HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation.

Jean-Marie Tiercy

doi:10.3389/fimmu.2014.00216

Abstract

An increasingly larger fraction of patients with hematological diseases are treated by hematopoietic stem cells transplantation (HSCT) from HLA matched unrelated donors. Polymorphisms of HLA genes represent a major barrier to HSCT because HLA-A, -B, -C and DRB1 incompatibilities confer a higher risk of acute graft-versus-host disease (aGVHD) and mortality. Although >22 million volunteer HLA-typed donors are available worldwide, still a significant number of patients do not find a highly matched HSC donor. Because of the large haplotypic diversity in HLA-B–C associations, incompatibilities occur most frequently at HLA-C, so that unrelated donors with a single HLA-C mismatch often represent the only possible choice. The ratio of HLA-C-mismatched HSCT over the total number of transplants varies from 15 to 30%, as determined in 12 multicenter studies. Six multicenter studies involving >1800 patients have reported a 21–43% increase in mortality risk. By using in vitro cellular assays, a large heterogeneity in T-cell allorecognition has been observed. Yet the permissiveness of individual HLA-C mismatches remains poorly defined. It could be linked to the position and nature of the mismatched residues on HLA-C molecules, but also to variability in the expression levels of the mismatched alleles. The permissive C*03:03–03:04 mismatch is characterized by full compatibility at residues 9, 97, 99, 116, 152, 156, and 163 reported to be key positions influencing T-cell allorecognition. With a single difference among these seven key residues the C*07:01–07:02 mismatch might also be considered by analogy as permissive. High variability of HLA-C expression as determined by quantitative RT-PCR has been observed within individual allotypes and shows some correlation with A–B–C–DRB1 haplotypes. Thus in addition to the position of mismatched amino acid residues, expression level of patient’s mismatched HLA-C allotype might influence T-cell allorecognition, with patients low expression-C alleles representing possible permissive mismatches.

Highlights

HLA compatibility is a crucial parameter that influences the clinical outcome of hematopoietic stem cells transplantation (HSCT)
In most transplant centers matching at HLA-A, -B, -C, DRB1, and DQB1 loci, a so-called 10/10 match, is the gold standard for unrelated donor selections [1,2,3]
Single DQB1 mismatches appear to be better tolerated than mismatches at other loci, they have an additive effect to A, B, C, DRB1 loci [1,2,3,4]

Summary

INTRODUCTION

HLA compatibility is a crucial parameter that influences the clinical outcome of hematopoietic stem cells transplantation (HSCT). Ten clinical studies including >100 patients have addressed the impact of HLA-C allele or antigen disparities and they all report a deleterious role of C-mismatches. RELATIVE IMPORTANCE OF INDIVIDUAL HLA-C MISMATCHES In a first attempt from the JMDP to disclose individual HLAC mismatches with higher clinical relevance, seven HLA-C allele mismatched combinations were reported to confer a higher risk of acute GVHD [29]. Using a random forest statistical analysis 13 amino acid (aa) substitutions in the HLA class I peptide-binding pocket have been reported to be associated with increased mortality at day 100 in low/intermediate risk patients transplanted with HSC from a single HLA class I mismatched donor, with positions 9, 99, 116, and 156 being the most clinically relevant [33]. It is relevant to note that the C*03:03–03:04 mismatch did result in a negative or weakly

No RIC

Findings

Residues in the PBS