The effects of blood transfusion, pregnancy and cyclosporin on antibody responses in rats and man
The studies in theis thesis investigate aspects of the problem of sensitisation occurring in dialysis patients prior to renal transplantation. Sensitised patients constitute an increasing proportion of those awaiting transplantation; methods to desensitise these patients or prevent sensitisation are, therefore, of increasing importance. Pregnancy associated antigens might explain the increased risk of sensitisation associated with parity. A pregnancy associated (Pa) antigen in rats was investigated using pregnancy derived sera and a monoclonal antibody to Pa. This study did not, however, confirm the presence of a unique pregnancy associated antigen in the rat. Sensitisation can also occur in response to blood transfusions which may be administered to improve graft survival. In a rat model cyclosporin suppressed a primary humoral response produced by blood transfusions, but did not abrogate the established immune response to previous pregnancy. Pre-treating blood transfusions with a variety of monoclonal antibodies led to a significant reduction in antibody titres in these rats. High antibody responders are most at risk of developing broad sensitisation. Cyclosporin abrogated a primary humoral response to blood transfusions and prevented the normal IgM/IgG switch in high responder rats. Splenocytes from these rats were found to have suppressor activity. Alloantibody titres in low responder rats fell after blood transfusions whether or not cyclosporin was administered. In sensitised rats cyclosporin prevented the maintenance of high antibody titres during blood transusions, accelerated the fall in antibody titres to class II antigens, but did not affect the spontaneous decline of antibody titres to class I antigens. Clinically, prevention of sensitisation was studied using cyclosporin during a blood transfusion protocol. Cyclosporin prevented the development of low titre anti-HLA antibodies and was associated with enhanced production of anti-idiotypic antibodies. Attempted desensitisation of a cohort of sensitised patients with donor specific transfusions plus cyclosporin was unsuccessful. Anti-idiotypic antibody production was detectable in platelet absorbed, cytotoxic sera from these patients. These studies give further insight into the effect of cyclosporin on primary and secondary alloantibody responses and suggest a mechanism by which anti-HLA antibody production can be inhibited during a blood transfusion protocol. The development of anti-idiotypic antibodies, possible mediators of the beneficial blood transfusion effect, was not inhibited by cyclosporin.