At present approximately 60,000 patients with chronic kidney disease are awaiting a kidney transplant but only 14,000 patients receive a graft each year due to a shortage of donor organs. Despite significant progress in the field of organ transplantation, loss of transplanted kidneys remains a major problem, largel. y due to accelerated vascular disease (""""""""transplant arteriosclerosis"""""""") as the result of vascular endothelial and smooth muscle cell proliferation. This is propagated by multiple factors including endothelial injury due to immune and non-immune processes, drug nephrotoxicity and hypertension and leads to progressive narrowing of the vascular lumen, ischemia, fibrosis and loss of kidney function. Given the extent of the problem, a molecular approach to inhibit vascular inflammation and neointimal proliferation would effectively ameliorate chronic vascular rejection and prolong graft survival, limiting the need for subsequent retransplantation or the return to dialysis. Our preliminary studies demonstrate a pivotal role for interleukin-10 (IL-10) in inhibiting vascular neointimal proliferation and inflammation in a rat model of chronic vascular rejection. The vascular protective effects of IL-10 are mediated via induction of heme oxygenase-1 (HO-1), an enzyme with recently recognized anti-inflammatory, anti-apoptotic and immunomodulatory functions. The overall hypothesis of this proposal is that IL-10 prevents chronic vascular rejection by inducing HO-1 expression inhibiting thereby neointimal proliferation and inflammation. To address this central hypothesis, four aims are proposed. The studies in Aim 1 will examine the role of HO-1 in mediating the effects of IL-10 on vascular neointimal proliferation and inflammation in aortic and kidney transplantation using HO-1-/- and HO-1+/+ recipient mice. The experiments in Aim 2 will determine the relative contribution of HO-1 expression in infiltrating hematopoietic cells versus locally in the graft vasculature in mediating the protective effects of IL- 10.
In Aim 3, the hematopoietic cell lineage required for the effects of IL-10 will be determined using adoptive transfer of specific cell populations from HO-1 and HO-1+/+ mice following aortic and kidney transplantation. Preclinical studies will be performed in Aim 4 to determine the link between IL-10 and HO-1 in an existing population of stable kidney allograft rhesus macaques that exhibit high levels of IL-10 and have no evidence of chronic vascular rejection. Lay Summary: Loss of kidney transplants due to progressive narrowing of blood vessels in the kidney is a significant clinical problem. The studies in this project will provide insights into potential novel therapies to prevent this condition and, hence, prolong survival of kidney transplants.
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