HLAMatchmaker-Defined Triplet Matching Is Not Associated with Better Survival Rates of Patients with Class I HLA Allele Mismatched Hematopoietic Cell Transplants from Unrelated Donors

Abstract

This report addresses the concept that permissible HLA mismatching, i.e. mismatches that do not generate an allogeneic response, in hematopoietic stem cell transplantation (HCT) can be determined with structural similarity of polymorphic regions. We have applied the triplet version of a structural algorithm called HLAMatchmaker that considers short sequences involving polymorphic amino acid residues on the molecular surface as key elements of immunogenic epitopes. The triplet matching effect was analyzed in a National Marrow Donor Program dataset consisting of 744 unrelated hematopoietic cell transplantation cases with one HLA-A,-B or -C mismatch and 1690 fully HLA-A,-B,-C,-DR,-DQ allele matched cases. In multivariate models adjusting for other significant clinical risk factors, the degree of triplet mismatching did not significantly correlate with patient survival, engraftment or acute graft versus host disease. Other structurally based strategies should be pursued to identify permissible HLA mismatches in HCT.

Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

“…[21][22][23][24][25] For HLA class II, structural variability has been extensively studied in the context of solid organ transplantation, with some in silico models predictive of antibody formation and/or kidney transplant outcome already entered into clinical use. 26, 27 These models did not prove equally valid for HCT outcome prediction, 23,28 probably reflecting the more complex nature of HLA-peptide recognition by the T-cell receptor (TCR) compared with allo-antibodies. 29,30 Here, we have addressed the functional role of AA polymorphism in HLA class II for clinical outcome of HCT in the context of nonpermissive TCE mismatches at HLA-DPB1, shown by some 4,9 but not all 31 multicenter studies to be associated with mortality after 10/10 HLA-matched unrelated HCT.…”

Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation

“…Although the use of a UD with a single HLA mismatch (7/8) increases access to transplantation, transplants from HLA mismatched donors are associated with significantly higher risks for mortality and morbidity compared with those from 8/8 HLA matched donors. [6][7][8][9][10] Several algorithms that score the risk associated with HLA mismatches based on the sharing of serologic epitopes 11 and the location 12 or physicochemical properties of the amino acid differences 13,14 have been developed. None of these, however, has proven useful in independent validation studies.…”

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

“…The humoral alloimmune response to HLA class I mismatches can be successfully predicted by the HLAMatchmaker algorithm (20,21). As HLAMatchmaker takes only Ab-accessible sites of the HLA molecules into consideration, it is not a suitable tool to predict T cell alloreactivity (22).…”