The broad long-term objective of this grant application from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) group is to improve patient and graft survival in renal allograft recipients. The study group consists of 24 pediatric renal transplant centers who have all agreed to carry out a common protocol. The centers are chosen so as to provide a pediatric patient population with a balanced geographic distribution, a diverse ethnic distribution, equitable gender representation and a total number large enough to ensure a study with significant results. The first specific aim of this application is to enroll 250 patients each year over a four year period into a randomized controlled trial of the following three induction therapies: (1) Upjohn antithymocyte globulin (ATG), (2) Ortho monoclonal antibody (OKT3), (3) IV Cyclosporine. This controlled trial will determine which of the immunosuppressive regimens is more effective with fewer adverse effects. The second specific aim of this application is to study gene expression of various cytokines in the renal biopsy tissue during episodes of rejection. Using reverse transcription assisted quantitative polymerase chain reaction (R-PCR) we will quantify mRNA encoding: cytotoxic T cell specific serine esterase (granzyme B); perforin; interleukin 2 (IL-2); IL- 7; IL-10; T cell receptor beta chain constant region (TCR c-beta); and the chemokine RANTES. This study will test our hypothesis that the quantification of selected intragraft gene expression at the time of clinical rejection will distinguish irreversible rejection from reversible rejection. The third specific aim of this application is to study intragraft gene expression in sequential surveillance biopsies in children under the age of six years since this is the group at high risk for irreversible rejection. This study will test our hypothesis that the heightened immune response in children progresses subclinically prior to becoming clinically evident and will determine if intragraft gene expression in surveillance biopsies will predict clinical rejection. The fourth specific aim of this application is to study fine needle aspiration (FNA) biopsy of renal tissue and peripheral blood monocytes (PBMC) for evidence of gene expression that correlates with the gene expression noted in core biopsies when simultaneously performed. A close correlation between FNA and PBMC with gene expression in core biopsy will eliminate the need for invasive procedures to diagnose acute rejection.
