New mechanisms by which complementýregulates the pathogenesis of experimental autoimmune uveitis

补体调节实验性自身免疫性葡萄膜炎发病机制的新机制

基本信息

批准号：
10397686
负责人：
FENG C LIN
金额：
$ 39.04万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397686
关键词：
Active Immunization Adoptive Transfer Antigen-Presenting Cells Apoptosis Arrestins Blindness Blood-Retinal Barrier C3AR1 gene CD55 Antigens Cell membrane Cell physiology Cells Clinical Complement Complement 3a Complement 5a Complement Activation Complement Inactivators Complement Receptor Data Dendritic Cells Dendritic cell activation Development Disease Disease remission Etiology Eye FOXP3 gene Foundations Future Generations Human In Vitro Inflammation Innate Immune System Knock-out Knockout Mice Lipid Bilayers Lipids Mediating Modeling Mus Nature Pathogenesis Pathogenicity Pathologic Patients Peripheral Permeability Production Proteins Publishing Rattus Reagent Recombinants Regulation Regulatory T-Lymphocyte Relapse Retina Rodent Control Role Signal Transduction Solid Surface T cell response T-Cell Activation T-Lymphocyte Tail Testing Therapeutic Tissues Transgenic Mice Tumor-infiltrating immune cells Work antagonist antigen-specific T cells autoimmune pathogenesis autoimmune uveitis autoreactive T cell cell motility clinical development cytokine effective therapy effector T cell efficacy evaluation efficacy testing experimental study improved in vivo inhibitor interstitial retinol-binding protein knockout gene migration monolayer mouse model nanoparticle new therapeutic target novel novel therapeutics prevent receptor recruit targeted treatment translational study

项目摘要

Abstract Autoimmune uveitis, a common cause of blindness, has an unknown etiology and no known cure. We have been studying experimental autoimmune uveitis (EAU) induced in mice deficient in various complement components, inhibitors, or receptors following active immunization with a retinal antigen and the adoptive transfer of already primed retinal antigen-specific T cells. Our findings strongly suggest that complement, particularly the complement receptors C3aR and C5aR, are required for not only the priming of autoreactive T cells in the periphery, but also the migration and/or re-stimulation of already activated pathogenic T cells in the retina. These findings suggest that these complement receptors could be new therapeutic targets for treating EAU and, eventually, autoimmune uveitis. In this proposed work, we will focus on the previously unknown role of complement in regulating the migration and/or re-stimulation of already primed autoreactive T cells in a target tissue, using EAU as a model. We will also elucidate the underlying mechanisms using various systemic and cell-specific complement-related gene knockout mice and other novel reagents. In addition, we will examine the efficacies and investigate the underlying mechanisms of our novel complement-targeted reagents for suppressing the migration and re- stimulation of previously activated uveitogenic T cells in the retina for the treatment of EAU both in mice and in rats. These studies will significantly improve our understanding of the pathogenesis of autoimmune uveitis and facilitate the development of novel complement-targeted therapeutics for the treatment of this blinding disease.

抽象的自身免疫性葡萄膜炎是失明的常见原因，其病因不明，也没有已知的治疗方法。我们一直在研究在缺乏各种补体的小鼠中诱导的实验性自身免疫性葡萄膜炎（EAU）视网膜抗原主动免疫和过继转移后的成分、抑制剂或受体已经引发的视网膜抗原特异性 T 细胞。我们的研究结果强烈表明补体，特别是补体受体 C3aR 和 C5aR 不仅是启动自身反应性 T 细胞所必需的周边，还包括视网膜中已激活的致病性 T 细胞的迁移和/或重新刺激。这些研究结果表明，这些补体受体可能成为治疗 EAU 的新治疗靶点，最终，自身免疫性葡萄膜炎。在这项拟议的工作中，我们将重点关注补体在调节使用 EAU 作为模型，迁移和/或重新刺激目标组织中已引发的自身反应性 T 细胞。我们还将利用各种系统性和细胞特异性补体相关的方法来阐明潜在的机制。基因敲除小鼠和其他新型试剂。此外，我们将检查功效并调查我们的新型补体靶向试剂抑制迁移和重新定位的基本机制刺激视网膜中先前激活的致葡萄膜 T 细胞，用于治疗小鼠和小鼠的 EAU 老鼠。这些研究将显着提高我们对自身免疫性葡萄膜炎发病机制的理解和促进开发新的补体靶向疗法来治疗这种致盲疾病。