title: Frequency and targeted detection of HLA-DPB1 T cell epitope disparities relevant in unrelated hematopoietic stem cell transplantation.
abstract: The majority of unrelated donor (UD) hematopoietic stem cell (HSC) transplants are performed across HLA-DP mismatches, which, if involving disparity in a host-versus-graft (HVG) direction for an alloreactive T cell epitope (TCE), have been shown by our group to be associated with poor clinical outcome in 2 cohorts of patients transplanted for hematopoietic malignancies and beta-thalassemia, respectively. Using site-directed mutagenesis of DPB1*0901, we show here that the TCE is abrogated by the presence of amino acids LFQG in positions 8-11 of the DP beta-chain. Based on this and on alloreactive T cell responsiveness, we have determined the presence or absence of the TCE for 72 DPB1 alleles reported in the ethnic groups representative of the worldwide UD registries, and predict that 67%-87% (mean 77%) of UD recipient pairs will not present a DPB1 TCE disparity in the HVG direction. We developed and validated in 112 healthy Italian blood donors an innovative approach of DPB1 epitope-specific typing (EST), based on 2 PCR reactions. Our data show that DPB1 TCE disparities may hamper the clinical success of a considerable number of transplants when DPB1 matching is not included into the donor selection criteria, and that a donor without DPB1 TCE disparities in the HVG direction can be found for the majority of patients. Moreover, the study describes the first protocol of targeted epitope-specific DPB1 donor-recipient matching for unrelated HSC transplantation. This protocol will facilitate large-scale retrospective clinical studies warranted to more precisely determine the clinical relevance of DPB1 TCE disparities in different transplant conditions.
authors: The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Milano, Italy.
authors: Elisabetta
authors: E
authors: Zino
authors: Luca
authors: L
authors: Vago
authors: Simona
authors: S
authors: Di Terlizzi
authors: Benedetta
authors: B
authors: Mazzi
authors: Laura
authors: L
authors: Zito
authors: Elisabetta
authors: E
authors: Sironi
authors: Silvano
authors: S
authors: Rossini
authors: Chiara
authors: C
authors: Bonini
authors: Fabio
authors: F
authors: Ciceri
authors: Maria Grazia
authors: MG
authors: Roncarolo
authors: Claudio
authors: C
authors: Bordignon
authors: Katharina
authors: K
authors: Fleischhauer
mesh_terms: D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005006:Ethnicity; D005787:Gene Frequency; D006682:HLA-DP Antigens / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D059868:HLA-DP beta-Chains; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000208:ethnology / Q000379:methods*; D006650:Histocompatibility Testing / Q000379:methods* / Q000592:standards; D006789:Host vs Graft Reaction / Q000235:genetics; D006801:Humans; D007558:Italy; D016297:Mutagenesis, Site-Directed; D014019:Tissue Donors; D014184:Transplantation, Homologous; D017086:beta-Thalassemia / Q000628:therapy
chemical_list: D018984:Epitopes, T-Lymphocyte; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen