A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation.
The importance of HLA-DPB1 matching for the outcome of allogeneic hematologic stem cell (HSC) transplantation is controversial. We have previously identified HLA-DPB1*0901 as a target of cytotoxic T cells mediating in vivo rejection of an HSC allograft. Here we show that HLA-DPB1*0901 encodes a T-cell epitope shared by a subset of DPB1 alleles that determines nonpermissive mismatches for HSC transplantation. Several T-cell clones obtained from the patient at the time of rejection showed HLA-DP restricted recognition of allogeneic targets expressing HLA-DPB1*0901, *1001, *1701, *0301, *1401, and *4501, but not other alleles. Based on these findings, we developed an algorithm for prediction of nonpermissive HLA-DPB1 mismatches. Retrospective evaluation of 118 transplantations showed that the presence of nonpermissive HLA-DPB1 mismatches was correlated with significantly increased hazards of acute grade II to IV graft-versus-host disease (HR = 1.87, P =.046) and transplantation-related mortality (HR = 2.69, P =.027) but not relapse (HR = 0.98, P =.939), as compared with the permissive group. There was also a marked but statistically not significant increase in the hazards of overall mortality (HR = 1.64, P =.1). These data suggest that biologic characterization of in vivo alloreactivity can be a tool for definition of clinically relevant nonpermissive HLA mismatches for unrelated HSC transplantation.
HLA Tissue Typing Laboratory, Immunohematology and Transfusion Medicine Service, San Raffaele Telethon Institue for Gene Therapy, Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico H. S. Raffaele, via Olgettina 60, I-20132 Milan, Italy.
Elisabetta
E
Zino
Guido
G
Frumento
Sarah
S
Marktel
Maria Pia
MP
Sormani
Francesca
F
Ficara
Simona
S
Di Terlizzi
Anna Maria
AM
Parodi
Ruhena
R
Sergeant
Miryam
M
Martinetti
Andrea
A
Bontadini
Francesca
F
Bonifazi
Daniela
D
Lisini
Benedetta
B
Mazzi
Silvano
S
Rossini
Paolo
P
Servida
Fabio
F
Ciceri
Chiara
C
Bonini
Edoardo
E
Lanino
Giuseppe
G
Bandini
Franco
F
Locatelli
Jane
J
Apperley
Andrea
A
Bacigalupo
Giovanni Battista
GB
Ferrara
Claudio
C
Bordignon
Katharina
K
Fleischhauer
D000465:Algorithms; D000483:Alleles; D000595:Amino Acid Sequence; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology; D006682:HLA-DP Antigens / Q000235:genetics / Q000276:immunology*; D059868:HLA-DP beta-Chains; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007519:Isoantigens / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D007519:Isoantigens