Commensal Bacteria in Regulation Of T gondii Induced IBD

共生细菌对弓形虫诱导的 IBD 的调节作用

• 批准号: 6804542
• 负责人: LLOYD H KASPER
• 金额: $ 23.7万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804542
• 关键词: Bacteroides; Peyer' s patches; Toxoplasma gondii; cellular immunity; confocal scanning microscopy; cytotoxic T lymphocyte; disease /disorder prevention /control; enteric bacteria; flow cytometry; immunoregulation; inflammatory bowel diseases; interleukin 10; intestinal mucosa; laboratory mouse; natural killer cells; polymerase chain reaction; polysaccharides; transforming growth factors

The proposed studies investigate the interaction of Toxoplasma gondii and commensal bacterial flora in the immune regulation of an experimental model of pathogen-driven inflammatory bowel disease (IBD). The hypothesis to be tested is that specific bacterial products derived from commensal intestinal flora can interact with the parasite-infected host and prevent the development of experimental IBD. We have observed that germ free mice are more susceptible to an acute necrotizing condition of the ileum and colon than conventional mice following oral parasite infection suggesting that intestinal microflora or their derived products are required to prevent the development of Toxoplasma induced IBD. In the first specific aim, we will compare intestinal tissue samples (phenotyping, chemokines cytokines production) in germ-free strains of resistant (BALB/c) and susceptible (C57BL/6) mice following oral Toxoplasma infection to conventional mice. We have identified a specific capsular polysaccharide of B. fragilis that can modulate the gut inflammatory process. Treatment of conventional mice with capsular polysaccharide (PS A) derived from Bacteroides fragilis prevents the development of T. gondii induced IBD. The mucosal tissue and more specifically lymphoid cells from the lamina propria, Peyer's patches and other organs from PS A treated conventional and germ free mice will be assessed for immunohistologic differences. Mechanisms (IL-10, TGF-b production) of immunomodulation induced by the PS A will be further investigated. As suggested by our preliminary data, particular attention will focus on TGF-b producing CD8+ intraepithelial lymphocytes (IEL) and on a population of IL-10 dependent CD4 regulatory T cells (CD45RB low, CD25). We will evaluate for the expression of these regulatory CD4+ T cells in the lamina propria and Peyer's patches of PS A treated mice and determine whether this cell population can be adaptively transferred to naive mice and prevent toxoplasma-driven IBD. NKT cells are also important regulatory cells that respond to polysaccharides. We will evaluate whether PS A treatment can induce a population of NKT cells that exert effector and immunoregulatory activity.

拟议的研究研究了弓形虫弓形虫和共生细菌菌群在病原体驱动炎症性肠病（IBD）实验模型的免疫调节中的相互作用。要测试的假设是，来自共生肠菌群的特定细菌产物可以与寄生虫感染的宿主相互作用，并防止实验IBD的发展。我们已经观察到，与口腔寄生虫感染后的常规小鼠相比，无胚胎和结肠的急性坏死病更容易受到急性坏死状态，这表明需要肠道微生物或其衍生产物来防止毒素引起的IBD的发展。在第一个特定目的中，我们将比较肠道组织样品（表型，趋化因子细胞因子的产生） 口服弓形虫感染对常规小鼠的抗性（BALB/C）和易感性（C57BL/6）小鼠的无菌菌株（C57BL/6）。我们已经确定了脆弱芽孢杆菌的特异性囊多糖，该多糖可以调节肠道炎症过程。用囊菌的毛囊多糖（PSA）处理常规小鼠，可防止gondii诱导的IBD的发育。粘膜组织和更具体的淋巴样细胞，来自椎板，佩耶的斑块和其他 将评估来自PS A的常规和无菌病小鼠的器官的免疫组织学差异。 PSA诱导的免疫调节的机理（IL-10，TGF-B产生）将进一步研究。正如我们的初步数据所暗示的那样，特别注意将集中在产生CD8+上皮内淋巴细胞（IEL）和IL-10依赖性CD4调节T细胞（CD45RB低，CD225）的群体上。我们将评估这些调节性CD4+ T细胞在Propia和Peyer的PS A处理的小鼠的斑块中的表达，并确定该细胞群是否可以适应性地转移到天真的小鼠中并预防弓形虫驱动的IBD。 NKT细胞也是对多糖反应的重要调节细胞。我们将评估PS A治疗是否可以诱导发挥效应子和免疫调节活性的NKT细胞群。