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

• Main Authors: Daphne Mytilineos, Chrysanthi Tsamadou, Christine Neuchel, Uwe Platzbecker, Donald Bunjes, Natalie Schub, Eva Wagner-Drouet, Gerald Wulf, Nicolaus Kröger, Niels Murawski, Hermann Einsele, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Martin Kaufmann, Mareike Dürholt, Bernd Hertenstein, Stefan Klein, Mark Ringhoffer, Carlheinz R. Mueller, Sandra Frank, Hubert Schrezenmeier, Daniel Fuerst, Joannis Mytilineos
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-01-01
• Series: Frontiers in Immunology
• Subjects: stem cell transplantation; graft-versus-host-disease; HLA-DPB1; HLA-DPB1 expression; HLA-DPB1-permissiveness
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2020.614976/full

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.