Renal transplantation is widely recognized as the treatment of choice for children with End Stage Renal Disease. 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, yet chronic rejection remains to be a major clinical problem in this patient population. Therefore, strategies designed to induce donor specific hyporesponsivenss/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 CD40L-CD40 pathway of T cell costimulation. Recent preclinical data in primates established the safety and efficacy of CD40L costimulatory signal blockade in preventing acute rejection, and clinical phase I studies in patients with autoimmune diseases confirmed the safety of such an approach in humans. CD40L blockade with a humanized monoclonal antibody is currently being studied in a phase IIa clinical trial in adult renal transplant recipients in a protocol which excludes the use of calcineurin inhibitors since these agents may abrogate the effect of CD40L blockade. The overall goal of this proposal is to study the immunomodulatory functions and mechanisms of CD40L blockade by a humanized monoclonal antibody (BG9588, Biogen Inc.) in pediatric renal transplant recipients. Specifically, we plan to study the following: 1. Determine the safety and study the immunomodulatory functions of BG9588 In pediatric primary renal transplant recipients. Our hypothesis is that CD40L blockade will prevent acute rejection and allows sparing of calcineurin inhibitors in this patient population. 2. Study the immunomodulatory functions of combining donor specific transfusion and T cell costimulatory blockade with BG9588 in pediatric primary living related transplant recipients. Out hypothesis is that the administration of donor alloantigen with T cell costimulatory blockade may result in induction of a donor specific hyporesponsive state. The fact that CD40L blockade is also effective in inhibiting CD40 signaling of B cells provides an added advantage of preventing sensitization; a major concern when using donor specific transfusion. 3. We plan to use sensitive and specific assays including peripheral and intragraft monitoring for expression patterns of activation and effector function markers to study the mechanisms of CD40L in humans. Our hypothesis is that CD40L blockade is associated with inhibition of T cell activation and the effector mechanisms of allograft rejection. The above studies will help to plan further """"""""tolerance"""""""" aimed clinical trials in pediatric transplant recipients.
