Autoimmune Diabetes: Gut Microbial Regulation in the IL10KO Mouse Model

 描述(申请人提供)：自身免疫，免疫系统的异常调节，影响了惊人的2350万美国人。自身免疫性疾病，如1型糖尿病(T1D)和炎症性肠病(IBD)是慢性疾病的主要原因，预计随着所有民族的发病率增加，这种疾病将会上升。肠道微生物群落的破坏(生物失调)与T1D和IBD高度相关；然而，肠道微生物作为疾病病理生理调节器的重要性直到最近才被强调。白介素10缺陷(IL10KO)小鼠是公认的IBD模型；然而，无菌(GF)IL10KO小鼠从不发生结肠炎。我们有了一个新的发现，即GF IL10KO小鼠出现了与临床T1D胰岛素炎非常相似的胰腺浸润。IL10KO模型是一个令人兴奋的机会，可以研究肠道微生物作为免疫病理调节因子的作用，介导T1D和/或宿主-微生物相互作用和疾病免疫调节之间的复杂相互作用。确定GF IL10KO小鼠是否表现出与1型糖尿病相关的胰岛素炎风险增加，并确定与传统饲养的同类动物相比，GF IL10KO小鼠中的免疫介质；[2]确定肠道微生物和粘膜免疫功能在IL10 KO小鼠抵抗胰岛素炎中的作用。采用免疫学、组织学和分子生物学方法的多学科方法将确定(1)胰岛炎症开始的时间窗口，(2)免疫病理学中涉及的特定免疫细胞类型，以及潜在的疾病生物标志物，以及(3)胰岛炎症对胰岛结构和宿主血糖稳态的影响。体内方法将测试IBD的表型，提出了两个中心目标：[1]通过过继转移模型实现自身免疫介导的病理生理学的可转移性，以及在生命的早期窗口引入特定的微生物是否可以预防胰岛素炎。这个模型有可能在新陈代谢、自身免疫、遗传学和微生物组领域开辟许多发现的途径；并需要进一步的表征来研究疾病的机制。这项拟议的研究将为胰腺自身免疫的启动和进展提供基本信息，并为预防性益生菌治疗降低T1D的发生率提供前提。

 DESCRIPTION (provided by applicant): Autoimmunity, the aberrant regulation of the immune system, affects an astounding 23.5 million Americans. Autoimmune disease such as Type 1 diabetes (T1D) and Inflammatory Bowel Diseases (IBD) are major causes of chronic illness and are expected to rise with increasing prevalence across all ethnic groups. Disruptions in gut microbial communities (dysbiosis) are highly associated with both T1D and IBD; however, the importance of gut microbes as regulators of disease pathophysiology has only recently been highlighted. The interleukin-10 deficient (IL10KO) mouse is a well-established model of IBD; however germ-free (GF) IL10KO mice never develop colonic inflammation. We made the novel discovery that GF IL10KO mice instead develop pancreatic infiltration that remarkably resembles clinical T1D insulitis. The IL10KO model is an exciting opportunity to investigate the role of gut microbes as regulators of immunopathology that mediate T1D and/or the complex interplay between host-microbial interactions and immunological regulation in disease. Determine whether GF IL10KO mice exhibit an increased risk for insulitis associated with Type 1 diabetes and identify the immune mediators in GF IL10KO compared to conventionally-raised counterparts ; [2] Determine the role of gut microbes and mucosal immune function in protection against insulitis in IL10 KO mice. A multidisciplinary approach using immunological, histological, and molecular strategies will identify (1) the window of time insulitis is initiated, (2) specific immune cell types involved in immunopathology, as well as potential biomarkers of disease, and (3) the impact of insulitis on islet architecture and host blood glucose homeostasis. In vivo approaches will test the IBD phenotypes, demonstrating Two central aims are proposed: [1] transferability of autoimmune-mediated pathophysiology via adoptive transfer models and whether introduction of specific microbes at an early window of life protects against insulitis. This model has the potential to open many avenues to discovery in the fields of metabolism, autoimmunity, genetics, and microbiome; and warrants further characterization to investigate mechanisms of disease. The proposed research will provide fundamental information about autoimmune initiation and progression in the pancreas and the premise for preventative probiotic therapies to decrease the incidence of T1D.