High HLA-DP Expression and Graft-versus-Host Disease.
BACKGROUND
Transplantation of hematopoietic cells from unrelated donors can cure blood disorders but carries a significant risk of acute graft-versus-host disease (GVHD). The risk is higher when the recipient and donor are HLA-DPB1-mismatched, but the mechanisms leading to GVHD are unknown. The HLA-DPB1 regulatory region variant rs9277534 is associated with HLA-DPB1 expression. We tested the hypothesis that the GVHD risk correlates with the rs9277534 allele linked to the mismatched HLA-DPB1 in the recipient.


METHODS
We genotyped rs9277534 in 3505 persons to define rs9277534-DPB1 haplotypes. Among 1441 recipients of transplants from HLA-A,B,C,DRB1,DQB1-matched unrelated donors with only one HLA-DPB1 mismatch, linkage of the rs9277534 A and G alleles to the mismatched HLA-DPB1 was determined. HLA-DPB1 expression was assessed by means of a quantitative polymerase-chain-reaction assay. The risk of acute GVHD among recipients whose mismatched HLA-DPB1 allele was linked to rs9277534G (high expression) was compared with the risk among recipients whose mismatched HLA-DPB1 allele was linked to rs9277534A (low expression).


RESULTS
The mean HLA-DPB1 expression was lower with rs9277534A than with rs9277534G. Among recipients of transplants from donors with rs9277534A-linked HLA-DPB1, the risk of acute GVHD was higher for recipients with rs9277534G-linked HLA-DPB1 mismatches than for recipients with rs9277534A-linked HLA-DPB1 mismatches (hazard ratio, 1.54; 95% confidence interval [CI], 1.25 to 1.89; P<0.001), as was the risk of death due to causes other than disease recurrence (hazard ratio, 1.25; 95% CI, 1.00 to 1.57; P=0.05).


CONCLUSIONS
The risk of GVHD associated with HLA-DPB1 mismatching was influenced by the HLA-DPB1 rs9277534 expression marker. Among recipients of HLA-DPB1-mismatched transplants from donors with the low-expression allele, recipients with the high-expression allele had a high risk of GVHD. (Funded by the National Institutes of Health and others.).
From the Division of Clinical Research, Fred Hutchinson Cancer Research Center (E.W.P., M.M., T.G., P.S.), and the Department of Medicine, University of Washington School of Medicine (E.W.P.) - both in Seattle; Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Frederick National Laboratories for Cancer Research, Frederick, MD (C.O., M.C.); Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston (M.C.); Center for International Blood and Marrow Transplant Research, Minneapolis (M.D.H., S.R.S.); and Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee (M.M.H., T.W.).
Effie W
EW
Petersdorf
Mari
M
Malkki
Colm
C
O'hUigin
Mary
M
Carrington
Ted
T
Gooley
Michael D
MD
Haagenson
Mary M
MM
Horowitz
Stephen R
SR
Spellman
Tao
T
Wang
Philip
P
Stevenson
D000293:Adolescent; D000328:Adult; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012045:Regulatory Sequences, Nucleic Acid; D061349:Unrelated Donors; D055815:Young Adult
D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen