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Intestinal T cells and microbiota as therapeutic targets in autoimmune uveitis

肠道 T 细胞和微生物群作为自身免疫性葡萄膜炎的治疗靶点

基本信息

批准号：
10669631
负责人：
Phoebe Lin
金额：
$ 51万
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：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669631
关键词：
Address Adoptive Transfer Affect Animals Anti-Inflammatory Agents Antibiotics Arthritis Autoimmune Diseases Bacteria Biological Assay Biological Markers Blindness Body part Cells Chronic Dietary Fiber Disease Disease Pathway Equilibrium Eye Fermentation Frequencies Goals Homeostasis Immune Immune system Immunity Immunophenotyping Immunosuppression In Vitro Inflammation Inflammatory Intervention Intestinal permeability Intestines Left Link Lymphoid Tissue Measures Mediating Medical Metronidazole Modeling Morphology Mus Pathogenesis Peripheral Production Propionates Proteins Severities T-Lymphocyte Testing Time Transgenic Organisms Uveitis Volatile Fatty Acids autoimmune uveitis cell motility cell type drinking water effector T cell fecal transplantation gut inflammation gut microbiota improved in vivo insight intestinal barrier intestinal epithelium intestinal homeostasis microbial microbiota microorganism migration mouse model new therapeutic target novel novel strategies novel therapeutic intervention prevent protective effect side effect therapeutic target trafficking

项目摘要

Project Summary Chronic autoimmune uveitis represents a medical management conundrum, which left untreated, is a significant cause of blindness in the US and worldwide. Yet due to an incomplete understanding of its pathogenesis, treatment has often required use of non-specific anti-inflammatory agents that can have untoward side effects. Emerging evidence links the intestinal microbiota to extraintestinal autoimmune diseases like uveitis, providing new clues into pathogenesis, and novel avenues for therapeutic targeting. Our goal is to investigate how the intestinal microbiota can be manipulated to re-establish intestinal and thus systemic immune homeostasis that has gone awry during the course of autoimmune uveitis. To do this, we are using a quintessential T-cell mediated model, experimental autoimmune uveitis (EAU). We will utilize two different interventions to alter the intestinal microbiota, antibiotics and short chain fatty acid (SCFA) metabolites of intestinal bacterial fermentation of dietary fiber, in EAU. Enhancement of intestinal Tregs (cells that usually suppress the immune system) by these microbiota-altering interventions will be tested by adoptive transfer of Tregs and in vitro Treg suppression assays. The impact of microbiota-altering interventions on intestinal immune cell migration to peripheral lymphoid tissues and the eye during EAU will also be investigated. Direct microbiota effects on enhancement of intestinal Treg abundance and uveitis severity will be tested by fecal microbial transplantation from antibiotic or SCFA-pre-treated animals. These results are expected to yield novel insights into autoimmune uveitis pathogenesis as well as lay groundwork for new treatment strategies targeting the intestinal microbiota to re-establish immune homeostasis.

项目总结