title: Specific B cell tolerance is induced by cyclosporin A plus donor-specific blood transfusion pretreatment: prolonged survival of MHC class I disparate cardiac allografts.
abstract: Donor-specific blood transfusion (DST), designed to prolong allograft survival, sensitized recipients of the high-responder PVG-RT1u strain, resulting in accelerated rejection of MHC-class I mismatched (PVG-R8) allografts. Rejection was found to be mediated by anti-MHC class I (Aa) alloantibody. By pretreating recipients 4 wk before grafting with cyclosporin A (CsA) daily (x7), combined with once weekly (x4) DST, rejection was prevented. The investigation explores the mechanism for this induced unresponsiveness. CD4 T cells purified from the thoracic duct of CsA/DST-pretreated RT1u rats induced rejection when transferred to R8 heart-grafted RT1u athymic nude recipients, indicating that CD4 T cells were not tolerized by the pretreatment. To determine whether B cells were affected, nude recipients were pretreated, in the absence of T cells, with CsA/DST (or CsA/third party blood) 4 wk before grafting. The subsequent transfer of normal CD4 T cells induced acute rejection of R8 cardiac allografts in third party- but not DST-pretreated recipients; prolonged allograft survival was reversed by the cotransfer of B cells with the CD4 T cells. Graft survival correlated with reduced production of anti-MHC class I (Aa) cytotoxic alloantibody. The results indicated that the combined pretransplant treatment of CsA and DST induced tolerance in allospecific B cells independently of T cells. The resulting suppression of allospecific cytotoxic Ab correlated with the survival of MHC class I mismatched allografts. The induction of B cell tolerance by CsA has important implications for clinical transplantation.
authors.affiliation: Immunology Research Group, Biological Sciences, Medical School, Manchester, United Kingdom.
authors.forename: C P
authors.initials: CP
authors.lastname: Yang
authors.forename: E
authors.initials: E
authors.lastname: Shittu
authors.forename: E B
authors.initials: EB
authors.lastname: Bell
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D001803:Blood Transfusion; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D003601:Cytotoxicity Tests, Immunologic; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects*; D007518:Isoantibodies / Q000096:biosynthesis / Q000633:toxicity; D018448:Models, Immunological; D051381:Rats; D011919:Rats, Inbred Strains; D011923:Rats, Nude; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; D016572:Cyclosporine