负性共刺激分子B7-H4在肠道口服耐受和炎性肠病中的作用和机制

Though the negative costimulatory molecule B7-H4 plays an important role in maintaining host peripheral tolerance and immune homestasis, the impact of B7-H4 in intestinal regional immune homestasis, especially in oral tolerance and inflammatory bowel disease, has not yet been studied. Our previous studies revealed that the expression of B7-H4 appeared in the lamina propria and Paneth cells of small bowel during development, while its ectopic expression was found in large intestine of colon cancer. So we suppose that the characteristic expression of B7-H4 is related to the balance of intestinal homestasis. And our hypothesis is that the deficiency of B7-H4 may lead to spontaneous chronic enteritis due to oral intolerance and colitis as a result of abnormal recovery from injury. Take advantage of our B7-H4 conditional knockout mice, we plan to explore the influence of B7-H4 to intestinal epithelium, microbiota and immune system in intestinal homestasis, based on mouse models of oral tolerance and induced gut injury. We’ll focus on the regulatory role of B7-H4 to intestinal regional immune system by detailed and dynamic analysis of immune cells and cytokines during the development of mouse intestine, construction of oral tolerance and recovery from gut injury. We try to uncover the mechanisms underlying construction and maintenance of intestinal regional immune homestasis by the regulation of negative costimulatory molecule B7-H4.

负性共刺激分子B7-H4在维持自身免疫耐受和机体免疫稳态中发挥着重要的作用，但在肠道稳态维持，尤其是口服耐受和炎性肠病中的作用及机制目前尚不清楚。我们前期的研究发现，随着肠道的发育成熟，B7-H4在小肠绒毛固有层和隐窝中出现特异表达。此外，随着肠癌的进展，该分子在结肠异位表达。由此推测，B7-H4在肠道不同时间不同部位出现表达与肠道稳态构建与维持密切相关。它的功能缺失有可能导致口服不耐受引发的慢性自发性小肠炎和损伤修复异常引起的结肠炎。本项目旨在充分利用特有的B7-H4条件性基因敲除小鼠，构建多种肠道口服耐受和炎性肠损伤模型，以B7-H4对肠道免疫稳态的影响为主要突破口，围绕肠道稳态的要素开展研究。通过不同层面的动态研究，分析肠道发育成熟及炎症损伤修复过程中介导B7-H4发挥作用的关键细胞和分子，揭示B7-H4在肠区域免疫稳态构建和维持的确切作用机制，具有重要的科学价值。

共刺激分子B7-H3和B7-H4在维持机体免疫稳态中发挥着重要的免疫调节作用。目前，这两个分子在炎性肠病中的作用尚无报道。我们首先分析了B7家族共刺激分子在小鼠小肠和结肠的表达与分布。利用自行构建的B7-H3和B7-H4敲除小鼠，构建了DSS诱导的急性肠炎和肠型放射损伤模型。结果显示，相比野生型小鼠，B7-H4敲除小鼠在急性肠炎和肠型放射损伤中的生存率没有显著变化。虽然B7-H3敲除小鼠在肠型放射损伤中生存率也无明显改变，但这种小鼠在DSS诱导的急性肠炎发病过程中，体重和生存率显著降低，肠粘膜损伤脱落严重，局部有炎性细胞浸润。Realtime PCR结果显示在肠炎小鼠结肠组织中总B7-H3分子的表达减少。B7-H3对小鼠急性肠炎的保护作用机制还有待进一步深入研究。