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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.

摘要