Our laboratory investigates the role of inflammation and podocyte injury in animal models of glomerulonephritis and kidney transplantation.

Anti-Proteinase 3 immune responses mediate podocyte and glomerular injury

Immune-complex negative (pauci-immune) necrotizing and crescentic glomerulonephritis is the most common finding seen in renal biopsies from patients with rapidly progressive glomerulonephritis at our institution, vastly outnumbering the lesions of anti-glomerular basement membrane (GBM) nephritis. Wegener’s Granulomatosis (WG) is a debilitating and life-threatening autoimmune disease, and a major cause of pauci-immune necrotizing and crescentic glomerulonephritis. Life-saving immunosuppressive therapy in the form of cyclophosphamide and corticosteroids has been useful in inducing remission in many of these patients. However, long-term follow-up of such patients has shown that relapses are rather common and morbidity and mortality resulting from both the disease and its treatment remain significant. In the absence of animal models that could explain the mechanisms that start and perpetuate WG, it is highly doubtful that further improvements in the course of this chronic and life-threatening diseases can be achieved. Therefore, the main goal of our laboratory has been the characterization of a novel animal model of Wegner’s Granulomatosis. Our preliminary data demonstrate that immunization of mice with recombinant mouse PR3 results in the breaking of tolerance towards self-PR3, glomerulonephritis and kidney failure similar to that observed in patients with WG. Further validation of this model as the first animal model of human Wegner’s Granulomatosis, elucidation of the pathogenesis of glomerular and podocyte injury, and evaluation of inflammation in the initiation of PR3-cANCA mediated disease are ongoing. We hypothesize that the outcome of the proposed studies will provide information that will aid in the follow-up and therapy of patients with necrotizing and crescentic glomerulonephritis.

The role of inflammation in podocyte injury and kidney transplantation

Induction of immunological tolerance to transplanted organs such as the kidney has become a major goal of transplantation research because modern immunosuppressive therapy has not improved chronic rejection rates, and is associated with significant side effects. A more complete, mechanistic understanding of the tolerance process, including the manner by which it is facilitated by anti-inflammatory agents, has profound implications for both basic and translational science. Our laboratory has been studying the role of anti-inflammatory agents in the therapy of immune-mediated kidney injury and kidney rejection. We have recently demonstrated that anti-inflammatory agents are effective therapies in the kidney transplantation. We have also observed that BLT1 plays a critical role in the infiltration of neutrophils and macrophages to ischemic kidneys, and in the pathogenesis of renal ischemia reperfusion injury. A detailed analysis of the mechanisms involved in immune-mediated kidney injury or in tolerization to transplanted kidneys will allow development of a more specific, targeted approach, and thus bring us closer to human clinical trials.