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 (×7), combined with once weekly (×4) 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.

Involution of Bursa Cloacalis (Fabricii) and Thymus in Cyclosporin A‐Treated Chickens

“…It is well known that CSA blocks the activation of T lymphocytes (Hess and Colombani, 1987), inhibits their maturation within the thymus (Gao et al., 1988; Jenkins et al., 1988), and strongly affects the thymic structure (Hattori et al., 1987; Kanariou et al., 1989; Milićević et al., 1991). On the other hand, CSA also affects the activation of peripheral B lymphocytes (Dongworth and Klaus, 1982; Muraguichi et al., 1983; Klaus, 1987; Sung et al., 1988; Yang et al., 2000). However, it has previously been unknown whether CSA affects the structure of central lymphatic organs in which B lymphocytes are produced.…”

“…The action of CSA on the immune system has been described in detail. On the one hand, CSA can inhibit the function of peripheral lymphocytes of both T (Hess and Colombani, 1987) and B (Dongworth and Klaus, 1982; Muraguichi et al., 1983; Klaus, 1987; Sung et al., 1988; Yang et al., 2000) lineages. On the other hand, CSA blocks the differentiation of T lymphocytes within the respective central lymphatic organ, i.e.…”

Blockade of CD40-CD154 at the time of donor-specific blood transfusion does not lead to prolonged kidney allograft survival in nonhuman primates1

“…As we have previously demonstrated, pretransplantation blood transfusions, combined with posttransplantation CsA, can lead to indefinite survival in rhesus monkeys (7). Also, in rodents, DST has been successfully combined with CsA treatment, which has resulted in prolonged graft survival (8,9).…”

B cell tolerance and xenotransplantation

“…Thus, experiences in presensitized allograft recipients are of some potential relevance to xenotransplantation. Combined pretransplant treatment with cyclosporine and donor-specific blood transfusion has been shown to tolerize allospecific B cells independently of T cells, permitting survival of major histocompatibility complex class I-mismatched allografts [60]. A recent strategy including plasmapheresis, intravenous immunoglobulin (IVIG), and quadruple immunosuppression has recently permitted kidney transplantation to patients with anti-donor HLA antibodies [61].…”