Faculty Collaboration Database

In silico prediction of nonpermissive HLA-DPB1 mismatches in unrelated HCT by functional distance. Blood Adv 2018 Jul 24;2(14):1773-1783

Date

07/26/2018

Pubmed ID

30042143

Pubmed Central ID

PMC6058232

DOI

10.1182/bloodadvances.2018019620

Scopus ID

2-s2.0-85071081213 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Arrieta-Bolaños E, Crivello P, Shaw BE, Ahn KW, Wang HL, Verneris MR, Hsu KC, Pidala J, Lee SJ, Fleischhauer K, Spellman SR

Authors

Kwang Woo Ahn PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Bronwen E. Shaw MBChB, PhD Center Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Child
Child, Preschool
Computer Simulation
Disease-Free Survival
Female
Graft vs Host Disease
HLA-DRB1 Chains
Hematologic Neoplasms
Hematopoietic Stem Cell Transplantation
Humans
Infant
Male
Middle Aged
Models, Biological
Predictive Value of Tests
Survival Rate