This proposal extends the research with donor specific transfusions and concomitant azathioprine immunosuppression (DST+A) in haplotype mismatched living donor kidney transplants to the cadaver situation. It is intended to demonstrate that pretreatment of potential renal allograft recipients with tissue typed and HLA-public antigen mismatched buffy coat transfusions (BCT) and concomitant azathioprine immunosuppression will result in improved cadaver renal allograft survival. Possible mechanisms of immunomodulation that suppress the allograft rejection response will be investigated in the blood (standard serologic and cellular immunologic tests) and in the allograft (fine needle aspiration) of the cadaver transplant recipient. The poteintial cadaver kidney transplant recipient will undergo three to six buffy coat transfusions over a six to ten week period from a single tissue typed volunteer donor (plasmapheresis program). Blood donors will be selected on the basis of the maximum number of public antigens mismatched for the recipient. A properly selected single donor can cover most of the public antigens not present in the recipient because of the limited number of different public anigens and their high frequency in the population. All recipients will receive continuous azathioprine immunosuppression starting prior to the transfusions and continuing into the posttransplant period. Cadaver kidney transplant will be performed two weeks to four weeks after the last transfusion using a donor kidney with public antigens the same as those present in the buffy coat transfusion. Recipients will undergo immunologic monitoring by: T- and B-cell crossmatch, mixed leukocyte reaction (MLR), antiidiotypic antibody analysis, interleukin 2 production during MLR, effects of recipient serum on the response to interleukin 2 (qualitative analysis), quantitative assay for interleukin 2 response inhibitory activity, and fine needle aspiration biopsy of the allograft analyzed for histocytology and cellular immunity. A major objective is to evaluate the contribution of IL-2 response inhibition to successful transplantation and its potential use as a test in assessing the induction of the salutary effects of DST+A/BCT+A. The ability to immunomodulate potential cadaver renal allograft recepients by down regulating the immune response to specific alloantigen would constitute an important advance in improving renal allograft survival over general nonspecific immunosuppressive measures.
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|Phelan, D L; Rodey, G E; Anderson, C B (1989) The development and specificity of antiidiotypic antibodies in renal transplant recipients receiving single-donor blood transfusions. Transplantation 48:57-60|
|Phelan, D L; Rodey, G E; Flye, M W et al. (1989) Positive B cell crossmatches: specificity of antibody and graft outcome. Transplant Proc 21:687-8|