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The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis
Date Issued
2021
Author(s)
Mytilineos, Daphne
Tsamadou, Chrysanthi
Neuchel, Christine
Platzbecker, Uwe
Bunjes, Donald
Schub, Natalie
Wagner-Drouet, Eva
Kröger, Nicolaus
Murawski, Niels
Einsele, Hermann
Schaefer-Eckart, Kerstin
Freitag, Sebastian
Casper, Jochen
Kaufmann, Martin
Dürholt, Mareike
Hertenstein, Bernd
Klein, Stefan
Ringhoffer, Mark
Mueller, Carlheinz R.
Frank, Sandra
Schrezenmeier, Hubert
Fuerst, Daniel
Mytilineos, Joannis
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.