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Matched unrelated donors (URD) are the most frequent source of stem cells for allogeneic hematopoietic cell transplantation (HCT) to date, with HCT performed mainly under conventional immunosuppression by methotrexate and cyclosporine. In this setting, every single allelic donor-recipient mismatch for HLA-A, -B, -C, -DRB1 (8/8), but not for HLA-DQB1, -DPB1, has a significant negative effect on overall survival (OS). When several 8/8 HLA-matched URD are available, donor age is the most important factor impacting OS. Moving forward from the traditional way of counting the number of donor-recipient HLA allele mismatches to biology-driven algorithms for functional matching has led to the unraveling of an association between permissive, low-risk HLA-DPB1 mismatches and improved outcome after URD HCT for malignant disease but not for nonmalignant disease. Functional HLA matching might prove to have increasing importance for URD selection in the era of new immunosuppressive regimens that have the potential to substantially reshuffle the role of HLA mismatches in URD HCT., Competing Interests: Conflict-of-interest disclosure: K.F. declares no competing financial interests., (© 2019 by The American Society of Hematology. All rights reserved.)

Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non-Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA-B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-NHL., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation., Methods: We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model., Findings: Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21 × 10 7 cells per kg compared with 21 × 10 7 cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 1·31-2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality., Interpretation: These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1., Funding: National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life‐saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor‐specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression‐minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor‐specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor‐specific‐antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR‐Cas9‐edited cells, to rebut the claim that the HLAMatchmaker eplets represent "functional epitopes." We further used unique sub‐cohorts of patients, those receiving an allograft with two HLA‐DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05‐heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor‐specific HLA‐DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA‐DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections. [ABSTRACT FROM AUTHOR]

We present a catalog of common and well‐documented (CWD) alleles of the German population for the six HLA loci A, B, C, DRB1, DQB1, and DPB1. This study is based on a sample of over 5 million volunteer adult hematopoietic stem cell donors from the 26 German donor centers. To establish the catalog, allele and haplotype frequencies were estimated with a validated implementation of the expectation‐maximization algorithm. CWD criteria similar to existing CWD catalogs were applied in order to be able to put our findings into the context of relevant existing references. Overall, 2155 HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1 alleles were identified as CWD in the German donor population representing about 20% of the HLA alleles at two‐field resolution in the IPD‐IMGT/HLA Database release v3.25.0 from July 2016 for these six loci. We found a substantial concordance of CWD alleles between the three catalogs and showed the contribution of the German donor population to the CWD alleles domain. In conclusion, the definition of CWD criteria that allow interoperability, scalability, and flexibility will be crucial for the development of a worldwide CWD catalog. [ABSTRACT FROM AUTHOR]

The article discusses research by E. W. Petersdorf and colleagues about the link of high expression HLA-DP molecules with the risk of blood disorders and acute graft-versus-host disease in patients who underwent hematopoietic cell transplantation. Topics mentioned include the expression of HLD-DP molecules by hematopoietic system, differential immunogenicity of DPB1 alleles, and the role of transcriptional and posttranscriptional regulation of HLA expression.

Summary: Background: The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell transplantation. Methods: HLA and clinical data for related-donor transplantations submitted to the International Histocompatibility Working Group in haemopoietic-cell transplantation were analysed retrospectively. HLA-DPB1 T-cell-epitope groups were assigned according to a functional algorithm based on alloreactive T-cell crossreactivity patterns. Recipients and unrelated donors matching status were classified as HLA-DPB1 match, non-permissive HLA-DPB1 mismatch (those with mismatched T-cell-epitope groups), or permissive HLA-DPB1 mismatch (those with matched T-cell-epitope groups). The clinical outcomes assessed were overall mortality, non-relapse mortality, relapse, and severe (grade 3–4) acute graft-versus-host disease (aGvHD). Findings: Of 8539 transplantations, 5428 (64%) were matched for ten of ten HLA alleles (HLA 10/10 matched) and 3111 (36%) for nine of ten alleles (HLA 9/10 matched). Of the group overall, 1719 (20%) were HLA-DPB1 matches, 2670 (31%) non-permissive HLA-DPB1 mismatches, and 4150 (49%) permissive HLA-DPB1 mismatches. In HLA 10/10-matched transplantations, non-permissive mismatches were associated with a significantly increased risk of overall mortality (hazard ratio [HR] 1·15, 95% CI 1·05–1·25; p=0·002), non-relapse mortality (1·28, 1·14–1·42; p<0·0001), and severe aGvHD (odds ratio [OR] 1·31, 95% CI 1·11–1·54; p=0·001), but not relapse (HR 0·89, 95% CI 0·77–1·02; p=0·10), compared with permissive mismatches. There were significant differences between permissive HLA-DPB1 mismatches and HLA-DPB1 matches in terms of non-relapse mortality (0·86, 0·75–0·98; p=0·03) and relapse (1·34, 1·17–1·54; p<0·0001), but not for overall mortality (0·96, 0·87–1·06; p=0·40) or aGvHD (OR 0·84, 95% CI 0·69–1·03; p=0·09). In the HLA 9/10 matched population, non-permissive HLA-DPB1 mismatches also increased the risk of overall mortality (HR 1·10, 95% CI 1·00–1·22; p=0·06), non-relapse mortality (1·19, 1·05–1·36; p=0·007), and severe aGvHD (OR 1·37, 95% CI 1·13–1·66; p=0·002) compared with permissive mismatches, but the risk of relapse was the same in both groups (HR 0·93, 95% CI 0·78–1·11; p=0·44). Outcomes for HLA 10/10-matched transplantations with non-permissive HLA-DPB1 mismatches did not differ substantially from those for HLA 9/10-matched transplantations with permissive HLA-DPB1 mismatches or HLA-DPB1 matches. Interpretation: T-cell-epitope matching defines permissive and non-permissive HLA-DPB1 mismatches. Avoidance of an unrelated donor with a non-permissive T-cell-epitope mismatch at HLA-DPB1 might provide a practical clinical strategy for lowering the risks of mortality after unrelated-donor haemopoietic-cell transplantation. Funding: National Institutes of Health; Associazione Italiana per la Ricerca sul Cancro; Telethon Foundation; Italian Ministry of Health; Cariplo Foundation; National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; Office of Naval Research; IRGHET Paris; Swedish Cancer Society; Children''s Cancer Foundation; Swedish Research Council; Cancer Society in Stockholm; Karolinska Institutet; and Leukemia and Lymphoma Society. [Copyright &y& Elsevier]

Aim Next-generation sequencing (NGS) provides a cost and time efficient approach for routine HLA typing. Analysis software typically presumes a diploid genotype with counts of sequencing reads from homozygous or heterozygous genotypes. However, chimeric samples with more than two alleles per locus and imbalanced read counts may occur, for instance, after partially HLA-mismatched hematopoietic stem cell transplantation. Detection of alleles at even very low allele frequencies can then become diagnostically relevant in the context of post-transplant relapse. Here, we describe and validate a novel algorithm for rare HLA allele detection using NGS data. Methods Sequencing reads are mapped against expected HLA-alleles in a chimeric DNA-sample. Only polymorphic nucleotide positions differentiating the expected allele sequences are considered for further analysis. Reads are classified based on the frequency of discriminatory di-nucleotides. The classification algorithm was validated using in vitro admixtures of DNA samples down to allelic frequencies of 0.5 percent based on NGS data targeting exons 2 and 3 for the HLA genes A, B, C, DQB1, DRB1, and DPB1. Results We found that sensitivity and specificity are allele and locus-specific and depend on the number of sequence differences between the alleles. In each of the analyzed admixture samples a subset of the 12 amplicons harbored sufficient sequence differences to detect genotypes at dilutions as low as 0.5 percent. Fig. 1 shows an example for 3 amplicons. Conclusions The proposed algorithm may support the application of cost effective NGS for sensitive detection of HLA microchimerism in different settings including transplantation and pregnancy. [ABSTRACT FROM AUTHOR]