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

 描述（由申请人提供）：认识到宿主-环境对话影响炎性和自身免疫介导的疾病的发展，包括1型糖尿病（T1 D）的发展;然而，对特定的异常宿主-环境对话知之甚少。此外，虽然环境因素对疾病的发展很重要，但研究的重点是单向的、环境驱动的对话。相反，我建议，而不是环境触发的具体性质，在这种环境信号在T1 D易感个体中的感知方式对疾病的发生和/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（T1 D）的发展，尽管不同个体的环境触发因素不同。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。在肠道界面接收的信息的总和决定了保护性免疫、炎症和耐受之间的微妙平衡。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，我建议调查T1 D特定的宿主环境对话在肠上皮细胞界面。我假设在T1 D中，异常的IEC介导的微生物传感会诱导胃肠道内的炎症环境而不是耐受性环境，并导致对自身抗原的耐受性破坏。到目前为止，缺乏强大的原代肠上皮细胞（IEC）培养已经落后于知识的进步，在这个竞技场。我们已经克服了这一障碍，通过成功的分离和培养的原代IEC从人类尸体供体以及小鼠模型。使用我们的新型培养系统，我的目标是评估和阐明在整个疾病进展过程中T1 D肠道微生物传感缺陷的动态，并将这些动态与常驻免疫细胞表型和功能的变化相关联。重要的是，我的目的是描绘与观察到的微生物诱导的反应性改变相关的机制。这项研究的意义在于，它将提供IEC与环境的相互作用启动或增强T1 D的机制的理解。这项研究的创新在于我们开发的工具，这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提供急需的洞察肠道内稳态的机制和肠道环境在T1 D的发展中的贡献。在理解肠道水平的起始事件方面的进展也可能有助于旨在口服耐受性的治疗方法。

 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.