The influence of immunosuppressive agents and pregnancy on sensitisation to major histocompatibility antigens
The studies in this thesis concern alloantibody responses against MHC class I antigens. These antibodies are induced by blood transfusions and strongly associated with clinical kidney allograft rejection. These findings were: 1. Cytotoxic antibodies in 11 multiparous patients, who had become broadly sensitised by blood transfusions, were of IgG class and directed to HLA class I antigens. In all patients, some of these antibodies were directed against class I specificities expressed by the partner by whom the patient was parous. 2. In high responder multiparous rats, humoral responses against paternal MHC class I antigens reencountered in blood transfusions given after pregnancy were suppressed. In contrast, minor histocompatibility antigens shared between the paternal and later blood donor strains enhanced anti-MHC class I antibody responses. 3. In multiparous rats, anti-paternal antibodies stimulated by pregnancy were not influenced by materno-paternal disparities at MHC class II or minor antigenic loci, and were directed to conventional MHC class I epitopes. 4. In high responder rats, there was no evidence for either humoral or cellular tolerance to non-inherited maternal MHC antigens. 5. In high responder rats pre-treated with blood transfusions and concomitant cyclosporin A, subsequent antibody responses to third party MHC class I antigens encountered in challenge transfusions, given without cyclosporin A, were suppressed only when minor histocompatibility antigens were shared between the initial and challenge transfusions. 6. Three drugs:- cyclosporin A, FK506 and rapamycin abrogated anti-MHC class I alloantibody responses to blood transfusions by naive rats and, at the same time, induced humoral tolerance. None of these drugs, however, inhibited either ongoing, alloantibody synthesis or humoral anamnestic responses in high responder rats with established humoral immunity.