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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1417-1424.
Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-04-1279.
Submitted April 24, 2003
Accepted October 4, 2003
A T cell epitope encoded by a subset of HLA-DPB1 alleles determines non-permissive mismatches for hematological stem cell transplantation
Elisabetta Zino, Guido Frumento, Sarah Marktel, Maria Pia Sormani, Francesca Ficara, Simona Di Terlizzi, Anna Maria Parodi, Ruhena Sergeant, Miryam Martinetti, Andrea Bontadini, Francesca Bonifazi, Daniela Lisini, Benedetta Mazzi, Silvano Rossini, Paolo Servida, Fabio Ciceri, Chiara Bonini, Edoardo Lanino, Giuseppe Bandini, Franco Locatelli, Jane Apperley, Andrea Bacigalupo, Giovanni B Ferrara, Claudio Bordignon, and Katharina Fleischhauer*
HLA Tissue Typing Laboratory, Immunohematology and Transfusion Medicine Service, IRCCS Istituto Scientifico H. S. Raffaele, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), IRCCS Istituto Scientifico H. S. Raffaele, Milan, Italy
Immunogenetics Laboratory, National Institute for Cancer Research, Genoa, Italy
Department of Hematology, Imperial College, London, United Kingdom
Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research, Genoa, Italy
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), IRCCS Istituto Scientifico H. S. Raffaele, Milan, Italy
HLA Tissue Typing Laboratory, Immunohematology and Transfusion Medicine Service, IRCCS Policlinico S. Matteo, Pavia, Italy
HLA Tissue Typing Laboratory, Immunohematology and Transfusion Medicine Service, University of Bologna, Ospedale S.Orsola-Malpighi, Bologna, Italy
Institute of Hematology and Medical Oncology, University of Bologna, Ospedale S.Orsola-Malpighi, Bologna, Italy
Department of Pediatric Hematology-Oncology, IRCCS Policlinico S. Matteo, Pavia, Italy
HLA Tissue Typing Laboratory, Immunohematology and Transfusion Medicine Service, IRCCS Istituto Scientifico H. S. Raffaele, Milan, Italy
Hematology and Bone Marrow Transplantation Unit, IRCCS S. Raffaele, Milan, Italy
Cancer Immunotherapy and Gene Therapy Program, IRCCS S. Raffaele, Milan, Italy
Department of Pediatric Hematology-Oncology, IRCCS G. Gaslini, Genoa, Italy
Department of Hematology, Ospedale San Martino, Genoa, Italy
Department of Oncology, Biology and Genetics, University of Genoa, Genoa, Italy; Immunogenetics Laboratory, National Institute for Cancer Research, Genoa, Italy
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), IRCCS Istituto Scientifico H. S. Raffaele, Milan, Italy; Hematology and Bone Marrow Transplantation Unit, IRCCS S. Raffaele, Milan, Italy; Cancer Immunotherapy and Gene Therapy Program, IRCCS S. Raffaele, Milan, Italy
* Corresponding author; email: fleischhauer.katharina{at}hsr.it.
The importance of human leucocyte antigen (HLA)-DPB1 matching for the outcome of allogeneic hematological stem cell (HSC) transplantation is controversial. We have previously identified HLA-DPB1*0901 as target of cytotoxic T cells mediating in vivo rejection of a HSC allograft. Here we show that HLA-DPB1*0901 encodes a T cell epitope shared by a subset of DPB1 alleles which determines non-permissive 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 non-permissive HLA-DPB1 mismatches. Retrospective evaluation of 118 transplants showed that the presence of non-permissive HLA-DPB1 mismatches was correlated with significantly increased hazards of acute grade II-IV graft versus host disease (HR=1.87, p=0.046) and transplant related mortality (HR=2.69, p=0.027) but not of relapse (HR=0.98, p=0.939), as compared to the permissive group. There was also a marked but statistically not significant increase in the hazards of overall mortality (HR=1.64, p=0.1). These data suggest that biological characterization of in vivo alloreactivity can be a tool for definition of clinically relevant non-permissive HLA mismatches for unrelated HSC transplantation.
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