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.