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Complement in Pathogenesis and Experimental Therapy of ANCA Disease

ANCA 疾病发病机制和实验治疗中的补体

基本信息

批准号：
10646187
负责人：
Wenchao Song
金额：
$ 72.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646187
关键词：
Adaptive Immune System Affect Alternative Complement Pathway Antibodies Antigens Antineutrophil Cytoplasmic Antibodies Autoantibodies Autoimmune Autoimmune Diseases Blood Cellular Immunity Clinical Complement Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Crescentic Glomerulonephritis Cytoplasm Development Disease Disease model Hemorrhage Human Immune Immune system Immunosuppression Immunosuppressive Agents Infection Inflammation Injury to Kidney Innate Immune System Investigational Therapies Kidney Kidney Failure Lung Mediating Modeling Mus Organ Pathogenesis Pathogenicity Pathologic Pathology Patients Peroxidases Play Properdin Proteinase 3 Proteins Respiratory System Role Series Specificity Steroids Symptoms T-Lymphocyte Testing Therapeutic Toxic effect Treatment Efficacy Treatment Protocols Vasculitis complement system disease phenotype human disease human model innovation lung injury mouse model neutrophil novel therapeutics organ injury prevent relapse prevention side effect systemic autoimmune disease

项目摘要

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.

虽然补体历来未被怀疑与“少免疫”抗中性粒细胞有关