Histocompatibility Differences Research Articles

Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD).

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option in the treatment of aggressive malignant and non-malignant blood disorders. However, the benefits of allo-HSCT can be compromised by graft-versus-host disease (GvHD), a prevalent and morbid complication of allo-HSCT. GvHD occurs when donor immune cells mount an alloreactive response against host antigens due to histocompatibility differences between the donor and host, which may result in extensive tissue injury. The reprogramming of cellular metabolism is a feature of GvHD that is associated with the differentiation of donor CD4+ cells into the pathogenic Th1 and Th17 subsets along with the dysfunction of the immune-suppressive protective T regulatory cells (Tregs). The activation of glycolysis and glutaminolysis with concomitant changes in fatty acid oxidation metabolism fuel the anabolic activities of the proliferative alloreactive microenvironment characteristic of GvHD. Thus, metabolic therapies such as glycolytic enzyme inhibitors and fatty acid metabolism modulators are a promising therapeutic strategy for GvHD. We comprehensively review the role of cellular metabolism in GvHD pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD.

Haplobanking induced pluripotent stem cells for clinical use.

The development of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and colleagues in 2006 has led to a potential new paradigm in cellular therapeutics, including the possibility of producing patient-specific, disease-specific and immune matched allogeneic cell therapies. One can envisage two routes to immunologically compatible iPSC therapies: using genetic modification to generate a 'universal donor' with reduced expression of Human Leukocyte Antigens (HLA) and other immunological targets or developing a haplobank containing iPSC lines specifically selected to provide HLA matched products to large portions of the population. HLA matched lines can be stored in a designated physical or virtual global bank termed a 'haplobank'. The process of 'iPSC haplobanking' refers to the banking of iPSC cell lines, selected to be homozygous for different HLA haplotypes, from which therapeutic products can be derived and matched immunologically to patient populations. By matching iPSC and derived products to a patient's HLA class I and II molecules, one would hope to significantly reduce the risk of immune rejection and the use of immunosuppressive medication. Immunosuppressive drugs are used in several conditions (including autoimmune disease and in transplantation procedures) to reduce rejection of infused cells, or transplanted tissue and organs, due to major and minor histocompatibility differences between donor and recipient. Such regimens can lead to immune compromise and pathological consequences such as opportunistic infections or malignancies due to decreased cancer immune surveillance. In this article, we will discuss what is practically involved if one is developing and executing an iPSC haplobanking strategy.

Pregnancy-Induced Sensitization Promotes Sex Disparity in Living Donor Kidney Transplantation.

The presence of sex disparity in living donor kidney transplantation (LDKT) remains controversial. To determine if women fall behind men in LDKT evaluation, we performed an intention to treat study of 2587 candidates listed for kidney transplant at a single transplant center over 7 years. We found that women and men kidney transplant candidates engaged an equivalent type and number of prospective living donors. However, sex-specific differences in sensitization history and histocompatibility reduced the rate of LDKT for women by 30%. Pregnancy-induced incompatibility with spouse donors was limiting given that spouses were among the individuals most likely to complete donation. Notably, participation in a kidney paired exchange program eliminated sex-based differences in LDKT. Collectively, these data suggest that pregnancy is a formidable biologic barrier for women and contributes uniquely to sex disparity in LDKT. Targeted efforts to improve transplant center participation in paired kidney exchanges may increase sex equity in LDKT.

Immunotherapy in acute myeloid leukemia.

Despite the remarkable progress made in some leukemias such as CML and CLL, cytotoxic treatment for AML remains essentially unchanged over the last 4 decades. Several lines of evidence, including the graft versus leukemia effect associated with allogeneic hematopoietic stem cell transplantation (HSCT), suggest that immunotherapy is an active modality in AML. Given the lack of progress for chemotherapy in this disease, many novel immunologic treatment approaches have been explored. The goals of non-transplant-based immune approaches have largely consisted of the stimulation or restoration of endogenous immune responses or the targeting of specific tumor antigens by immune cells. These strategies have been associated with less toxicity than allogeneic HSCT but typically have inferior efficacy. Allogeneic HSCT exploits major and minor histocompatibility differences between the donor and recipient in order to recognize and eradicate malignancy. With the recognition that the immune system itself provides a basis for treating AML, immunotherapy continues to be an attractive modality to exploit in the treatment of this disease.

Competition for antigen selects T cell responses that undergo memory inflation and maintains clonal dominance during MCMV infection (P6091)

Abstract Cytomegalovirus (CMV) establishes a life-long, persistent/latent infection. Continuous immune surveillance by CMV-specific CD8+ T cells results in their accumulation over time, a process called “memory inflation”. These “inflationary” T cells migrate systemically and comprise the largest T cell populations in humans, making CMV-based vaccines attractive. Using recombinant murine (M)CMV expressing the SIINFEKL peptide, we found that SIINFEKL-specific T cells inflated at the expense of T cells specific for other MCMV-derived peptides. However, co-infecting mice with viruses expressing and lacking SIINFEKL enabled T cells with multiple specificities to inflate, implying T cell competition for antigen at the level of the infected target. Such competition was also observed among SIINFEKL-specific T cells. Adoptively transferred OT-I T cells, which have a high affinity for the SIINFEKL peptide, were preferentially enriched shortly after infection and inhibited the inflation of host-derived T cells specific for SIINFEKL. Importantly, we observed sporadic, late rejection of OT-Is as a result of minor histocompatibility differences, and only such rejection enabled host-derived T cells to inflate robustly. These data imply that relative clonal abundance is actively maintained by competition. Together, these data show that T cell competition for antigen during MCMV infection dictates which T cell responses inflate and even which clones dominate within a response.

Competition between T cells maintains clonal dominance during memory inflation induced by MCMV.

Both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) establish persistent infections that induce the accumulation of virus-specific T cells over time in a process called memory inflation. It has been proposed that T cells expressing T-cell receptors (TCRs) with high affinity for HCMV-derived peptides are preferentially selected after acute HCMV infection. To test this in the murine model, small numbers of OT-I transgenic T cells, which express a TCR with high affinity for the SIINFEKL peptide, were transferred into congenic mice and recipients were challenged with recombinant MCMV expressing SIINFEKL. OT-I T cells were selectively enriched during the first 3 weeks of infection. Similarly, in the absence of OT-I T cells, the functional avidity of SIINFEKL-specific T cells increased from early to late times postinfection. However, even when exceedingly small numbers of OT-I T cells were transferred, their inflation limited the inflation of host-derived T cells specific for SIINFEKL. Importantly, subtle minor histocompatibility differences led to late rejection of the transferred OT-I T cells in some mice, which allowed host-derived T cells to inflate substantially. Thus, T cells with a high functional avidity are selected shortly after MCMV infection and continuously sustain their clonal dominance in a competitive manner.

Financial and Legal Aspects of the Organ Transplantation

In practical terms, whenever tissues are transplanted from one person to another it is essential to suppress the immune response of the recipient, no matter how perfect the HLA matching has been. When cellular (i.e. histo) compatibility differences exist, between donor and recipient, it is necessary to modify or suppress the immune response in order to enable the recipient to accept a graft. Immunosuppressive therapy, in general, suppresses all immune responses, including those to bacteria, fungi, viruses and even malignant tumors. Current scientific research and real life experiences show that the immunosuppression process can be more safely induced by utilizing the pharmacological means. Agents used in humans to suppress the immune response are discussed in more detail in the continuation of our paper. Financing of the organ transplantation will most probably be among one of the key questions, which need to be answered, before the patients begin to undergo this complex, tedious and costly procedure. The average actual costs and the associated financial contributions for the transplantation of liver and kidney, as well as other organs, have been reduced in the last decade. The main reason for this cost reduction is particularly the reduction of the time period of the patients’ hospital stay. Other reasons that contribute to this reduction, among others, include, (e.g. the pressure from the taxpayers as well as the increased innovation and availability of the new, highly potent and more effevctive and efficient immunosuppressive agents). The process of the cost estimation, in simplified terms, usually includes the costs involved in the following actions and procedures: (i.e. in the evaluation of the transplantation suitability, proper maintenance of the transplantatory candidacy, the costs related to the procurement of the compatible organs from the living and deceased-cadaveric donors, all hospital and physicians’ costs, post transplant care as well as the funding of the cost of the immunosuppressive medications within the first year after the organ transplantation). Finally, the aspect of the interest group lobbying and their effect on the key policy decision makers must also be mentioned. The population of patients who, due to their medical conditions, have to prepare for, undergo and follow up after the organ transplantation, by utilizing the special and costly immunosuppressive therapy must have the keen interest in improving their medical, legal and financial status.

Should Methotrexate plus Calcineurin Inhibitors Be Considered Standard of Care for Prophylaxis of acute Graft-versus-Host Disease?

In a rapidly developing field, one can always anticipate that different interpretations of similar data will coexist. Stem cell transplanters can be a contentious lot, especially in the absence of controlled randomized trials. Thus, although improvements in the basic understanding of acute graft-versus-host disease (aGVHD) has led to many testable hypotheses in the management of GVHD, there remains little consensus regarding the most effective and least toxic approach to GVHD prevention. In the 1980s, the comparison would have been between cyclosporine-based regimens and ex vivo T cell depletion (TCD). Although ex vivo TCD is still used in some settings, pharmacologic-based therapy and in vivo TCD with serotherapy now predominate. This review is meant to highlight the advantages and disadvantages of the "standard of care" and assess the prospects for future regimens that may be more effective.

Genetic dissection of MHC-associated susceptibility to Lepeophtheirus salmonis in Atlantic salmon

BackgroundGenetic variation has been shown to play a significant role in determining susceptibility to the salmon louse, Lepeophtheirus salmonis. However, the mechanisms involved in differential response to infection remain poorly understood. Recent findings in Atlantic salmon (Salmo salar) have provided evidence for a potential link between marker variation at the major histocompatibility complex (MHC) and differences in lice abundance among infected siblings, suggesting that MHC genes can modulate susceptibility to the parasite. In this study, we used quantitative trait locus (QTL) analysis to test the effect of genomic regions linked to MHC class I and II on linkage groups (LG) 15 and 6, respectively.ResultsSignificant QTL effects were detected on both LG 6 and LG 15 in sire-based analysis but the QTL regions remained unresolved due to a lack of recombination between markers. In dam-based analysis, a significant QTL was identified on LG 6, which accounted for 12.9% of within-family variance in lice abundance. However, the QTL was located at the opposite end of DAA, with no significant overlap with the MHC class II region. Interestingly, QTL modelling also revealed evidence of sex-linked differences in lice abundance, indicating that males and females may have different susceptibility to infection.ConclusionOverall, QTL analysis provided relatively weak support for a proximal effect of classical MHC regions on lice abundance, which can partly be explained by linkage to other genes controlling susceptibility to L. salmonis on the same chromosome.

Role of dendritic cells and chemokines in acute graft-versus-host disease

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. GVHD is caused by donor T cells that recognize and react to recipient histocompatibility differences, resulting in significant morbidity and mortality. The pathophysiology of GVHD is complex, which occurs in three phases: induction phase, activation phase and effector phase. Numerous studies have demonstrated that GVHD involves multiple inflammatory cells and cytokines, in particular of antigen presenting cells, chemokines and T cell subsets. This review will discuss roles of a special antigen presenting cell: dendritic cell and chemokines in T cell-mediated acute GVHD.

KIR Ligands and Prediction of Relapse after Unrelated Donor Hematopoietic Cell Transplantation for Hematologic Malignancy

Recurrent malignancy remains a significant complication after allogeneic hematopoietic cell transplantation (HCT). Efforts to decrease relapse have included donor lymphocyte infusion to stimulate donor anti-recipient T-cell allorecognition of major and minor histocompatibility differences. Recently, alloreactive effects of donor natural killer cell-mediated inhibitory killer immunoglobulin-like receptor (KIR) recognition of recipient HLA-C and -B ligands have been described. We examined KIR ligand effects on risk of relapse in 1770 patients undergoing myeloablative T-replete HCT from HLA-matched or -mismatched unrelated donors for the treatment of myeloid and lymphoid leukemias. KIR ligands defined by HLA-B and -C genotypes were used to determine donor-recipient ligand incompatibility or recipient lack of KIR ligand. Among HLA-mismatched transplantations, recipient homozygosity for HLA-B or -C KIR epitopes predicted lack of KIR ligand and was associated with a decreased hazard of relapse (hazard ratio, 0.61; 95% confidence interval, .043-0.85; P = .004). Absence of HLA-C group 2 or HLA-Bw4 KIR ligands was associated with lower hazards of relapse (hazard ratio, 0.47; 95% confidence interval, 0.28-0.79, P = .004; hazard ratio, 0.56; 95% confidence interval, 0.33-0.97; P = .04, respectively). The decrease in hazard of relapse in patients with acute myelogenous leukemia was similar to that in patients with chronic myelogenous leukemia and acute lymphoblastic leukemia ( P = .95). Recipient homozygosity for HLA-B or -C epitopes that define KIR ligands is likely to be a predictive factor for leukemia relapse after myeloablative HCT from HLA-mismatched unrelated donors. This effect was not observed in HLA-identical unrelated transplants.

Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning

In the absence of irradiation or other cytoreductive conditioning, endogenous hematopoietic stem cells (HSCs) are thought to fill the unique niches within the bone marrow that allow maintenance of full hematopoietic potential and thus prevent productive engraftment of transplanted donor HSCs. By transplantation of purified exogenous HSCs into unconditioned congenic histocompatible strains of mice, we show that ∼0.1–1.0% of these HSC niches are available for engraftment at any given point and find no evidence that endogenous HSCs can be displaced from the niches they occupy. We demonstrate that productive engraftment of HSCs within these empty niches is inhibited by host CD4+ T cells that recognize very subtle minor histocompatibility differences. Strikingly, transplantation of purified HSCs into a panel of severe combined immunodeficient (SCID) mice leads to a rapid and complete rescue of lymphoid deficiencies through engraftment of these very rare niches and expansion of donor lymphoid progenitors. We further demonstrate that transient antibody-mediated depletion of CD4+ T cells allows short-term HSC engraftment and regeneration of B cells in a mouse model of B(-) non-SCID. These experiments provide a general mechanism by which transplanted HSCs can correct hematopoietic deficiencies without any host conditioning or with only highly specific and transient lymphoablation.

Is Autograft the Gold Standard in Achieving Radiographic Fusion in One-Level Anterior Cervical Discectomy and Fusion With Rigid Anterior Plate Fixation?

A review of 66 consecutive patients at a single institution who underwent one-level anterior cervical discectomy and fusion (ACDF) with rigid anterior plate fixation with allograft or autograft. To address the efficacy of allograft to autograft with primary respect to fusion rate and secondary attention to risk factors and clinical outcome in patients undergoing one-level ACDF with rigid anterior plate fixation. Although autograft is considered the gold standard in achieving optimal fusion, when compared with allograft in noninstrumented one-level ACDF and in plated and nonplated multilevel ACDF, the efficacy of allograft to autograft in one-level ACDF with rigid anterior plate fixation is not thoroughly understood. Sixty-six consecutive patients (mean age, 45 years) at a single institution who underwent one-level ACDF with rigid anterior plate fixation with allograft (n = 35) or autograft (n = 31) were reviewed for radiographic fusion (mean, 12 months), risk factors, and clinical outcome (mean, 17 months). Smokers entailed 33.3% of the patients, and 45.5% of all patients presented with a work-related injury. An independent blinded observer reviewed at last follow-up lateral neutral and flexion/extension plain radiographs for radiographic fusion and instrumentation integrity. Clinical outcome was assessed on last follow-up and rated according to the Odom criteria. The threshold for statistical significance was established at P < 0.05. Solid fusion was achieved in 63 patients (95.5%). Fusion was noted in 100% of the allograft patients, whereas 90.3% of the autograft cases achieved fusion. No statistically significant difference was noted between allograft to autograft with regard to fusion rate (P > 0.05). Three patients developed nonunions (1 smoker; 2 nonsmokers) and entailed Orion instrumentation. In the one patient who was a nonsmoker with a nonunion, slight screw penetration into the involved and uninvolved interbody spaces was noted. No other intraoperative, postoperative, or radiographic complication was noted. All of the nonunions occurred early in the series. Postoperatively, excellent results were reported in 19.7%, good results in 71.2%, and fair results in 9.1% of the patients. Satisfactory clinical outcome was noted in all nonunion patients. A nonstatistically significant difference was noted with regard to clinical outcome of fused and nonfused patients, demographics, and the presence of a work-related injury (P > 0.05). The impact of smoking was not a factor influencing fusion or clinical outcome in this series (P > 0.05). A statistically significant difference was noted in plate-type on fusion rate (P < 0.05). A 100% and 90.3% radiographic fusion rate was obtained for allograft and autograft in one-level ACDF procedures with rigid anterior plate fixation, respectively. Although autograft achieved a higher incidence of nonunion than allograft, this may be attributed to the use of autograft early in the experience of plate application and fixation in this series. The effects of smoking were not found to be a significant factor influencing fusion in these plated patients. In 90.9% of the patients, excellent and good clinical outcome results were reported. The use of allograft in one-level ACDF with rigid plate fixation yields similar and high fusion rates as autograft. The use of allograft bone eliminates complications and pitfalls associated with autologous donor site harvesting. However, the use of autograft is a viable alternative to avoid the risk of infection, disease transmission, and histocompatibility differences associated with allograft. The use of allograft or autograft bone in properly selected patients for one-level ACDF with rigid anterior plate fixation can result in high fusion rates with excellent and good clinical outcomes.

Immunopathogenesis of Acute Graft‐versus‐Host Disease: Implications for Novel Preventive and Therapeutic Strategies

AbstractFor Abstract see ChemInform Abstract in Full Text.

In vivo spatial and temporal analyses in mice reveal redundancy of lymphoid tissues in inducing acute GVHD after allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation is an effective therapy for the treatment of malignant and non-malignant disorders, and yet graft-versus-host disease (GVHD) remains a major obstacle. Given the dynamic changes in immune cell subsets and tissue organization, which occur in GVHD, localization and timing of critical immunological events in vivo may reveal basic pathogenic mechanisms of GVHD. We transplanted light-emitting luciferase transgenic allogeneic splenocytes, and non-invasively monitored their tissue distribution in living mice with major histocompatibility differences.

Update on graft versus host disease.

Update on graft versus host disease.

Immunopathogenesis of acute graft-versus-host disease: implications for novel preventive and therapeutic strategies.

Acute graft-versus-host disease (GVHD) is a primary T-cell-mediated complication of allogeneic hematopoietic stem cell transplantation (HSCT), occurring when donor-derived T cells are stimulated by host antigen-presenting cells (APCs), enhanced by proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha. Recent data indicate that besides differences in major histocompatibility and minor histocompatibility antigens, cytokine gene polymorphisms have a predictive value for the complication of GVHD. Patients with a high anti-inflammatory IL-10 production have been demonstrated to be protected from GVHD while patients with high TNF-alpha serum levels were more at risk for GVHD. Pharmacological immunosuppression for GVHD prophylaxis and therapy, including unspecific approaches with corticosteroids or methotrexate (MTX), as well as more specific therapy with cyclosporin A (CsA), tacrolimus (FK506), sirolimus, mycophenolate mofetil (MMF), antithymocyte globulin (ATG), and monoclonal antibodies (MAbs) directed against CD3, CD25, CD52, cytotoxic T-lymphocyte antigen (CTLA)-4, CD40 ligand, or TNF-alpha, have been proven to be effective. Recent data on novel techniques to selectively deplete alloreactive T cells by removal, destruction, or anergy induction while preserving leukemia-specific T-cell clones suggest a clinical benefit from these approaches. Gene-modified T cells that can selectively be depleted and CD4(+)CD25(+) regulatory T cells are under investigation for their ability to modulate alloreactivity after HSCT. With a better understanding of the immunopathogenesis of acute GVHD and the technical improvement of recently described therapeutic approaches, such as removal of naive T cells, selection of Th2 cells, suicide gene transduced T cells, and adoptive transfer of regulatory T cells, the use of alloreactivity as a treatment modality may be expanded to nonhematological disease entities such as solid tumors or autoimmune disorders.

Prognostic implications of declining plasma gelsolin levels after allogeneic stem cell transplantation

The idiopathic pneumonia syndrome (IPS) represents a common and often fatal complication of hematopoietic stem cell transplantation (HSCT). Gelsolin is a highly conserved actin-binding protein normally present in plasma that may serve a basic physiological role in limiting acute lung injury of diverse etiologies. We hypothesized that depletion of circulating gelsolin following HSCT might play a permissive role in the pathogenesis of IPS. Plasma gelsolin levels were measured by immunoblotting in frozen samples obtained weekly from 24 patients undergoing allogeneic HSCT. Patients with and without IPS were similar with respect to age, diagnosis, histocompatibility differences between donor and recipient, and conditioning regimen. Mean gelsolin levels in the 9 patients with rapidly fatal IPS were significantly lower than those in patients without this complication by week 3 after HSCT (101 +/- 61 mg/L versus 221 +/- 54 mg/L; P =.0002). Seven (88%) of the 8 patients with gelsolin levels of less than 100 mg/L in the first month after HSCT died from IPS within 3 months; conversely, gelsolin levels fell to less than 100 mg/L in 7 (78%) of the 9 patients who died from IPS within 3 months of HSCT (P =.0007). These findings suggest that gelsolin levels shortly after allogeneic HSCT can predict the later development of fatal IPS. Gelsolin replacement in selected transplant patients may offer a novel strategy to prevent or reverse IPS.

Recipient cytokine genotypes for TNF-alpha and IL-10 and the minor histocompatibility antigens HY and CD31 codon 125 are not associated with occurrence or severity of acute GVHD in unrelated cord blood transplantation: a retrospective analysis.

BACKGROUND In HLA-identical sibling bone marrow transplantation, certain recipient cytokine gene polymorphism genotypes and minor histocompatibility differences influence the occurrence and severity of acute graft-versus-host disease (aGvHD). The present study investigated the role of cytokine tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 gene polymorphisms HY, HA-1, and CD31 minor histocompatibility antigen (mHag) mismatch in the development of aGvHD after unrelated cord blood (CB) transplant (CBT). METHODS DNA samples of 115 CB recipients and their unrelated CB grafts were analyzed for genotype associated with TNF-alpha (TNFd3/d3) and IL-10 (IL-10(-1064), 11-16) and for disparities in major and three minor histocompatibility antigens, HY, HA-1, and CD31 codon 125. Results were correlated with the incidence of aGvHD grades II to IV. RESULTS Neither the donor nor the recipient GvHD risk alleles TNFd3/d3 and IL-10(-1064) (11-16) were associated with the development of aGvHD grades II to IV and I to IV. Because of the heterogeneity of CBTs, the data were reanalyzed separately for patients with malignancies (n=83) or with inborn errors (n=24). No significant association was observed between the severity of aGvHD and the possession of either TNFd3/d3 or IL-10 (11-16) genotypes. Mismatches for the mHags HY, HA-1, and CD31 exon 125 between donor and recipient did not associate with aGvHD grades II to IV. CONCLUSIONS In contrast to HLA-identical sibling bone marrow transplantation, in mismatched unrelated CBT, neither the cytokine genotypes TNFd3/d3 alone or in combination with IL-10(-1064) alleles nor the minor histocompatibility antigens HY, HA-1, and CD31 exon 125 were associated with aGvHD grades II to IV. Further determination of the cytokine gene polymorphism genotypes in CBTs compared with bone marrow transplants may identify those polymorphisms that could be potential predictive markers for the occurrence of aGvHD.

Recipient cytokine genotypes for TNF-alpha and IL-10 and the minor histocompatibility antigens HY and CD31 codon 125 are not associated with occurrence or severity of acute GVHD in unrelated cord blood transplantation: a retrospective analysis.

In HLA-identical sibling bone marrow transplantation, certain recipient cytokine gene polymorphism genotypes and minor histocompatibility differences influence the occurrence and severity of acute graft-versus-host disease (aGvHD). The present study investigated the role of cytokine tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 gene polymorphisms HY, HA-1, and CD31 minor histocompatibility antigen (mHag) mismatch in the development of aGvHD after unrelated cord blood (CB) transplant (CBT). DNA samples of 115 CB recipients and their unrelated CB grafts were analyzed for genotype associated with TNF-alpha (TNFd3/d3) and IL-10 (IL-10(-1064), 11-16) and for disparities in major and three minor histocompatibility antigens, HY, HA-1, and CD31 codon 125. Results were correlated with the incidence of aGvHD grades II to IV. Neither the donor nor the recipient GvHD risk alleles TNFd3/d3 and IL-10(-1064) (11-16) were associated with the development of aGvHD grades II to IV and I to IV. Because of the heterogeneity of CBTs, the data were reanalyzed separately for patients with malignancies (n=83) or with inborn errors (n=24). No significant association was observed between the severity of aGvHD and the possession of either TNFd3/d3 or IL-10 (11-16) genotypes. Mismatches for the mHags HY, HA-1, and CD31 exon 125 between donor and recipient did not associate with aGvHD grades II to IV. In contrast to HLA-identical sibling bone marrow transplantation, in mismatched unrelated CBT, neither the cytokine genotypes TNFd3/d3 alone or in combination with IL-10(-1064) alleles nor the minor histocompatibility antigens HY, HA-1, and CD31 exon 125 were associated with aGvHD grades II to IV. Further determination of the cytokine gene polymorphism genotypes in CBTs compared with bone marrow transplants may identify those polymorphisms that could be potential predictive markers for the occurrence of aGvHD.