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Principal Investigator: FENG C LIN
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2021
Award: $402,500
Funding agency: National Eye Institute
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.
Terms: <Active Immunization><Adoptive Transfer><Antigen-Presenting Cells><Apoptosis><Apoptosis Pathway><Arrestins><Blindness><Blood-Retinal Barrier><Body Tissues><C3 a><C3AR><C3AR1><C3AR1 gene><C3a><C5 a><C5a><CD55 Antigens><Causality><Cell Body><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Process><Cell Signaling><Cell membrane><Cell physiology><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Clinical><Common Rat Strains><Complement><Complement 3a><Complement 5a><Complement Activation><Complement C3a><Complement C5a><Complement Inactivators><Complement Inhibitors><Complement Proteins><Complement Receptor><Cytoplasmic Membrane><Data><Decay-Accelerating Factor><Dendritic Cells><Dendritic cell activation><Development><Disease><Disease remission><Disorder><Etiology><Eye><Eyeball><FOXP3><FOXP3 gene><Forkhead Box P3><Foundations><Future><Generations><Human><IRBP><Immune infiltrates><In Vitro><Inflammation><Innate Immune System><Intracellular Communication and Signaling><JM2><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lipid Bilayers><Lipids><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Motility><Murine><Mus><Nature><Null Mouse><Pathogenesis><Pathogenicity><Pathologic><Patients><Peripheral><Permeability><Plasma Membrane><Production><Programmed Cell Death><Proteins><Publishing><Rat><Rats Mammals><Rattus><Reagent><Receptor Protein><Recombinant C5a><Recombinants><Regulation><Regulatory T-Lymphocyte><Relapse><Remission><Retina><Retinal S-Antigen><Rodent Control><Role><SCURFIN><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Subcellular Process><Surface><T cell infiltration><T cell response><T cell tumor trafficking><T-Cell Activation><T-Cells><T-Lymphocyte><Tail><Teff cell><Testing><Therapeutic><Tissues><Transgenic Mice><Treg><Tumor-infiltrating immune cells><Veiled Cells><Work><accessory cell><antigen-specific T cells><autoimmune attack><autoimmune destruction><autoimmune pathogenesis><autoimmune uveitis><autoreactive T cell><biological signal transduction><causation><cell motility><clinical development><complement pathway regulation><cytokine><developmental><disease causation><effective therapy><effective treatment><effector T cell><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><efficacy testing><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><immune cell infiltrate><immune infiltration><improved><in vivo><inhibitor><inhibitor/antagonist><interphotoreceptor retinoid-binding protein><interphotoreceptor retinol-binding protein><interstitial retinol-binding protein><intratumoral immune cell><knockout gene><lipid bilayer membrane><migration><monolayer><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><plasmalemma><prevent><preventing><receptor><recruit><regulatory T-cells><self-reactive T cell><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><translational study><tumor immune cell><vision loss><visual loss>