HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

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.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

“…In this respect, analogy with HLA-C is instructive, as this is the most recent HLA gene to be part of the search criteria for an unrelated donor. 47 Indeed, 68% (vs 88% for MICA) of donors matched at high resolution for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 were found to be also a full match at HLA-C. 48 Matching at this locus diminishes the risk for acute GVHD (HR, 1.19-2.02) 47 in near-identical proportions as that for MICA. Finally, for patients at high risk for relapse because of advanced or aggressive malignancy, the risk for GVHD associated with the use of a MICA-mismatched donor could be balanced against the potential benefits of lowered disease recurrence via the observed graft-versus-leukemia effect.…”

Quantification of classical HLA class I mRNA by allele‐specific, real‐time polymerase chain reaction for most Han individuals

“…It has been confirmed that the expression levels of different alleles on the same HLA class I locus can vary dramatically . This differential HLA expression according to alleles could have a broad clinical impact, such as influencing virus infection control, risk of autoimmune disorders, and haematopoietic stem cell transplantation (HSCT) outcomes . However, due to the extreme polymorphism and similarity of HLA alleles, detecting the protein of a particular allele with a specific antibody is challenging .…”

How to select the best available related or unrelated donor of hematopoietic stem cells?

“…1,[5][6][7]11,19,20 A comprehensive review of the impact of HLA-C incompatibilities on clinical outcome has been published recently. 21 In a large CIBMTR study on patients with chronic myeloid leukemia no significant difference in overall survival was noted between patients transplanted with HLA class I or class II mismatched grafts. 22 With regards to HLA class II disparities, several studies indicated that HLA-DQB1 disparities are not associated with mortality.…”