Specific B cell tolerance is induced by cyclosporin A plus donor-specific blood transfusion pretreatment: Prolonged survival of MHC class I disparatecardiac allografts

Donor-specific blood transfusion (DST), designed to prolong allograft survi val, sensitized recipients of the high-responder PVG-RT1(u) strain, resulti ng in accelerated rejection of MHC-class I mismatched (PVG-RS) allografts. Rejection was found to be mediated by anti-MHC class I (A(a)) alloantibody. By pretreating recipients 4 wk before grafting with cyclosporin A (CsA) da ily (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 RT1(u) rats induced rejection when transferred to RS heart-grafted RT1(u) athymic nude recipients, indicating that CD4 T cells were not tolerized by the pretreatm ent. To determine whether B cells were affected, nude recipients were pretr eated, 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-pretre ated recipients; prolonged allograft survival was reversed by the cotransfe r of B cells with the CD4 T cells. Graft survival correlated with reduced p roduction of anti-MHC class I (A(a)) cytotoxic alloantibody. The results in dicated that the combined pretransplant treatment of CsA and DST induced to lerance in allospecific B cells independently of T cells. The resulting sup pression of allospecific cytotoxic Ab correlated with the survival of MHC c lass I mismatched allografts, The induction of B cell tolerance by CsA has important implications for clinical transplantation.