The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis.

D Mytilineos ,Daniel Fuerst,Stefan Klein,Gerald Wulf,Chrysanthi Tsamadou,Eva Wagner-Drouet,Bernd Hertenstein,Nicolaus Kröger,Sebastian Freitag,Mark Ringhoffer,Hermann Einsele,Sandra Frank,Mareike Dürholt,Hubert Schrezenmeier,Donald Bunjes,Joannis Mytilineos,Natalie Schub,Christine Neuchel,Jochen Casper,Martin Kaufmann,Uwe Platzbecker,Niels Murawski,Kerstin Schaefer‐Eckart ,Carlheinz Mueller

doi:10.3389/fimmu.2020.614976

Abstract

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.

Highlights

Allogeneic hematopoietic stem cell transplantation has become an established clinical treatment for various, otherwise often incurable diseases of the lympho-hematopoietic system
Retrospective genotyping of HLA-DPB1 locus in patients and their respective donors confirmed the high prevalence of HLADPB1 mismatches in both, 10/10 and 9/10 HLA-matched transplantations already reported elsewhere [7, 25, 26]
For the remainder of the transplantations the HLA-DPB1 mismatches were non-permissive with even sub

Summary

INTRODUCTION

Allogeneic hematopoietic stem cell transplantation has become an established clinical treatment for various, otherwise often incurable diseases of the lympho-hematopoietic system. Later it was discovered using cytotoxicity assays that HLA-DPB1 alleles may be grouped according to their T-cell immunogenicity into three groups [13] This led to the T-cell epitope matching algorithm, which allows grouping of DP-mismatches between patient and donor in permissive and non-permissive and which has been shown to associate with clinical outcome in large retrospective cohorts [7, 14]. Another proposed model relates to the expression levels of HLA-DPB1 mismatches, which is influenced by an SNP in the 3’UTR of HLA-DPB1 alleles (rs9277534) [15]. As this study represents a validation study of previous analyses, a significance level of 0.05 was considered sufficient for confirmation

RESULTS

DISCUSSION

ETHICS STATEMENT