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

 描述(由申请人提供)：宿主-环境对话被认为影响炎症性和自身免疫介导性疾病的发展，包括1型糖尿病(T1D)；然而，对特定的异常宿主-环境对话知之甚少。此外，尽管环境因素显然对疾病发展很重要，但研究的重点是单向的、以环境为导向的对话。相反，我认为，与环境触发因素的具体性质不同，对T1D易感个体而言，这些环境信号被感知的方式对疾病的启动和/或进展最为重要。通过关注宿主解释环境信号的方式的缺陷，拟议的研究可以解释常见疾病表型(T1D)的发展，尽管不同的个体存在不同的环境触发因素。胃肠道(GI)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。肠道界面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，肠上皮细胞(IECS)作为第一道防线，具有参与免疫调节的能力。因此，在这里，我建议研究肠道上皮细胞界面上的T1D特异性宿主-环境对话。我推测，在T1D中，异常的IEC介导的微生物感应在胃肠道内诱导炎性环境，而不是耐受性环境，并促使对自身抗原耐受性的打破。到目前为止，缺乏健壮的原代肠道上皮细胞(IEC)培养落后于这一领域的知识进步。我们成功地从人类身体捐赠者和小鼠模型中分离和培养了原代IECs，从而克服了这一障碍。使用我们的新型培养系统，我的目标是评估和阐明T1D肠道微生物感知缺陷在整个疾病进展过程中的动态，并将这些动态与常驻免疫细胞表型和功能的变化相关联。重要的是，我的目标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与环境相互作用启动或增强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内稳态的机制和肠道环境在T1D发生中的作用提供亟需的见解。在了解肠道水平的启动事件方面的进展也可能有助于以口服耐受为目标的治疗方法。

 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.