The Role of Intestinal Immunity in Type 1 Diabetes Initiation and Progression

肠道免疫在 1 型糖尿病发生和进展中的作用

• 批准号: 8901363
• 负责人: Christina Lynn Graves
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-16 至 2017-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901363
• 关键词: Address; Affect; American; Antigen Presentation; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biochemical; Biology; Cadaver; Cell Adhesion Molecules; Cell Communication; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Cellular Immunity; Culture Techniques; Data; Defect; Development; Diabetes Mellitus; Disease; Disease Progression; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Equilibrium; Event; Exhibits; Gastrointestinal tract structure; Goals; Health; Homeostasis; Human; Human body; Humoral Immunities; Immune; Immune Tolerance; Immune system; Immunity; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intestines; Knowledge; Lead; Ligands; Lymphocyte; Mediating; Mediator of activation protein; Mentors; Modeling; Molecular; Mus; Nature; Onset of illness; Oral; Permeability; Phenotype; Play; Population; Primary Cell Cultures; Regulation; Reporting; Research; Role; Signal Transduction; Site; Staging; System; Therapeutic; Tissues; Toll-like receptors; clinically significant; cost; cytokine; disease phenotype; food antigen; gastrointestinal; human tissue; immune activation; innate immune function; innovation; insight; intestinal homeostasis; microbial; novel; nutrient absorption; oral tolerance; public health relevance; receptor expression; signal processing; tool; trafficking

 DESCRIPTION (provided by applicant): The host-environment dialogue is appreciated to influence the development of inflammatory and autoimmune- mediated diseases, including that of type-1 diabetes (T1D); however, the specific aberrant host-environmental dialogues are poorly understood. In addition, while it is clear that environmental factors are important for disease development, studies have focused on a unidirectional, environmentally-driven dialogue. Instead, I propose that rather than the specific nature of environmental triggers, the way in which such environmental signals are perceived in individuals susceptible to T1D is most important to disease initiation and/or progression. By focusing on defects in the way a host interprets environmental signals, the proposed studies can explain development of a common disease phenotype (T1D) despite heterogeneous environmental triggers in different individuals. The gastrointestinal (GI) tract is the largest single environmental interface of the human body, and is a major site of immune activation and tolerance induction. The summation of information received at the intestinal interface dictates a delicate balance among protective immunity, inflammation, and tolerance. In addition, as a first line of defense, intestinal epithelial cells (IECs) have the ability to participate in immune regulation. Thus, here I propose to investigate T1D-specific host-environment dialogues at the intestinal epithelial cell interface. I hypothesize that in T1D, aberrant IEC-mediated microbial sensing induces an inflammatory rather than a tolerogenic environment within the gastrointestinal tract and precipitates a break in tolerance to self-antigens. To date, lack of robust primary intestinal epithelial cell (IEC) culture has hindere advancement of knowledge in this arena. We have overcome this hurdle through the successful isolation and culture of primary IECs from human cadaver donors as well as murine models. Using our novel culture systems, I aim to evaluate and elucidate the dynamics of microbial-sensing defects in the intestine in T1D throughout the course of disease progression and correlate these dynamics with changes in resident immune cell phenotype and function. Importantly I aim to delineate the mechanisms associated with alterations in microbial induced responsiveness observed. The significance of this research is that it will provide understanding of mechanisms by which IEC interactions with the environment either initiate or enhance T1D. The innovation of this research lies in the tools we have developed which will allow us to elegantly address the questions posed above. In summary, successful completion of these studies will provide much needed insight into mechanisms of intestinal homeostasis and the contribution of the intestinal environment in the development of T1D. Advances in understanding initiating events at the intestinal level may also aid therapeutic approaches aimed at oral tolerance.

 描述（由申请人提供）：宿主-环境对话被认为会影响炎症和自身免疫介导疾病的发展，包括 1 型糖尿病 (T1D)；然而，人们对具体的异常宿主-环境对话知之甚少。此外，虽然环境因素对于疾病的发展很重要，但研究重点是单向的、环境驱动的对话。相反，我认为，对于疾病的发生和/或进展来说，最重要的不是环境触发因素的具体性质，而是易患 T1D 的个体感知此类环境信号的方式。通过关注宿主解释环境信号方式的缺陷，拟议的研究可以解释常见疾病表型（T1D）的发展，尽管不同个体的环境触发因素不同。胃肠道是人体最大的单一环境界面，是免疫激活和耐受诱导的主要部位。在肠道界面接收到的信息的总和决定了保护性免疫、炎症和耐受性之间的微妙平衡。此外，作为第一道防线，肠上皮细胞（IEC）具有参与免疫调节的能力。因此，在这里我建议研究肠上皮细胞界面上 T1D 特异性宿主环境对话。我推测，在 T1D 中，异常的 IEC 介导的微生物感应会诱发胃肠道内的炎症而非耐受性环境，并导致对自身抗原耐受性的破坏。迄今为止，缺乏强大的原代肠上皮细胞（IEC）培养物阻碍了这一领域知识的进步。通过从人类尸体捐赠者和小鼠模型中成功分离和培养原代 IEC，我们克服了这一障碍。使用我们的新型培养系统，我的目标是评估和阐明 T1D 整个疾病进展过程中肠道微生物感知缺陷的动态，并将这些动态与常驻免疫细胞表型和功能的变化联系起来。重要的是，我的目的是描述与观察到的微生物诱导反应性变化相关的机制。这项研究的意义在于，它将提供对 IEC 与环境相互作用引发或增强 T1D 的机制的理解。这项研究的创新之处在于我们开发的工具，这些工具将使我们能够优雅地解决上述问题。总之，这些研究的成功完成将为了解肠道稳态机制以及肠道环境在 T1D 发展中的贡献提供急需的见解。了解肠道水平起始事件的进展也可能有助于针对口服耐受的治疗方法。