Although complement is historically not suspected to be implicated in the ?pauci-immune? anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), recent clinical and experimental evidence has shown it to play a key role in amplifying the initial inflammation and subsequent orchestration of innate and adaptive autoimmune organ injury in AAV. Human AAV is a severe systemic autoimmune disease that affects small vessels in multiple organs, but most prominently the kidney and the respiratory tract. If untreated, AAV is fatal with an average survival of only 5 months. Current treatment regimens of AAV is limited to non-specific immunosuppression which carries significant side effects and is not always efficacious in preventing relapse. Therefore, more effective and less toxic therapeutic approaches are needed. A defining feature of AAV is the presence in patient?s blood of ANCA with specificity to one of two neutrophil cytoplasmic antigens, myeloperoxidase (MPO) and proteinase 3. How complement contributes to ANCA-mediated organ injury such as necrotizing crescentic glomerulonephritis (NCGN) and lung hemorrhage is not yet fully understood. In this project, we will use a robust mouse model of MPO ANCA disease that we have recently developed to dissect the role of complement in NCGN and lung hemorrhage. Additionally, we will use this mouse model to test anti- complement therapies to provide proof of concept for targeting specific complement proteins in the treatment of NCGN and lung hemorrhage.
Our specific aims are:
Aim 1. To test the hypothesis that pathogenesis of both necrotizing crescentic glomerulonephritis (NCGN) and lung hemorrhage in our mouse MPO ANCA disease model requires the interplay between MPO-specific antibodies, alternative pathway of complement, and pre- existing anti-MPO cellular immunity;
Aim 2. To test the role and mechanism of action of complement proteins and effectors, including properdin, C5aR and membrane attack complex (MAC), in the development of MPO ANCA-induced NCGN and lung hemorrhage;
Aim 3. To test and compare therapeutic efficacy of systemically blocking properdin, C5, C5a or C5aR in preventing and treating MPO ANCA-induced NCGN and lung hemorrhage. Our innovative mouse model of MPO ANCA disease fully recapitulates the human disease phenotype, including development of NCGN and lung hemorrhage. By using this model, we expect to shed new light on the role of complement in the pathogenesis of AAV, and validate the therapeutic potential of blocking complement in the treatment of both NCGN and lung hemorrhage, two major disease manifestations of human AAV.
This project will use an innovative mouse model of human ANCA-associated vasculitis (AAV) to understand how the potentially fatal disease in humans is caused and what newer and safer treatment options can be developed. AAV is an autoimmune disease characterized by patient?s own immune system attacking their vital organs such as the kidney and lung. If untreated, patients can die from kidney failure and lung bleeding. The current treatments are consisted with immunosuppressive drugs that carry high toxicity from long-term use and are not always efficacious to prevent relapses. In this project, we will test the hypothesis that complement, a series of proteins in the blood which are normally involved in protecting us from infection, may misdirect its attack on the kidney and lung to cause the pathological symptoms seen in AAV. We will also test several inhibitors of complement in our model to see if they can prevent or reduce kidney and lung injury. These studies may lead to the development of novel therapeutics that are more effective and safer than nonspecific immunosuppressive drugs (e.g. steroids) currently used in human AAV patients with significant side effects.
