Intestinal T cells and microbiota as therapeutic targets in autoimmune uveitis

项目摘要 慢性自身免疫性葡萄膜炎是一个医疗管理难题，如果不加以治疗，是一种 在美国和世界范围内导致失明的重要原因。然而，由于对其不完全的理解 发病机制，治疗往往需要使用非特异性抗炎药，可以有 不好的副作用。新出现的证据表明肠道微生物区系与肠外自身免疫有关 葡萄膜炎等疾病，为发病机制提供了新的线索，并为治疗靶向提供了新的途径。我们的 目标是研究如何操纵肠道微生物区系来重建肠道，从而 在自身免疫性葡萄膜炎的过程中，系统免疫动态平衡发生了变化。为了做到这一点，我们 使用典型的T细胞介导的模型，实验性自身免疫性葡萄膜炎(EAU)。我们将利用两个 改变肠道微生物区系、抗生素和短链脂肪酸(SCFA)代谢产物的不同干预措施 肠道细菌发酵的膳食纤维，在EAU。增强肠道树突状细胞(通常 通过这些改变微生物区系的干预措施)将通过过继转移 Tregs和体外Treg抑制试验。改变微生物区系的干预措施对肠道的影响 免疫细胞在EAU期间向外周淋巴组织和眼睛的迁移也将被研究。直接 微生物区系对增强肠道Treg丰度和葡萄膜炎严重程度的影响将通过粪便进行测试 来自抗生素或SCFA预处理动物的微生物移植。预计这些结果将产生 对自身免疫性葡萄膜炎发病机制的新见解以及为新的治疗策略奠定基础 以肠道微生物区系为靶点，重新建立免疫平衡。

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.