Impact of HLA Epitope Matching on Outcomes After Unrelated Bone Marrow Transplantation.

Makoto Iwasaki,Yukiyasu Ozawa,Hidenori Tanaka,Yoshinobu Kanda,Yoshiko Atsuta,Takahide Ara,Noriko Doki,Naoyuki Uchida,Keisuke Kataoka,Takahiro Fukuda,Makoto Onizuka,Tatsuo Ichinohe,Takahiko Sato,Tetsuya Eto,Shuichi Ota,Satoko Morishima,Junya Kanda,Yuta Katayama,Takero Shindo

doi:10.3389/fimmu.2022.811733

Abstract

The significance of antibody-identified epitopes stimulating humoral alloimmunity is not well understood in the identification of non-permissive human leukocyte antigen (HLA) mismatching patterns in hematopoietic stem cell transplantation (HSCT). This was a retrospective study in a cohort of 9,991 patients who underwent their first HSCT for hematologic malignancies from unrelated bone marrow donors in the Transplant Registry Unified Management Program (TRUMP). HLA eplet mismatches (EMM) were quantified using HLAMatchmaker (HLAMM). The median age of patients was 48 years (range, 16 to 77). The number of EMM in recipient-donor pairs in our study population ranged from 0 to 37 in HLA class I (median, 0) and 0 to 60 in HLA class II (median, 1). In addition to the known high-risk mismatch patterns in the Japanese cohort, HLA-C EMM in the GVH direction was associated with a significantly higher risk for grade III-IV aGVHD, leading to a higher risk of non-relapse mortality and lower overall survival (compared with HLA-C matched patients, HR 1.67, 95% CI 1.44–1.95; HR 1.39, 95% CI 1.25–1.54; HR 1.20, 95% CI 1.10–1.30, respectively). HLAMM-based epitope matching might be useful for identifying patients who are at high risk for serious complications after HSCT from HLA mismatched unrelated donors.

Highlights

Human leukocyte antigen (HLA) disparity causes an immune reaction between recipient and donor cells after hematopoietic stem cell transplantation (HSCT)
We found a significant association of antibody-identified human leukocyte antigen (HLA) epitopes quantified by HLAMM with HSCT outcomes and a high-risk HLA-C mismatch pattern other than amino-acid substitutions that are known to be associated with a high risk for severe aGVHD, leading to a higher incidence of non-relapse mortality (NRM) and poor overall survival (OS) after transplantation
We found that class I eplet mismatches (EMM) in the GVH direction had a negative impact on the incidence of severe aGVHD and class II EMM in the HVG direction had a negative impact on neutrophil engraftment

Summary

Introduction

Human leukocyte antigen (HLA) disparity causes an immune reaction between recipient and donor cells after hematopoietic stem cell transplantation (HSCT). Extensive studies have demonstrated that HLA disparity is associated with a higher risk of graft-versus-host disease (GVHD) and a longer time to engraftment, leading to a poor prognosis of HLA-mismatched recipient-donor pairs in transplantation from unrelated donors. Studies focused on the number of mismatched HLA antigens or alleles, and the quantification of HLA antigens and alleles is prioritized in donor selection [1, 2]. Prognostic HLA mismatching patterns have been investigated based on HLA supertypes and haplotypes [7– 9]. It is not yet fully understood what underlies the heterogeneous effect of HLA mismatching on HSCT outcomes

Objectives

Methods

Results

Conclusion