Innate/Adaptive Immune Interactions in Gut Inflammation

总体描述(由申请人提供)：受控或生理性炎症是肠道中正常粘膜相关淋巴组织的标志，与一般音调(至少在Gl区)抑制有关。指导该计划项目拨款的总体假设是，这种控制需要免疫系统的两个手臂，先天的和适应性的，以及非免疫屏障的组成部分，以发展一个严格的调节系统，很可能是一个互动的系统。这个网络的任何组件的缺陷都可能导致炎症。因此，我们的重点放在先天性、适应性和非免疫反应的不同方面，这些反应有助于整体上抑制Gl区的音调，并定义不同通路之间的特定相互作用。这一调控的核心可能是一种细胞类型，即IEC，在这一过程中所扮演的角色。在项目1中，我们通过由肠上皮细胞表达的非经典I类分子激活T细胞亚群来解决先天免疫的作用。项目2着眼于趋化因子/趋化因子受体在促进炎症与调节炎症中的作用。项目3评估了一种新的丝氨酸/苏氨酸激酶MAST205在调节IL12转录和由此引起的炎症中的作用，最后项目4研究了干扰素调节的基因(由IL12激活引起)在许多炎症性肠病模型中介导肠道炎症的作用。这笔赠款的核心是病理学/准入核心，它制定了一项战略，以有组织和及时的方式获取和处理肠道组织。本提案中详述的项目应使我们能够定义不同的监管路径，并确定它们之间相互作用的程度。它将炎症视为一个总的过程，并剖析出对肠道的正常功能和维持宿主内的动态平衡至关重要的成分。通过分析这一过程中可能发生的异常，在不受控制的炎症(IBD)的背景下，我们将有一个更好的窗口来定义正常。结果是宿主的健康和疾病治疗干预的新可能性。

DESCRIPTION, OVERALL (provided by applicant): Controlled or physiologic inflammation is the hallmark of the normal mucosa associated lymphoid tissue in the gut associated with a general tone (at least in the Gl tract) of suppression. The overall hypothesis guiding this program project grant is that this control requires both arms of the immune system, innate and adaptive, as well as components of the non-immune barrier, to develop a system of tight regulation, most likely an interactive one. A defect in any component of this network may result in inflammation. Thus our focus is on the distinct aspects of innate, adaptive and non-immune responses which contribute to the overall suppressed tone of the Gl tract and to define specific interactions between the various pathways. What may be central to this regulation is the role that one cell type, the IEC, plays in this process. In project 1 we address the role of innate immunity via activation of a subpopulations of T cells by non-classical class I molecules expressed by intestinal epithelial cells. Project 2 looks at the role of chemokines/chemokine receptors in promoting vs. regulating inflammation. Project 3 assesses the role of a novel serine/threonine kinase MAST205 in regulating IL12 transcription and resulting inflammation and finally project 4 takes a look at interferon regulated genes (resulting from IL12 activation) in mediating intestinal inflammation in a number of models of inflammatory bowel disease. A centerpiece for this grant is the pathology/.accessioning core which has developed a strategy to acquire and process intestinal tissues in an organized and timely fashion. The projects detailed in this proposal should allow us to define distinct regulatory pathways and determine the level of their interactions. It looks at inflammation as a total process and dissects out components that are critical to the normal functioning of the gut and the preservation of homeostasis in the host. By analyzing abnormalities in this process, which might occur in the setting of uncontrolled inflammation (IBD), we will have a better window in which to define normality. The result is the health of the host and new possibilities for therapeutic intervention in disease.