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

被引:27
作者
Arrieta-Bolanos, Esteban [1 ]
Crivello, Pietro [1 ]
Shaw, Bronwen E. [2 ]
Ahn, Kwang Woo [2 ]
Wang, Hai-Lin [2 ]
Verneris, Michael R. [3 ]
Hsu, Katharine C. [4 ]
Pidala, Joseph [5 ]
Lee, Stephanie J. [2 ,6 ]
Fleischhauer, Katharina [1 ]
Spellman, Stephen R. [7 ]
机构
[1] Univ Hosp Essen, Inst Expt Cellular Therapy, Hufelandstr 55, D-45122 Essen, Germany
[2] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA
[3] Univ Colorado, Pediat Bone Marrow Transplantat, Aurora, CO USA
[4] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA
[5] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA
[6] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA
[7] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA
基金
美国国家卫生研究院;
关键词
HLA CLASS-I; HEMATOPOIETIC-CELL TRANSPLANTATION; VERSUS-HOST-DISEASE; ACUTE GVHD; MARROW TRANSPLANTATION; T-CELLS; DONOR; EPITOPE; RISK; SELECTION;
D O I
10.1182/bloodadvances.2018019620
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1773 / 1783
页数:11
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