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学管理难题，如果不治疗， 在美国和全世界都是致盲的重要原因。然而，由于对它的不完全理解， 在发病机制中，治疗通常需要使用非特异性抗炎剂， 不良副作用新出现的证据将肠道微生物群与肠外自身免疫联系起来 这为研究葡萄膜炎等疾病的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 目的是研究如何操纵肠道微生物群来重建肠道， 在自身免疫性葡萄膜炎的过程中，系统免疫稳态发生了变化。为此，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 改变肠道菌群、抗生素和短链脂肪酸（SCFA）代谢物的不同干预措施 肠道细菌发酵的膳食纤维，在EAU。增强肠道THP（细胞通常 抑制免疫系统），将通过过继转移来测试这些改变微生物群的干预措施。 Treg和体外Treg抑制测定。微生物改变干预对肠道菌群的影响 还将研究EAU期间免疫细胞向外周淋巴组织和眼睛的迁移。直接 微生物群对肠Treg丰度和葡萄膜炎严重程度的增强的作用将通过粪便试验来测试。 来自抗生素或SCFA预处理的动物的微生物移植。这些结果预计将产生 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 靶向肠道微生物群以重建免疫稳态。

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.