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HLA-B leader and cord-blood transplantation
HLA-B alleles,28 the sheer number of polymorphisms pres- ents a challenge in understanding the immunogenetic basis of transplant outcome. We surmised that if HLA-B alleles are described by two lineages, one family that encodes M-leaders and one that encodes T leaders, that this dichotomy may aid the identification of HLA-B mis- matches that influence GvHD and relapse. In CBT, HLA- C and high-resolution matching influence clinical out- come.25-27 A limitation of the current analysis is the lack of HLA-C and high-resolution typing and although the basic principle that the leader informs cord blood transplant outcomes can be readily tested, the results of the current study require validation in an independent cohort.
We identified two potential associations between the HLA-B leader and cord blood outcomes among HLA-A, -DRB1-matched transplants with one HLA-B mismatch. First, as the number of M-leader(s) in the cord blood unit increased, the risk of relapse increased. Secondly, non- relapse mortality was lower when the mismatched alleles were from different lineages and when the matched allele encoded an M leader than when the alleles were from the same lineage and the matched allele contributed a T leader even after adjustment for various factors including the use of ATG. Interestingly, HLA-B leader genotype and matching did not definitively correlate with GvHD risk, and in this way, the impact of the leader on outcome differs between cord blood and unrelated donor transplantation.19,20 The associations of the HLA-B leader to outcome were observed among HLA-A and -DRB1-matched transplants with one HLA-B mismatch, and future validation of these findings in large independent populations is warranted.
The current study was not designed to identify the puta- tive mechanisms of leader-associated effects on relapse and mortality and there many be several potential reasons for the different associations observed in CBT and unrelated donor transplantation. Unrelated transplantation and CBT procedures differ with respect to GvHD prophylaxis regi- mens as well as graft characteristics. GvHD has been reported to be lower in children who have received a cord blood or HLA-identical sibling bone marrow transplant.6 Similarly, the incidence of relapse and grades III-IV acute GvHD were lower in cord blood compared to matched or mismatched unrelated donor transplantation for leukemia.12 Compared to unrelated grafts, immature cord blood cells might be less likely activated during the allore- action following transplant while NK-cell activation appears early after cord blood transplantation mitigating the risk of relapse.29 Possible mechanisms for higher relapse with lower non-relapse mortality among M-leader trans- plants could be related to the role of M-leader associated HLA ligands in both T-cell and NK-cell alloreactivity. M leaders influence inhibitory NK alloresponses.30,31 The exon 1-encoded leader is physicially linked to exons 2 and 3 that define the peptide-binding region of HLA-B molecules, and the peptide-binding region of M leader linked allotypes have striking differences when compared to T leader linked allotypes. Non-relapse mortality might include infectious causes of death for which both NK and T cells may play critical roles. NK surveillance in de novo and reactivation of viral infections after cord blood transplanta- tion may shape relapse through the enhancement of NK maturation.32-36 We hypothesize that inhibitory NK responses involved in M leader associated relapse might occur concurrently with T-cell recognition of viral or bacte- rial peptide/HLA-B complexes. These mechanisms could
manifest as higher relapse with lower non-relapse mortali- ty. Together with previous studies that have implicated NK KIR and HLA ligand interactions in relapse,8,18 the observa- tions from the current study provide additional evidence for a potential role of the innate immune system in CBT out- comes. Future studies in double CBT may provide new information on key maternal-fetal interactions underpin- ning immune reactivity as a potential mechanism for the lower GvHD and relapse rates observed in CBT compared to adult hematopoietic stem cells.
Although recent data suggest that more comprehensive HLA matching between the patient and the cord blood unit is associated with improved outcomes,25,26,37 a major advantage of cord blood transplantation is the less strin- gent requirement for matching than is needed in unrelated donor transplantation. In this way, both cord blood trans- plantation and haploidentical transplantation significantly advance the availability of these curative modalities. The inherently low GvHD rates coupled with the ability to lower relapse through the judicious selection of cord blood units based on the HLA-B leader, enhances the cur- ative potential of CBT and provides rationale to explore the leader in haploidentical transplantation.
The general clinical applicability of our findings to enhance CBT is facilitated by the one-to-one correlation of the leader to each serologically-defined HLA-B deter- minant, a feature that significantly simplifies the selection of mismatched units when matched units are not avail- able, as the assignment of the leader requires only sero- logic-level definition of HLA-B. The observations from the current analysis suggest that when an MM or MT patient has multiple HLA-A, -DRB1-matched cord blood units, selection of leader-mismatched units with a shared M leader allele may help to lower non-relapse mortality. The HLA-B leader might also have implications for NK immunotherapy.38-40 The frequencies of TT, MT and MM in cord blood units and patients in the current study, together with those observed in unrelated donor trans- plants and over 2 million US volunteer donors, suggest that patients will have choices.
Disclosures
EG reports grant from the Centre Scientifique de Monaco. EWP, TG, CM report grants from the National Institutes of Health. TG reports Kiadis Pharma and Regimmune. No other disclosures were reported.
Contributions
EWP and EG designed the study; EG, FV, CK, AM, CM, SQ, VR, RT, CC, HR and AR assembled the data; TG per- formed statistical analysis; EWP drafted the manuscript. All authors critically reviewed, edited the manuscript and approved the final version.
Acknowledgments
We are indebted to the clinical transplant teams who performed the transplants described in the study (Online Supplementary Table S1).
Funding
Supported by a grant to Eurocord (to EG) from the Centre Scientifique de Monaco; grants from the National Institutes of Health, USA (AI069197 to EWP, TG, CMK; CA100019 to EWP, TG, CMK; CA18029 to EWP and TG; CA72978 to EWP; CA015704 to TG).
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