Graft failure following transplantation results from either acute or chronic rejection. There are currently many immunosuppressive agents that are effective at preventing acute rejection. There are no such reagents for the prevention of chronic rejection. In the kidney, chronic rejection is characterized by the development of fibrotic changes, which include interstitial fibrosis, tubular atrophy, glomerulosclerosis, and concentric intimal hyperplasia. This process has been termed chronic allograft nephropathy (CAN).

1,25-Dihyroxyvitamin D₃ [1,25-(OH)₂D₃] is the active metabolite of vitamin D. Its long-known function is to regulate calcium metabolism. Recent evidence suggests that 1,25-(OH)₂D₃ also regulates the growth and differentiation of many cell types, and in particular that 1,25-(OH)₂D₃ regulates immune responses. We have shown that 1,25-(OH)₂D₃ treatment prolongs allograft survival. Importantly, we have shown in a retrospective study that renal transplant patients who received 1,25-(OH)₂D₃ supplementation because of renal insufficiency had stabilized graft function.

The mechanisms that lead to the development of CAN are unknown, but are thought to involve both immune and non-immune factors. The cytokine transforming growth factor beta (TGFß) has been implicated in the pathogenesis of the fibrotic changes in CAN. We and others have shown an interaction between the TGFß and 1,25-(OH)₂D₃ signal transduction pathways. Thus, we hypothesize that 1,25-(OH)₂D₃ will be an effective agent in preventing CAN and that 1,25-(OH)₂D₃ may regulate TGFß-mediated fibrosis. We intend to determine whether 1,25-(OH)₂D₃, when used in combination with low-dose standard immunosuppression, is effective in preventing CAN, and to determine the effect of 1,25-(OH)₂D₃ treatment on the expression of genes for proteins that regulate fibrotic changes, namely the matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases.

The experiments proposed in this application should lead to a greater understanding of the mechanisms underlying CAN and may identify new targets for therapy.