
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Martin, Paul J., David M. Levine, Barry E. Storer, Sarah C. Nelson, Xinyuan Dong, and John A. Hansen. "Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation." Blood Advances 4, no. 14 (2020): 3224–33. http://dx.doi.org/10.1182/bloodadvances.2020001927.
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Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.
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Li, Hongmei, Daniel Kaplan, Anthony Jake Demetris, Jennifer McNiff, Mark Shlomchik, and Warren D. Shlomchik. "Recipient Langerhans Cells Are Neither Required Nor Sufficient for GVHD Induction in MHC-Matched Allogeneic BMT, but a Langerin+ Cell Is a Pivotal Regulator of Langerhans Cell Turnover Post Transplantation." Blood 112, no. 11 (2008): 3511. http://dx.doi.org/10.1182/blood.v112.11.3511.3511.
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Abstract Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by professional antigen-presenting cells (APCs) to undergo clonal expansion and maturation. Host APCs that survive pretransplant conditioning play an essential role in this T cell activation, and are an attractive target for GVHD prevention and treatment. However, APCs are diverse in phenotype, location and function and an understanding of the roles of distinct subsets is an important first step in developing APC-targeted therapies. Skin is the most frequently affected organ in GVHD. Langerhans cells (LCs), characterized by expression of Langerin, are a major APC in the epidermis, and thus it was logical to hypothesize that host LCs would have a role in GVHD induction. Indeed, in an MHC-mismatched model, Merad et al. showed that host LCs persist after T cell-depleted (TCD) but not T cell-replete bone marrow transplant (BMT), and that these host LCs in donor→host chimeras are sufficient to induce skin GVHD after a second allogeneic bone marrow transplant (alloBMT). However, this work did not examine the role of recipient LCs when all other APCs are intact, the scenario at the time of transplant in all patients. To address this question, we created a transgenic mouse that constitutively lacks epidermal LCs. We did so by expressing diphtheria toxin A chain (DTA) driven by the human Langerin gene (Kaplan, et al 2005) in a bacterial artificial chromosome (BAC). We used Langerin-DTA BAC transgene positive (Tg+) mice or Tg-littermates as recipients in the C3H.SW (H-2b)→B6 (H-2b) strain paring, in which recipient APCs are necessary and sufficient for GVHD induction. Tg+ and Tg− CD8 recipients developed similar GVHD as measured by weight loss and clinical skin disease. Tg+ and Tg− CD8 recipients also had comparable pathologic GVHD of the skin, ear, liver and colon. To generalize these findings, we used B6bm12 →B6 strain pairing, an MHCII-mismatched CD4-dependent GVHD model, in which recipient APCs are also required (Teshima et al, 2002). Tg+ and Tg− CD4 recipients developed similar weight loss and pathologic changes in the tongue and liver, primary sites of GVHD in this model. Thus, in both MHC-matched and MHC-mismatched models in which recipient APCs are absolutely required, the specific absence of recipient epidermal LCs did not affect clinical or histological GVHD. We also analyzed LC turnover in these alloBMT recipients. As previously reported, LCs remained host-derived in B6 Tg− recipients of TCD C3H.SW bone marrow. Given our prior result that C3H.SW → B6 chimeras are resistant to GVHD induction by a second alloBMT from C3H. SW donors (Shlomchik, et al 1999), unlike in the MHC-mismatched model employed by Merad, residual host LCs are insufficient to initiate GVHD in this MHC-matched system. In B6 Tg− recipients of TCD C3H.SW bone marrow plus GVHD-inducing CD8 cells, LC turnover varied by mouse and ranged from all host or donor to a mix of donor and host LCs. This variability could relate to the extent of skin GVHD, as we previously found that epidermal MHCII+ cells in skin GVHD lesions in this model are donor-derived (Matte et all, 2004). Strikingly, in contrast to Tg− recipients, donor-derived LCs developed in Tg+ recipients of TCD C3H.SW bone marrow. Donor LCs also engrafted in Tg+ recipients of TCD bone marrow from Tg− but otherwise syngeneic littermates or B6 RAG1−/− T cell-deficient donors. Thus, in contrast to LC-replete mice, neither allogeneic donor T cells nor UV-induced inflammation was required for donor LC engraftment in LC-deficient hosts. These data indicate that a Langerin+ cell, absent in Langerin-DTA Tg+ mice, regulates LC turnover in the absence of inflammation. Work is underway to identify this key cell.
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Ugai, Tomotaka, Keitaro Matsuo, and Yasuo Morishima. "ALDH2 Polymorphism Has a Significant Impact on Transplant Related Mortality after HLA-Matched Bone Marrow Transplantation." Blood 128, no. 22 (2016): 3391. http://dx.doi.org/10.1182/blood.v128.22.3391.3391.
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Abstract Background : Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme known to degrade acetaldehyde metabolized from ethanol, is also involved in critically important biological processes such as drug metabolism and DNA repair in hematopoietic stem cells. Based on its role in these biological processes, we hypothesized that a functional ALDH2Glu504Lys polymorphism, which is highly prevalent in East Asian populations, could affect the outcome of hematopoietic transplant recipients. Here, we investigated the association between recipient and donor ALDH2 polymorphism and the clinical outcomes of bone marrow transplantation (BMT). Methods. : We analyzed the Japanese national registry data for 409 patients who underwent allogeneic BMT from an HLA-matched unrelated donor through the Japan Marrow Donor Program. The probability of overall survival (OS) was estimated according to the Kaplan-Meier method. The probabilities of relapse, transplant-related mortality (TRM), engraftment, and graft-versus-host disease (GVHD) were estimated based on cumulative incidence curves. Competing events were death without relapse for relapse, relapse for TRM, death without engraftment for engraftment, and death without GVHD for GVHD. To evaluate the impact of recipient and donor ALDH2 polymorphism on transplant outcomes, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders. The Cox proportional hazards model was used to evaluate the effect on OS, whereas Fine and Gray's proportional hazards model was used for the other endpoints. Results.: The median follow-up period in survivors was 6.3 years (range, 0.3-13.1 years). The unadjusted 3-year OS rate was 51% (95% CI, 43%-57%) in Glu/Glu genotype recipients, 52% (43%-60%) in Glu/Lys genotype recipients, and 43% (25%-60%) in Lys/Lys genotype recipients. We did not observe a statistically significant association between the recipient ALDH2 polymorphism and OS. The cumulative incidence of unadjusted 3-year TRM was 28% (21%-34%) in Glu/Glu genotype recipients, 25% (18%-33%) in Glu/Lys genotype recipients, and 50% (29%-68%) in Lys/Lys genotype recipients. The recipient ALDH2 Lys/Lys genotype was significantly associated with a higher TRM, with a HR relative to Glu/Glu genotype of 2.45 (95% CI = 1.22-4.90, P = 0.01). Among the causes of TRM, the incidence rate of organ failure in recipients with the Lys/Lys genotype was twice as high as in recipients with the Glu/Glu genotype (5.9 vs. 3.0 per 1,000 person-days). A statistically significant association between the recipient ALDH2 polymorphism and relapse or GVHD was not observed. With regard to engraftment, the cumulative incidence of platelet engraftment at day 50 was 82% (76%-87%) in Glu/Glu genotype recipients, 80% (72%-85%) in Glu/Lys genotype recipients, and 65% (47%-78%) in Lys/Lys genotype recipients. Compared to the recipient Glu/Glu genotype, the recipient Lys/Lys genotype was marginally significantly associated with delayed platelet engraftment (HR = 0.60, 95% CI = 0.43-1.03, P = 0.06). In contrast, donor ALDH2 polymorphism did not show any significant association with transplant outcomes. Conclusions: We observed poor TRM and delayed platelet engraftment in HLA-matched unrelated BMT recipients with ALDH2 Lys/Lys genotype. Taken functional significance of this polymorphism, our results might indicate that recipient ALDH2 polymorphism could affect the metabolism of chemotherapeutic agents leading to higher TRM and delayed platelet engraftment. Disclosures No relevant conflicts of interest to declare.
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Fast, Loren D. "Recipient elimination of allogeneic lymphoid cells: donor CD4+ cells are effective alloantigen-presenting cells." Blood 96, no. 3 (2000): 1144–49. http://dx.doi.org/10.1182/blood.v96.3.1144.
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Abstract The encounter with allogeneic major histocompatibility complex (MHC) molecules expressed on donor leukocytes during transfusion of blood products has been shown to impact the recipient's immune responses in a number of settings. To better understand the responses induced by the transfer of allogeneic cells, a murine model was used to characterize the recipient responses that control the fate of the allogeneic lymphoid cells. Recipient CD8+ cells could rapidly eliminate a large number of donor cells within 3 days after injection. When elimination responses were studied in the absence of CD8+ cells, it was found that alloantibody production was the secondary elimination mechanism. Optimal recipient CD8+ and B cell responses in this model required help from CD4+ cells that could be provided by 3 different pathways. Although recipient CD4+ cells could provide help when activated by direct recognition of allogeneic MHC class II molecules expressed on donor cells or by indirect recognition of processed alloantigen presented on recipient antigen-presenting cells (APCs), the most rapid recipient responses were generated by help provided by donor CD4+ cells. Purified donor CD4+ cells were also able to induce these rapid responses, indicating that activated donor CD4+cells expressing allogeneic MHC molecules were able to effectively stimulate responses by both recipient CD8+ and B cells.
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Fast, Loren D. "Recipient elimination of allogeneic lymphoid cells: donor CD4+ cells are effective alloantigen-presenting cells." Blood 96, no. 3 (2000): 1144–49. http://dx.doi.org/10.1182/blood.v96.3.1144.015k46_1144_1149.
Full textAbstract:
The encounter with allogeneic major histocompatibility complex (MHC) molecules expressed on donor leukocytes during transfusion of blood products has been shown to impact the recipient's immune responses in a number of settings. To better understand the responses induced by the transfer of allogeneic cells, a murine model was used to characterize the recipient responses that control the fate of the allogeneic lymphoid cells. Recipient CD8+ cells could rapidly eliminate a large number of donor cells within 3 days after injection. When elimination responses were studied in the absence of CD8+ cells, it was found that alloantibody production was the secondary elimination mechanism. Optimal recipient CD8+ and B cell responses in this model required help from CD4+ cells that could be provided by 3 different pathways. Although recipient CD4+ cells could provide help when activated by direct recognition of allogeneic MHC class II molecules expressed on donor cells or by indirect recognition of processed alloantigen presented on recipient antigen-presenting cells (APCs), the most rapid recipient responses were generated by help provided by donor CD4+ cells. Purified donor CD4+ cells were also able to induce these rapid responses, indicating that activated donor CD4+cells expressing allogeneic MHC molecules were able to effectively stimulate responses by both recipient CD8+ and B cells.
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Ma, Wenzhi, Jia Wang, Weijun Gao, and Hua Jia. "The Safe Recipient of SSC Transplantation Prepared by Heat Shock With Busulfan Treatment in Mice." Cell Transplantation 27, no. 10 (2018): 1451–58. http://dx.doi.org/10.1177/0963689718794126.
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Safety is the chief consideration in recipient preparation of spermatogonial stem cell (SSC) transplantation in mammals, especially humans. In this study, we compared the safety of the SSC transplantation recipients that were prepared both by testes heat shock plus testes busulfan injection (heat shock+busulfan(t)) and by busulfan intraperitoneal injection (busulfan i.p.) only. Our results showed that heat shock+busulfan(t) treatment significantly ( p < 0.05) reduced mortality in mice and did not produce bone marrow cell toxicity. Furthermore, heat shock+busulfan(t) treatment directly damaged SSCs and exhausted almost all of the germ cells in the testis; the exhaustion of these cells is considered a key factor in the successful preparation of the recipients. Therefore, we used heat shock+busulfan(t) treatment to prepare recipients of SSC transplantation. Two months after SSC transplantation, the number and length of donor SSC-derived colonies in the testis of recipient in heat shock+busulfan(t) group was closed to that in busulfan i.p. group. Therefore, compared with busulfan i.p. treatment, heat shock+busulfan(t) treatment improved the safety of recipient preparation without reducing the efficiency of SSC transplantation. Two GFP-positive offspring were produced from 1 of the 20 recipients that had mated with female mice 72 days after SSC transplantation. In conclusion, heat shock with busulfan treatment is a safe method to prepare the recipient of SSC transplantation in mice.
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Newell, Laura, Gabrielle Meyers, and Shernan G. Holtan. "Elevated Placental Growth Factor Levels after Allogeneic Hematopoietic Cell Transplantation: Clinical and Peripheral Blood Mononuclear Cell Receptor Expression Correlates." Blood 124, no. 21 (2014): 5870. http://dx.doi.org/10.1182/blood.v124.21.5870.5870.
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Abstract Background: Placental growth factor-1 (PlGF) is a member of the vascular endothelial growth factor (VEGF) family of angiogenic factors possessing inflammatory properties as well as a chemotactic effect for monocytes. Additionally, circulating PlGF levels are associated with disease severity in hypoxic conditions including sickle cell disease and coronary artery disease. We have recently identified that circulating levels of PlGF are significantly elevated in recipients of allogeneic hematopoietic cell transplantation (HCT), and most significantly at the onset of acute graft versus host disease [(aGVHD), Holtan, SG et al, ASH 2014]. It is currently unknown whether PlGF levels are associated with an alteration of expression levels of angiogenic factor receptors on mononuclear cells subsets or other clinical factors post-allogeneic HCT. Thus, as PlGF could play an immunomodulatory role on the developing donor-derived immune system, we sought to characterize peripheral blood mononuclear cell (PBMC) subset expression of the PlGF receptor (VEGFR1) using HCT donor cells collected prior to stem cell collection compared to HCT recipient PBMC collected at 3 months post-HCT. We also correlated clinical factors with PlGF levels and VEGF receptor expression on PBMCs at 3 months post-HCT. Patients and methods: Plasma and PBMCs from a cohort of 14 adult patients undergoing allogeneic HCT at Oregon Health & Science University were collected at 3 months post-HCT and compared to samples obtained from their matched sibling donors (MSD) prior to stem cell donation. Plasma levels of PlGF were quantified by ELISA. Lymphocyte and monocyte expression of VEGFR1 was determined by multiparameter flow cytometry. Comparison of donor and recipient plasma PlGF levels and PBMC phenotypes were performed by Wilcoxon signed rank. Correlations were determined using Spearman's rho. Survival curves generated using Kaplan Meier estimates with differences between curves determined by log rank. Results: PlGF and clinical correlates: PlGF levels were 3.5-fold higher (25.1 versus 7.1 pg/mL, p=0.006) in recipients at 3 months post-HCT compared to their MSD. Donor PlGF levels were not associated with donor age or donor sex. Allogeneic HCT recipient PlGF levels were not associated with donor age, donor sex, recipient age, recipient sex, sex mismatch, conditioning intensity, disease risk index, or disease type. PlGF levels were not associated with the development of acute GVHD prior to the 3-month post-HCT blood draw (p=0.4); however, PlGF levels were negatively associated with steroid dose as a continuous variable (Spearman's rho -0.6, p=0.02). Recipient PlGF levels >25.1 pg/ml at 3 months post-HCT were associated with improved overall survival. PBMC subsets: Allogeneic HCT recipients had significantly higher levels of circulating monocytes (15.4 vs 8.1%, p=0.05) and approximately double the percentage of CD8+ T-cell (1.5 vs 0.6%, p=0.009) and CD3-CD11b+DRlo/- subsets (6.0 vs 3.3%, p=0.01) expressing VEGFR1 as compared to their donors. CD16+ NK cells (r=0.62, p=0.02), CD14+16+ monocytes (r=0.64, p=0.01), and CD14+16+VEGFR1+ monocytes (r=0.61, p=0.02) correlated with PlGF levels in recipients. Conclusion: Elevated PlGF in HCT recipients is associated with an increase in monocyte percentage and an approximate doubling of VEGFR1-expressing lymphoid and myeloid cells compared to their MSD. Despite published association of elevated PlGF levels and chronic inflammatory states, in our small series, higher PlGF levels were associated with improved early survival. Studies are ongoing to correlate PlGF levels with later time points. Further research into the direct angiogenic and immune regulatory effects of PlGF in allogeneic HCT recipients, as well as larger scale studies of the impact of PlGF in late complications of HCT, are indicated. Figure. Figure. Kaplan-Meier estimate of PlGF levels at 3 months post-HCT and overall survival. Disclosures No relevant conflicts of interest to declare.
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Godthelp, Barbara C., Maarten J. D. van Tol, Jaak M. Vossen, and Peter J. van den Elsen. "T-Cell Immune Reconstitution in Pediatric Leukemia Patients After Allogeneic Bone Marrow Transplantation With T-Cell–Depleted or Unmanipulated Grafts: Evaluation of Overall and Antigen-Specific T-Cell Repertoires." Blood 94, no. 12 (1999): 4358–69. http://dx.doi.org/10.1182/blood.v94.12.4358.
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Abstract To evaluate the role of T-cell selection in the thymus and/or periphery in T-cell immune reconstitution after allogeneic bone marrow transplantation (allo-BMT), we have analyzed the overall and antigen-specific T-cell repertoires in pediatric allo-BMT recipients treated for leukemia. We observed a lack of overall T-cell receptor (TCR) diversity in the repopulating T cells at 3 months after allo-BMT, as was deduced from complementarity determining region 3 (CDR3) size distribution patterns displaying reduced complexity. This was noted particularly in recipients of a T-cell–depleted (TCD) graft and, to a lesser extent, also in recipients of unmanipulated grafts. At 1 year after allo-BMT, normalization was observed of TCR CDR3 size complexity in almost all recipients. Analysis of the antigen-specific T-cell repertoire at 1 year after BMT showed that the T cells responding to tetanus toxoid (TT) differed in TCR gene segment usage and in amino acid composition of the CDR3 region when comparing the recipient with the donor. Moreover, the TT-specific TCR repertoire was found to be stable within a given allo-BMT recipient, because TT-specific T cells with completely identical TCRs were found at 3 consecutive years after transplantation. These observations suggest an important role for T-cell selection processes in the complete restoration of the T-cell immune repertoire in children after allo-BMT.
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Godthelp, Barbara C., Maarten J. D. van Tol, Jaak M. Vossen, and Peter J. van den Elsen. "T-Cell Immune Reconstitution in Pediatric Leukemia Patients After Allogeneic Bone Marrow Transplantation With T-Cell–Depleted or Unmanipulated Grafts: Evaluation of Overall and Antigen-Specific T-Cell Repertoires." Blood 94, no. 12 (1999): 4358–69. http://dx.doi.org/10.1182/blood.v94.12.4358.424k02_4358_4369.
Full textAbstract:
To evaluate the role of T-cell selection in the thymus and/or periphery in T-cell immune reconstitution after allogeneic bone marrow transplantation (allo-BMT), we have analyzed the overall and antigen-specific T-cell repertoires in pediatric allo-BMT recipients treated for leukemia. We observed a lack of overall T-cell receptor (TCR) diversity in the repopulating T cells at 3 months after allo-BMT, as was deduced from complementarity determining region 3 (CDR3) size distribution patterns displaying reduced complexity. This was noted particularly in recipients of a T-cell–depleted (TCD) graft and, to a lesser extent, also in recipients of unmanipulated grafts. At 1 year after allo-BMT, normalization was observed of TCR CDR3 size complexity in almost all recipients. Analysis of the antigen-specific T-cell repertoire at 1 year after BMT showed that the T cells responding to tetanus toxoid (TT) differed in TCR gene segment usage and in amino acid composition of the CDR3 region when comparing the recipient with the donor. Moreover, the TT-specific TCR repertoire was found to be stable within a given allo-BMT recipient, because TT-specific T cells with completely identical TCRs were found at 3 consecutive years after transplantation. These observations suggest an important role for T-cell selection processes in the complete restoration of the T-cell immune repertoire in children after allo-BMT.
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Roux, E., C. Helg, F. Dumont-Girard, B. Chapuis, M. Jeannet, and E. Roosnek. "Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts." Blood 87, no. 9 (1996): 3984–92. http://dx.doi.org/10.1182/blood.v87.9.3984.bloodjournal8793984.
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We have studied the repopulation of the T-cell compartment in 27 patients transplanted with bone marrow from an (HLA)-identical sibling. Significant differences were found between recipients of unmanipulated and T-cell depleted grafts. Analysis of the T cells by a method based on amplification of minisatellite DNA regions showed that without depletion > 99.9% of the clones responding to a mitogenic stimulus after transplantation were of donor origin. In contrast, when the graft had been depleted with Campath-1M plus complement, a significant part of the T cells cloned during the first weeks after transplantation comprised of recipient T cells that had survived the preconditioning. This mixed population of low numbers donor and recipient T cells (19 +/- 31/mm3 at day 14) expanded rapidly (predominantly CD8+ T cells) during the first 2 months, without a significant change of the ratio of recipient/donor T cells. In 11 of 17 evaluable patients a late wave ( > 9 months) of donor T cells occurred. As a consequence, T-cell chimerism changed in favor of donor T cells and the CD4/CD8 ratio that had been reversed ( < 0.5) after the first expansion, normalized (1.5 +/- 0.51). Analysis of the T-cell receptor repertoire showed that in recipients of a T-cell depleted graft, the recipient as well as the donor T cells that repopulated the peripheral T-cell pool during the first month, were the progeny of a limited number of precursors. Because without depletion, when larger numbers of donor T cells had been cotransfused with the marrow, the repertoire was much more diverse, these data show that immediately after transplantation, the peripheral pool is repopulated primarily through expansion of circulating T cells.
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Tiberghien, P., DL Longo, JW Wine, WG Alvord, and CW Reynolds. "Anti-asialo GM1 antiserum treatment of lethally irradiated recipients before bone marrow transplantation: evidence that recipient natural killer depletion enhances survival, engraftment, and hematopoietic recovery." Blood 76, no. 7 (1990): 1419–30. http://dx.doi.org/10.1182/blood.v76.7.1419.1419.
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Abstract Natural killer (NK) cells are reported to have an important role in the resistance of lethally irradiated recipients to bone marrow transplantation (BMT). Therefore, we investigated the effects of recipient NK depletion on survival, chimerism, and hematopoietic reconstitution after lethal irradiation and the transplantation of limiting amounts of T-cell-deficient bone marrow (BM). When administered before BMT, anti-asialo GM1 (ASGM1) antiserum treatment, effective in depleting in vivo NK activity, was associated with a marked increase in survival in 3 of 3 allogeneic combinations (BALB/c into C3H/HeN, C57B1/6, or C3B6F1). This enhanced survival was independent of the susceptibility of each recipient strain to accept BALB/c BM. Moreover, recipient anti-ASGM1 treatment was also effective in increasing survival in recipients of syngeneic BM, suggesting that NK cells can adversely affect engraftment independent of genetically controlled polymorphic cell surface determinants. Analysis of chimerism in surviving animals 2 months post-BMT showed that recipient NK depletion significantly increased the level of donor engraftment when high doses of BM were transplanted. These studies also demonstrated that anti-ASGM1 pretreatment mainly resulted in an increase in extramedullary hematopoiesis in the second and third week after irradiation. Anti-ASGM1 treatment also dramatically accelerated the rate of appearance of donor-derived cells with a higher level of donor- cell engraftment apparent at a time when the differences in survival between NK-depleted and control BMT recipients became significant. Peripheral cell counts were also affected by NK depletion, with significantly enhanced platelet and red blood cell recovery and a moderate increase in granulocyte recovery. The overall favorable influence of anti-ASGM1 recipient treatment on hematopoietic events post-BMT suggests that, in humans, pretransplant regimens aimed toward NK depletion should be evaluated.
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Tiberghien, P., DL Longo, JW Wine, WG Alvord, and CW Reynolds. "Anti-asialo GM1 antiserum treatment of lethally irradiated recipients before bone marrow transplantation: evidence that recipient natural killer depletion enhances survival, engraftment, and hematopoietic recovery." Blood 76, no. 7 (1990): 1419–30. http://dx.doi.org/10.1182/blood.v76.7.1419.bloodjournal7671419.
Full textAbstract:
Natural killer (NK) cells are reported to have an important role in the resistance of lethally irradiated recipients to bone marrow transplantation (BMT). Therefore, we investigated the effects of recipient NK depletion on survival, chimerism, and hematopoietic reconstitution after lethal irradiation and the transplantation of limiting amounts of T-cell-deficient bone marrow (BM). When administered before BMT, anti-asialo GM1 (ASGM1) antiserum treatment, effective in depleting in vivo NK activity, was associated with a marked increase in survival in 3 of 3 allogeneic combinations (BALB/c into C3H/HeN, C57B1/6, or C3B6F1). This enhanced survival was independent of the susceptibility of each recipient strain to accept BALB/c BM. Moreover, recipient anti-ASGM1 treatment was also effective in increasing survival in recipients of syngeneic BM, suggesting that NK cells can adversely affect engraftment independent of genetically controlled polymorphic cell surface determinants. Analysis of chimerism in surviving animals 2 months post-BMT showed that recipient NK depletion significantly increased the level of donor engraftment when high doses of BM were transplanted. These studies also demonstrated that anti-ASGM1 pretreatment mainly resulted in an increase in extramedullary hematopoiesis in the second and third week after irradiation. Anti-ASGM1 treatment also dramatically accelerated the rate of appearance of donor-derived cells with a higher level of donor- cell engraftment apparent at a time when the differences in survival between NK-depleted and control BMT recipients became significant. Peripheral cell counts were also affected by NK depletion, with significantly enhanced platelet and red blood cell recovery and a moderate increase in granulocyte recovery. The overall favorable influence of anti-ASGM1 recipient treatment on hematopoietic events post-BMT suggests that, in humans, pretransplant regimens aimed toward NK depletion should be evaluated.
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Zheng, Yama W. L., K. C. Allen Chan, Hao Sun, et al. "Nonhematopoietically Derived DNA Is Shorter than Hematopoietically Derived DNA in Plasma: A Transplantation Model." Clinical Chemistry 58, no. 3 (2012): 549–58. http://dx.doi.org/10.1373/clinchem.2011.169318.
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Abstract BACKGROUND Plasma DNA is predominantly hematopoietic in origin. The size difference between maternal- and fetal-derived DNA in maternal plasma prompted us to investigate whether there was any discrepancy in molecular size between hematopoietically and nonhematopoietically derived DNA in plasma. METHODS Plasma DNA samples from 6 hematopoietic stem cell transplant recipients and 1 liver transplant recipient were analyzed by massively parallel paired-end sequencing. The size of each fragment was deduced from the alignment positions of the paired reads. In sex-mismatched transplant recipients, the reads from chromosome Y were used as markers for the male donor/recipient. For other transplant recipients, the reads of the donor- and recipient-specific alleles were identified from the single-nucleotide polymorphism genotypes. RESULTS In male patients receiving female hematopoietic stem cells, more chromosome Y–derived DNA molecules (nonhematopoietically derived) were ≤150 bp than the autosome-derived ones (mainly hematopoietically derived) (median difference, 9.9%). In other hematopoietic stem cell transplant recipients, more recipient-specific DNA molecules (nonhematopoietically derived) were ≤150 bp than the donor-specific ones (hematopoietically derived) (median difference, 14.8%). In the liver transplant recipient, more donor-derived DNA molecules (liver derived) were ≤150 bp than the recipient-derived ones (mainly hematopoietically derived) (difference, 13.4%). The nonhematopoietically derived DNA exhibited a reduction in a 166-bp peak compared with the hematopoietically derived DNA. A 10-bp periodicity in size distribution below approximately 143 bp was observed in both DNA populations. CONCLUSIONS Massively parallel sequencing is a powerful tool for studying posttransplantation chimerism. Plasma DNA molecules exhibit a distinct fragmentation pattern, with the nonhematopoietically derived molecules being shorter than the hematopoietically derived ones.
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Baker, M. B., N. H. Altman, E. R. Podack, and R. B. Levy. "The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice." Journal of Experimental Medicine 183, no. 6 (1996): 2645–56. http://dx.doi.org/10.1084/jem.183.6.2645.
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The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)-defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD-associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage.
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Pieracci, Fredric M., Carlton C. Barnett, Nicole Townsend, et al. "Sexual Dimorphism in Hematocrit Response Following Red Blood Cell Transfusion of Critically Ill Surgical Patients." ISRN Hematology 2012 (March 22, 2012): 1–7. http://dx.doi.org/10.5402/2012/298345.
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The change in hematocrit (ΔHct) following packed red blood cell (pRBCs) transfusion is a clinically relevant measurement of transfusion efficacy that is influenced by post-transfusion hemolysis. Sexual dimorphism has been observed in critical illness and may be related to gender-specific differences in immune response. We investigated the relationship between both donor and recipient gender and ΔHct in an analysis of all pRBCs transfusions in our surgical intensive care unit (2006–2009). The relationship between both donor and recipient gender and ΔHct (% points) was assessed using both univariate and multivariable analysis. A total of 575 units of pRBCs were given to 342 patients; 289 (49.9%) donors were male. By univariate analysis, ΔHct was significantly greater for female as compared to male recipients (3.81% versus 2.82%, resp., ). No association was observed between donor gender and ΔHct, which was 3.02% following receipt of female blood versus 3.23% following receipt of male blood (). By multivariable analysis, recipient gender remained associated significantly with ΔHct (). In conclusion, recipient gender is independently associated with ΔHct following pRBCs transfusion. This association does not appear related to either demographic or anthropomorphic factors, raising the possibility of gender-related differences in recipient immune response to transfusion.
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van Tol, MJ, EJ Gerritsen, GG de Lange, et al. "The origin of IgG production and homogeneous IgG components after allogeneic bone marrow transplantation." Blood 87, no. 2 (1996): 818–26. http://dx.doi.org/10.1182/blood.v87.2.818.bloodjournal872818.
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Pediatric recipients (n = 25) of an allogeneic bone marrow (BM) graft were selected on the basis of informative IgG allotype (Gm) differences between the BM donor and the recipient. To investigate the kinetics of the appearance of IgG of donor origin and the disappearance of IgG of recipient origin, G1m and G2m allotype levels were quantified in sera obtained at regular intervals between 3 months and 5 years after BM transplantation (BMT). For this quantification, a dot immunobinding assay (DIBA) has been developed. In 19 of 22 informative recipients, the Gm allotype distribution had reached the range of values expected on the basis of the Gm phenotype of the donor within 6 months after BMT. Remarkably, IgG of recipient origin persisted in 15 of 18 informative recipients until last follow up, ie, for several years after BMT. In addition to the origin of total IgG production, the origin of homogeneous IgG components (H-IgG) appearing after BMT was investigated. H-IgG of donor origin could be detected as early as 3 weeks after BMT, but also H-IgG of recipient origin were present in 8 of 13 informative recipients for a period of up to 1 year after BMT. We conclude that host-type IgG-producing cells were not eradicated by the (myeloablative) conditioning regimen and persisted in a high number of graft recipients. It is our hypothesis that lack of graft-versus-host disease (GVHD) in the majority of these recipients results in the persistence of IgG-producing cells of host origin. These observations may be relevant for the evaluation of patients who received allogeneic BMT for the treatment of multiple myeloma.
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Holmfeldt, Per, Jennifer Pardieck, Anjelica C. Saulsberry, et al. "Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival." Blood 122, no. 17 (2013): 2987–96. http://dx.doi.org/10.1182/blood-2013-04-493973.
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Key Points HSPCs fail to persist in the bone marrow of lethally irradiated recipients in the absence of Nfix. Nfix-deficient HSPCs display increased apoptosis during ex vivo culture and in recipient marrow.
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Loren, Alison Wakoff, Greta R. Bunin, Christian Boudreau, et al. "Impact of Prior Pregnancy on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation." Blood 104, no. 11 (2004): 1638. http://dx.doi.org/10.1182/blood.v104.11.1638.1638.
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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) can cure adults with hematologic malignancies, but results in significant morbidity and mortality. Graft-vs.-host disease (GVHD) is a major complication; attempts to reduce the risk of GVHD include selecting donors based on several characteristics, including parity, a criterion which has been controversial. This retrospective cohort study using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) is the first multi-center analysis of the effects of donor and recipient parity on outcomes of HSCT in the modern transplant era. Methods: We studied patients at least 18 years old who received a non-T-cell-depleted, myeloablative HLA-identical sibling HSCT between 1995 and 1999, for acute lymphoblastic or myelogenous leukemia or chronic myelogenous leukemia. The study endpoints included acute and chronic GVHD, overall survival, and relapse. There were 2,626 patients who met inclusion criteria and had complete information on both donor and recipient pregnancy status. Donors and recipients were categorized as: males, nulliparous females, or parous (one or more pregnancies) females. Analysis: We compared all possible combinations of donor and recipient pregnancy status (9 groups in total); the reference group was male donor/male recipient pairs. Multivariate Cox proportional hazards regression was used to adjust for other prognostic factors. Because multiple groups were compared, significant p-values were considered to be less than or equal to 0.006. Results: After controlling for important patient-, disease-, and transplant-related covariates, the risk of chronic GVHD was significantly increased in parous female donor/male recipient pairs (HR 1.56, 95% CI 1.23 – 1.94, p < 0.0001). Neither donor nor recipient parity had an impact on overall survival, acute GVHD, or relapse risk. Conclusions: This multi-center retrospective registry study showed that parous female donors resulted in a significantly increased risk of chronic GVHD in male recipients, but without concomitant reduction in relapse. Thus, H-Y antigens may be important targets of GVHD, but not of a graft-versus-leukemia effect. As when selecting unrelated donors, avoidance of parous female donors, particularly for male patients, in HLA-identical sibling transplants is recommended when possible.
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Narayan, A. Daisy, Jessica L. Chase, Rachel L. Lewis, et al. "Human embryonic stem cell–derived hematopoietic cells are capable of engrafting primary as well as secondary fetal sheep recipients." Blood 107, no. 5 (2006): 2180–83. http://dx.doi.org/10.1182/blood-2005-05-1922.
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The human/sheep xenograft model has proven valuable in assessing the in vivo hematopoietic activity of stem cells from a variety of fetal and postnatal human sources. CD34+/lineage- or CD34+/CD38- cells isolated from human embryonic stem cells (hESCs) differentiated on S17 feeder layer were transplanted by intraperitoneal injections into fetal sheep. Chimerism in primary transplants was established with polymerase chain reaction (PCR) and flow cytometry of bone marrow and peripheral blood samples. Whole bone marrow cells harvested from a primary recipient were transplanted into a secondary recipient. Chimerism was established as described before. This animal was stimulated with human GM-CSF, and an increase in human hematopoietic activity was noted by flow cytometry. Bone marrow aspirations cultured in methylcellulose generated colonies identified by PCR to be of human origin. We therefore conclude that hESCs are capable of generating hematopoietic cells that engraft primary recipients. These cells also fulfill the criteria for long-term engrafting hematopoietic stem cells as demonstrated by engraftment and differentiation in the secondary recipient.
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Goh, Su Kah, Vijayaragavan Muralidharan, Christopher Christophi, Hongdo Do, and Alexander Dobrovic. "Probe-Free Digital PCR Quantitative Methodology to Measure Donor-Specific Cell-Free DNA after Solid-Organ Transplantation." Clinical Chemistry 63, no. 3 (2017): 742–50. http://dx.doi.org/10.1373/clinchem.2016.264838.
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Abstract BACKGROUND Donor-specific cell-free DNA (dscfDNA) is increasingly being considered as a noninvasive biomarker to monitor graft health and diagnose graft rejection after solid-organ transplantation. However, current approaches used to measure dscfDNA can be costly and/or laborious. A probe-free droplet digital PCR (ddPCR) methodology using small deletion/insertion polymorphisms (DIPs) was developed to circumvent these limitations without compromising the quantification of dscfDNA. This method was called PHABRE-PCR (Primer to Hybridize across an Allelic BREakpoint-PCR). The strategic placement of one primer to hybridize across an allelic breakpoint ensured highly specific PCR amplification, which then enabled the absolute quantification of donor-specific alleles by probe-free ddPCR. METHODS dscfDNA was serially measured in 3 liver transplant recipients. Donor and recipient genomic DNA was first genotyped against a panel of DIPs to identify donor-specific alleles. Alleles that differentiated donor-specific from recipient-specific DNA were then selected to quantify dscfDNA in the recipient plasma. RESULTS Lack of amplification of nontargeted alleles confirmed that PHABRE-PCR was highly specific. In recipients who underwent transplantation, dscfDNA was increased at day 3, but decreased and plateaued at a low concentration by 2 weeks in the 2 recipients who did not develop any complications. In the third transplant recipient, a marked increase of dscfDNA coincided with an episode of graft rejection. CONCLUSIONS PHABRE-PCR was able to quantify dscfDNA with high analytical specificity and sensitivity. The implementation of a DIP-based approach permits surveillance of dscfDNA as a potential measure of graft health after solid-organ transplantation.
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Sedlak, Ruth Hall, Joshua A. Hill, Thuy Nguyen, et al. "Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR." Journal of Clinical Microbiology 54, no. 5 (2016): 1223–27. http://dx.doi.org/10.1128/jcm.03275-15.
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The presence of inherited chromosomally integrated human herpesvirus 6 (ciHHV-6) in hematopoietic cell transplant (HCT) donors or recipients confounds molecular testing for HHV-6 reactivation, which occurs in 30 to 50% of transplants. Here we describe a multiplex droplet digital PCR clinical diagnostic assay that concurrently distinguishes between HHV-6 species (A or B) and identifies inherited ciHHV-6. By applying this assay to recipient post-HCT plasma and serum samples, we demonstrated reactivation of HHV-6B in 25% (4/16 recipients) of HCT recipients with donor- or recipient-derived inherited ciHHV-6A, underscoring the need for diagnostic testing for HHV-6 infection even in the presence of ciHHV-6.
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Ito, Koichi, Akira Nakano, Kyoko Ito, Ikuo Kashiwakura, and Hideaki Sato. "Double-Unit Umbilical Cord Blood Transplantation Induces MHC-Matched Single-Unit Dominance with Development of Immunocompetent Lymphocytes in Recipient Mice." Blood 120, no. 21 (2012): 4097. http://dx.doi.org/10.1182/blood.v120.21.4097.4097.
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Abstract Abstract 4097 Background: Double-unit umbilical cord blood cell (dUCBC) transplantation has emerged as an effective strategy for improving the engraftment of umbilical cord blood stem cells in the bone marrow of recipients. Due to a lack convenient animal models, analyses of the differentiation capacity of dUCBC in recipients have been limited to in vivo xenogeneic experiments and clinical observations. In the present study, we evaluated the characteristics of immune reconstitution induced by dUCBC transplantation in mice. Materials and Methods: Natural killer cells were depleted from female C57BL/6 (B6) [H-2b] recipient mice by intraperitoneal administration of rabbit anti-asialo GM1 polyclonal antibody 1 day before transplantation. On the following day, the lethal X-ray-irradiated B6 recipients were given transplants of three different combinations of dUCBC {group (1) GFP-Tg B6 [H-2b] and BALB/c [H-2d]; group (2) GFP-Tg B6 [H-2b] and C3H [H-2k]; group (3) BALB/c [H-2d] and C3H [H-2k]}, each combination containing an equal number of cells. At 16 weeks after transplantation, reconstitution of immune cells was evaluated by flow cytometric analysis utilizing specific antibodies against lineage markers such as CD3 (T cells), CD45R/B220 (B cells), CD11b (macrophages), or Ly-6G (granulocytes). The donor origin of each lineage population was determined by anti-H-2Kk (for C3H) and/or H-2Kd (for BALB/c) antibody staining. GFP+ lineage cells were identified as being of B6 donor origin. Skin grafting was then performed in all recipients to assess the functional maturity of the newly developed T and B cells induced by dUCBC transplantation. Results: The survival rate at 16 weeks after transplantation was 73% (8/11) for case (1), 92% (12/13) for case (2), and 50% (3/6) for case (3). In the great majority of cases (1) and (2), in which dUCBC were administered as a stem cell source, the MHC-matched single unit from GFP-Tg B6 acts as the sole source of long-term hematopoiesis (75% (6/8) for case (1); 100% (12/12) for case (2)). CD3+ T cell peripheral blood chimerism from BALB/c was observed in two of the eight B6 survival recipient mice in case (1) at an early stage of hematopoiesis, predicting the long-term engrafting unit. On the other hand, hematopoiesis in case (3) with fully allogenenic dUCBC transplantation was reconstituted by the B6 recipients' own X-ray-resistant hematopoietic stem cells (HSC). Our results indicate that MHC-matched UCBC-HSC predominantly engraft in the recipient's bone marrow after dUCBC transplantation. However, the nature of this selective mechanism remains largely unknown. In all cases, alloreactive cytotoxic cells in recipient may participate in such selection. In dUCBC transplantation, the included allogeneic cells probably act as stimulators for promoting the differentiation and maturation of MHC-matched HSC through activation of certain types of signal transduction (for example, through cytokine secretion). Currently, we are investigating the possible presence of alloreactive cytotoxic cells in bone marrow. Functionally, these recipients were tolerant of skin grafted from B6, whereas they rejected skin from BALB/c and C3H within 20 days, indicating that both CD4+ helper and CD8+ killer T cells were functionally mature in the recipient mice. Correspondingly, only the alloantibody to BALB/c and C3H was produced in the recipients. One of two chimeric recipient mice in case (1) reacted to only C3H skin with T and B cells. Conclusions: dUCBC transplantation clearly rescued mice that had been subjected to lethal X-ray irradiation. Furthermore, our observations indicate that T and B cells derived from dUCBCs transplants are immunologically fully competent with the ability to distinguish self from non-self MHC antigens. However, a clear understanding of the mechanisms underlying the predominant engraftment of MHC-matched HSCs in the recipient's bone marrow will be necessary. Disclosures: No relevant conflicts of interest to declare.
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Liang, Ying, Gary Van Zant, and Stephen J. Szilvassy. "The Effect of Aging on Hematopoietic Stem Cell Homing and Engraftment." Blood 104, no. 11 (2004): 2673. http://dx.doi.org/10.1182/blood.v104.11.2673.2673.
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Abstract The efficiency with which hematopoietic stem (HSC) and progenitor cells (HPC) home to bone marrow (BM) critically impacts their engraftment after transplantation. Little is known about the effects of aging on this parameter. The present study was thus initiated to test the hypothesis that homing efficiency of HSCs and HPCs to the BM will vary with aging of the donor, recipient, or both. Young or old C57BL/6 BM cells were intravenously injected into lethally irradiated old or young Ly-5 congenic recipient mice. Three or 24 hours later, the numbers of HPCs or HSCs that could be recovered from the BM and spleen were assayed using an in vitro colony-forming cell assay or an in vivo limiting-dilution competitive repopulating unit (CRU) assay and compared to the number of such cells that were initially transplanted. The frequency of CRU in old BM was two-fold higher than that in young BM (~1 per 10,000 vs. 24,000 cells). However, old CRU homed less efficiently to young BM after 24 hours than did young HSCs (3% vs. 10%). The proliferative potential of individual HSCs (measured as the overall level of engraftment in mice transplanted with 1 CRU) did not change with donor age, but was reduced by advanced recipient age, and was also reduced by prior transplantation as observed previously. HSC differentiation potential (defined by the proportion of lymphocytes and myeloid cells in mice transplanted with 1 CRU) was also skewed toward myelopoiesis at the expense of lymphopoiesis with both donor and recipient age. Donor and recipient aging exerted similar effects on the 3 hour BM and spleen seeding efficiency of HPCs, both leading to a 40% decrease in BM homing, and a 5-fold decrease in spleen homing compared with young HPCs transplanted into young recipients. In terms of the rate of hematopoietic engraftment, advanced recipient age resulted in slower erythrocyte and platelet recovery, but moderately accelerated leukocyte regeneration compared with young cells transplanted into young recipients. Conversely, old donor cells exhibited faster leukocyte and platelet recovery, but erythrocyte recovery was essentially unchanged compared to young donor cells. In sum, these data suggest that primitive hematopoietic cells undergo intrinsic aging-related changes in homing efficiency, proliferation/differentiation potential, and engraftment capability that are also extrinsically affected by an older BM microenvironment. These findings have important implications for clinical stem cell transplantation where older individuals often serve as donors for elderly patients.