Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study
International Histocompatibility Working Group in Hematopoietic Cell Transplantation
(2020) The Lancet Haematology, volume 7, issue 1, pp. e50 - e60
(Article)
Abstract
BACKGROUND: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence
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natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. METHODS: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. FINDINGS: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. INTERPRETATION: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. FUNDING: The National Institutes of Health, USA.
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Keywords: Adolescent, Adult, Exons/genetics, Female, Graft vs Host Disease/genetics, HLA-B Antigens/genetics, Hematopoietic Stem Cell Transplantation/methods, Histocompatibility, Histocompatibility Testing, Humans, Male, Middle Aged, Multivariate Analysis, Retrospective Studies, Journal Article
ISSN: 2352-3026
Publisher: Lancet Publishing Group
Note: Funding Information: A strategy to guide the selection of mismatched donors when matched donors are unavailable remains an unmet need in HCT. The need is particularly acute for HLA-B because of its extreme polymorphism within the peptide-binding region. We uncovered a role for the HLA-B leader in outcome after HLA-B -mismatched HCT. The leader discloses that HLA-B mismatches are not equally deleterious; furthermore, the shared and the mismatched allotypes all contribute to outcome. GVHD risk is increased when the non-shared HLA-B allotypes have different leaders, and when the shared HLA-B contributes an M leader. When HLA-matched donors are unavailable, the leader can be useful in identifying high-risk HLA-B mismatches that should be avoided. Traditional concepts posit that risks are conferred by the HLA mismatch itself and current practice places emphasis on the donor's HLA mismatch exclusively. In our study, transplantations with one HLA-B mismatch provided a model for evaluating the clinical significance of both non-shared and shared allotypes. Comparison of haplotypes that differed for the leaders but not haplotype-linked HLA-E, KIR ligands, and HLA-Bw removed the potential contribution by these variables. Dissection of effects of non-shared allotypes from those of the shared allotype suggests that GVHD is a complex clinical phenotype related to the biology of leaders and to genetic distance. That both HLA haplotypes contribute to the immune response has been shown in HLA-associated diseases, 10,11,20 but the findings are novel in transplantation in which the focus has traditionally been the donor HLA mismatch. 2 Notably, patients with the MT genotype present an entirely new approach for reducing GVHD risk because they encode one M leader and one T leader allotype, and GVHD risk depends on whether matching the donor should be attempted for the M leader or the T leader allotype. When matched donors are unavailable, patients with the MT genotype benefit not only from leader matching but also from sharing a T leader allotype with their donor. Furthermore, patients benefit when the non-shared leader-matched allotypes are allele-mismatched rather than antigen-mismatched. For the 94·6% (1378 of 1457) of patients in need of a transplantation (MT and TT), the frequency of donors in the current 2019 US registry suggests that consideration of leader lineage is feasible in clinical practice. The use of phylogeny to group HLA-B allotypes into two functional lineages according to a polymorphism that is not currently tested in clinical practice, provides a novel approach for identifying combinations of mismatched allotypes that are better tolerated (mismatching between allotypes from the same leader lineage, termed leader-matched) than other combinations (mismatching between allotypes from different leader lineages, termed leader-mismatched). The specific allotypes within each leader lineage would not otherwise have been predicted had sequence features within the peptide-binding region been used as the basis for comparing pairwise allotypes. In this way, the delineation of HLA-B allotypes by their leader lineage might enhance patient care and further understanding of the immunobiology of GVHD. The novel findings in this retrospective study are being independently validated and warrant further research in prospective trials. A limitation of the current study is that it was not designed to test specific mechanisms through which the HLA-B leader influences GVHD, and they remain to be elucidated in the future with functional models. Nonetheless, the association of distance with GVHD supports T-cell recognition of the peptide-binding region. The contribution of the shared allotype to GVHD implicates a feature of M lineage allotypes, either the HLA-B leader itself or a proxy in positive linkage disequilibrium with the leader dimorphism. Although the absence of correlation between HLA-A expression, GVHD, and leader genotype makes HLA-E expression a less promising candidate, 10,11 the differential effect of HLA-E*01:03 on outcome still leaves open the possibility of cytotoxic T cell with or without CD94/NKG2 recognition of HLA-E variation. HLA-E*01:01 and E*01:03 were the dominant alleles in the transplantation cohort, similar to other populations. 9,25 A larger number of transplantations will be required to address the significance of rare HLA-E variation, the role of regulatory regions, 26 HLA-G , 27 receptor diversity and affinity, 28 and to examine the leader effect in other mismatched populations including two-locus mismatched unrelated donor, haploidentical and cord blood transplantations, and with different immunosuppression regimens including post-transplant cyclophosphamide. We did not observe an association between leaders and relapse. Whether the underlying leukaemia could alter HLA expression remains to be defined. The relative contribution of NK and T-cell pathways to GVHD remains an important question, information which might clarify a role for pharmacological HLA-E/NKG2A blockade if HLA-E/NKG2A are confirmed to be target molecules. 29 In conclusion, our preliminary findings suggest that HLA-B serves as a cornerstone of the immune response, playing a key role in the development of GVHD. The HLA-B leader is a sequence feature outside of the peptide-binding region that is not currently considered in the support of patients undergoing HCT. If validated in prospective studies, consideration of the HLA-B leader might enhance donor selection when matched donors are unavailable. Most patients in need of a transplantation have the MT or TT leader genotype, for whom donors who are leader-matched and share a T leader allotype are preferred. The high risk of GVHD associated with M leader allotypes supports consideration of better immunosuppressive regimens for patients with MM and MT genotypes, which is readily defined by the patient's HLA-B tissue type. Contributors EWP and MC designed the study. All authors collected the data. COh, MJM, PS, and TG did statistical analysis. EWP drafted the manuscript. All authors critically reviewed and edited the manuscript and approved the final version. Declarations of interests EWP, TG, MH, MM, CM, PS, and SRS report grants from the National Institutes of Health. MH and SRS report grants from the US Office of Naval Research. MH reports grants from Actinium Pharmaceuticals, Amgen, Amneal Biosciences, Angiocrine Bioscience, Anthem, Bluebird Bio, Bristol-Myers Squibb, Chimerix, CSL Behring, Cyto-Sen Therapeutics, Daiicho Sankyo, Gamida Cell, GlaxoSmithKline, Incyte Corporation, Janssen, Jazz Pharmaceuticals, Kite Pharma, Mesoblast, Miltenyi Biotech, Neovii Biotech, Oncoimmune, Pfizer, Pharmacyclics LLC, Regeneron, Sanofi, Seattle Genetics, Shire, Takeda, Medac; and grants and consulting fees from Magenta. MC and COh report support from the Frederick National Laboratory for Cancer Research. JV reports grants from the Swiss FNRS and the Philanthropy Settlement Foundation and personal fees from Astellas and Onelambda. All other authors declare no competing interests. Acknowledgments This study was supported by grants from the National Institutes of Health , USA ( AI069197 to EWP, TG, PS, MM, MH, CM, and SRS; CA100019 to EWP, TG, PS, MM, CM; CA18029 to EWP, MM, and TG; CA72978 to EWP; CA015704 to TG and PS; 5U24CA076518 to MH and SRS; HL069294 to MH and SRS); the US Office of Naval Research ( N00014-17-1-2388 and N00014-17-1-2850 to MH and SRS); Swiss FNRS N°310030_173237/1 and the Philanthropy Settlement Foundation to JV. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research , under contract number HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the National Institutes of Health, Frederick National Lab, Center for Cancer Research. The views expressed in this article do not necessarily reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. We thank Mike Haagenson, Dawn Miller, and Mark Gatterman for outstanding support. Funding Information: This study was supported by grants from the National Institutes of Health, USA (AI069197 to EWP, TG, PS, MM, MH, CM, and SRS; CA100019 to EWP, TG, PS, MM, CM; CA18029 to EWP, MM, and TG; CA72978 to EWP; CA015704 to TG and PS; 5U24CA076518 to MH and SRS; HL069294 to MH and SRS); the US Office of Naval Research (N00014-17-1-2388 and N00014-17-1-2850 to MH and SRS); Swiss FNRS N?310030_173237/1 and the Philanthropy Settlement Foundation to JV. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the National Institutes of Health, Frederick National Lab, Center for Cancer Research. The views expressed in this article do not necessarily reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. We thank Mike Haagenson, Dawn Miller, and Mark Gatterman for outstanding support. Publisher Copyright: © 2020 Elsevier Ltd
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