In silico prediction of nonpermissive HLA-DPB1 mismatches in unrelated HCT by functional distance

Abstract: In silico prediction of high-risk donor–recipient HLA mismatches after unrelated donor (UD) hematopoietic cell transplantation (HCT) is an attractive, yet elusive, objective. Nonpermissive T-cell epitope (TCE) group mismatches were defined by alloreactive T-cell cross-reactivity for 52/80 HLA-DPB1 alleles (TCE-X). More recently, a numerical functional distance (FD) scoring system for in silico prediction of TCE groups based on the median impact of exon 2–encoded amino acid polymorphism on T-cell alloreactivity was developed for all DPB1 alleles (TCE-FD), including the 28/80 common alleles not assigned by TCE-X. We compared clinical outcome associations of nonpermissive DPB1 mismatches defined by TCE-X or TCE-FD in 8/8 HLA-matched UD-HCT for acute leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia between 1999 and 2011 (N = 2730). Concordance between the 2 models was 92.3%, with most differences arising from DPB1*06:01 and DPB1*19:01 being differently assigned by TCE-X and TCE-FD. In both models, nonpermissive mismatches were associated with reduced overall survival (hazard ratio [HR], 1.15, P < .006 and HR, 1.12, P < .03), increased transplant-related mortality (HR, 1.31, P < .001 and HR, 1.26, P < .001) as well as acute (HR, 1.16, P < .02 and HR, 1.22, P < .001) and chronic (HR, 1.20, P < .003 and HR, 1.22, P < .001) graft-versus-host disease (GVHD). We show that in silico prediction of nonpermissive DPB1 mismatches significantly associated with major transplant outcomes is feasible for any DPB1 allele with known exon 2 sequence based on experimentally elaborated FD scores. This proof-of-principle observation opens new avenues for developing HLA risk-prediction models in HCT and has practical implications for UD searches.