This proposal is designed to obtain an understanding of the events that regulate the production of anti-HLA antibodies in recipients of renal allografts. We will test the hypothesis that anti-idiotypic responses to idiotopes on anti-HLA antibody molocules and to idiotypic receptors of alloreactive T cells mediate specific suppression of anti-HLA immunity. Our proposal comprises two distinct but integrated arts. The first part deals with the role of anti-anti-HLA antibodies (Ab2) in down regulating specific anti-HLA antibodies (AB1). We will determine whether: a) patients who exhibited Ab2 at the time of transplantation tolerate the graft in spite of previous sensitization to the donor's HLA antigens; b) the presence of Ab1-potentiating antibodies (presumed to represent Ab3) increases the risk of rejection; c) the prognostic significance of anti-anti-HLA antibodies to MHC-Class I and MHC-Class II antigens is the same; d) the presence of Ab2 following transplantation correlates with allograft acceptance. The second part of our proposal focus on the specificity, function, and control of anti-idiotypic T cell response, in recipients of renal allografts. These studies will be performed on recipients of kidneys from living related donors. We will test the patients capacity to exibit secondary AMLC responses directed against autologous T lymphoblasts primed to the donor. We will then determine whether such AMLC-reactive cells act as suppressors of the recognition, effector, or regulatory arm of alloimmune reactions. Results of these experiments will be related to the outcome of the graft to determine their clinical significance. Understanding of network mechanisms which regulate the immune response to HLA may open new avenues for immunotherapy and may permit a better selection of suitable donors for highly sensitized recipients.
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