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

• 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
• 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

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.

尽管历史上并未怀疑补体与“寡免疫”抗中性粒细胞有关 细胞质抗体（ANCA）相关性血管炎（AAV），最近的临床和实验证据表明 表明它在放大最初的炎症以及随后的先天性和 AAV 中的适应性自身免疫器官损伤。人类 AAV 是一种严重的系统性自身免疫性疾病，影响 多个器官中的小血管，但最突出的是肾脏和呼吸道。如果不治疗，AAV 致命，平均存活期只有5个月。目前 AAV 的治疗方案仅限于非特异性治疗 免疫抑制具有显着的副作用，并且并不总是能有效预防复发。 因此，需要更有效且毒性更低的治疗方法。 AAV 的一个决定性特征是 患者血液中存在对两种中性粒细胞胞质抗原之一具有特异性的 ANCA， 髓过氧化物酶 (MPO) 和蛋白酶 3. 补体如何促进 ANCA 介导的器官损伤，例如 由于坏死性新月体肾炎（NCGN）和肺出血尚未完全了解。在这个 项目中，我们将使用我们最近开发的 MPO ANCA 疾病的稳健小鼠模型来剖析 补体在 NCGN 和肺出血中的作用。此外，我们将使用该小鼠模型来测试抗 补体疗法为针对特定补体蛋白的治疗提供概念证明 NCGN 和肺出血。我们的具体目标是： 目标 1. 检验以下假设：两者的发病机制 小鼠 MPO ANCA 疾病中的坏死性新月体肾小球肾炎 (NCGN) 和肺出血 模型需要 MPO 特异性抗体、补体替代途径和前体之间的相互作用 现有的抗 MPO 细胞免疫；目标 2. 测试补体蛋白的作用和作用机制 MPO 开发过程中的效应物，包括备解素、C5aR 和膜攻击复合物 (MAC) ANCA 诱导的 NCGN 和肺出血；目标 3. 测试并比较系统性治疗的疗效 阻断备解素、C5、C5a 或 C5aR 预防和治疗 MPO ANCA 诱导的 NCGN 和肺部 出血。我们创新的 MPO ANCA 疾病小鼠模型完全重现了人类疾病 表型，包括 NCGN 的发展和肺出血。通过使用这个模型，我们期望摆脱 补体在 AAV 发病机制中的作用有了新的认识，并验证了补体的治疗潜力 阻断补体治疗 NCGN 和肺出血这两种主要疾病表现 人类AAV。