Renal transplantation is widely recognized as the treatment of choice for children with End Stage Renal Disease. Recent reports show that children have excellent outcomes of kidney transplantation, but the success in achieving excellent short-term results is imperfect and short-lived since patients have to be maintained on long-term immunosuppression for life. Drug side effects, compliance and chronic rejection continue to be major clinical problems in this patient population. Therefore, strategies designed to induce donor specific hypo-responsiveness tolerance with no or minimal long-term immunosuppression will have unique beneficial effects for children. Recent advances in our understanding of the cellular and molecular mechanisms of allograft rejection have lead to development of novel strategies to promote long-term allograft survival and induce donor specific tolerance in experimental animal models. One such effective strategy involves blocking the B7 pathway of T cell costimulation. Recent clinical data in adult transplant recipients established the safety and efficacy of CTLA4Ig LEA29Y, a fusion protein that blocks B7 costimulatory pathway, in preventing acute rejection in adult renal transplant recipients. The overall goal of this application is to study the immunomodulatory functions and mechanisms of B7 blockade in pediatric renal transplant recipients. Specifically, we plan to study the following: 1. Determine the safety and study the immunomodulatory functions of CTLA4Ig in pediatric primary renal transplant recipients. Our hypothesis is that B7 blockade will prevent acute rejection and allows sparing of calcineurin inhibitors and corticosteroids in this patient population. 2. Study the immunomodulatory functions of combining donor specific transfusion and T cell costimulatory blockade with CTLA4Ig in pediatric primary living related transplant recipients. Our hypothesis is that the administration of donor alloantigen with T cell costimulatory blockade may result in induction of a donor specific hyporesponsive state and will provide the opportunity to decrease chronic immunosuppression further. 3. We plan to use novel immunological assays including peripheral and intragraft monitoring for expression patterns of activation and effector function markers to study the mechanisms of CTLA4Ig in humans. Our hypothesis is that B7 blockade is associated with inhibition of T cell activation and the effector's mechanisms of allograft rejection. The above studies will help to plan further """"""""tolerance"""""""" aimed clinical trials in pediatric transplant recipients.
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