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: 10199968
• 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/10199968
• 关键词: ANCA vasculitis; 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; Development; Disease; Disease model; Hemorrhage; Human; Immune; Immune system; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Injury to Kidney; Investigational Therapies; Kidney; Kidney Failure; Lead; Light; Lung; Mediating; Modeling; Mus; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peroxidases; Play; Properdin; Proteinase 3; Proteins; Relapse; 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; 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.

尽管从历史上看不怀疑完成在“ pauci-rmune”抗中性营养中 细胞质抗体（ANCA）相关的血管炎（AAV），最近的临床和实验证据具有 表明它在放大先天和随后的安排和随后的安排中起着关键作用 AAV的自适应自身免疫器官损伤。人AAV是一种严重的系统性自身免疫性疾病，会影响 多个器官中的小血管，但最突出的是肾脏和呼吸道。如果未经治疗，AAV是 致命的平均存​​活仅为5个月。 AAV的当前治疗方案仅限于非特异性 免疫抑制会带来重大副作用，并且并不总是有效预防继电器。 因此，需要更有效，更毒性的疗法方法。 AAV的一个定义特征是 在患者的ANCA血液中，对两个中性粒细胞胞质抗原之一的特异性，特异性， 髓过氧化物酶（MPO）和蛋白酶3。如何完成ANCA介导的器官损伤 由于坏死性新月肾小球肾炎（NCGN）和肺出血尚未完全了解。在这个 项目，我们将使用最近开发的MPO ANCA疾病的强大小鼠模型来进行剖析 完成在NCGN和肺出血中的作用。此外，我们将使用此鼠标模型测试抗 - 补充疗法以提供概念证明，以靶向特定补体蛋白 NCGN和肺出血。我们的具体目的是：目标1。检验两者的发病机理的假设 我们的小鼠MPO ANCA病中的坏死新月肾小球肾炎（NCGN）和肺出血 模型需要MPO特异性抗体，替代途径的替代途径和前 现有的抗MPO细胞免疫；目标2。测试补体蛋白质作用的作用和机理 在MPO的发展中，包括适当丁，C5AR和膜攻击复合物（MAC）在内的效果 ANCA引起的NCGN和肺出血；目标3。测试和比较系统的治疗效率 阻止适当的C5，C5A或C5AR预防和治疗MPO ANCA诱导的NCGN和肺 出血。我们创新的MPO ANCA疾病的小鼠模型完全概括了人类疾病 表型，包括NCGN和肺出血的发展。通过使用此模型，我们希望脱落 关于完成在AAV发病机理中的作用的新灯，并验证治疗潜力 在治疗NCGN和肺出血时阻止了完成，两种主要疾病表现 人类AAV。