Immuno-regulation of GI nematode infection

描述（由申请人提供）：土壤传播的蠕虫仍然是所有慢性人类感染中最普遍的，估计全世界有20亿人感染。现场和实验研究表明，感染个体的免疫力与辅助性T型2 （Th2）细胞因子的表达有关，而持续的重度感染可导致促炎细胞因子的过量产生和严重肠道炎症的发展。本提案的目标是确定感染后发生的先天免疫事件，并询问这些反应如何影响T辅助细胞分化和随后的抵抗或对感染的易感性。我们的初步研究采用了一个Trichuris感染的实验模型，确定了肠上皮细胞（IECs）在对感染的先天反应中的关键作用。对IEC功能的操纵表明IEC可以调节抗寄生虫免疫反应的多个方面。首先，iec中MHC II类的表达似乎对Th2细胞因子依赖性免疫的发展至关重要。其次，IECs分泌的细胞因子胸腺基质淋巴生成素（TSLP）似乎是影响树突状细胞和CD4+ T细胞反应的重要早期事件，而树突状细胞和CD4+ T细胞反应是蠕虫驱逐和预防肠道炎症所必需的。第三，TSLP-TSLPR相互作用似乎在对继发性滴虫感染的免疫中起关键作用，这表明iec来源的细胞因子可能对Th2记忆细胞的功能有重要影响。利用MHC II类、TSLP或TSLPR的细胞谱系特异性缺失，该项目的三个具体目标将确定(i) iec内在MHC II类表达如何控制Th2细胞因子反应的发展和调节，（II） TSLP-TSLPR相互作用如何在Th2细胞因子反应的发展和预防肠道炎症中发挥双重作用，以及（iii） iec衍生的TSLP如何调节trichuris反应的Th2记忆细胞的维持和功能。这些研究结果将为测试操纵IEC反应在促进抗蠕虫Th2反应和治疗胃肠道线虫感染后感染诱导的肠道炎症中的治疗潜力提供一个框架。此外，希望这些研究的发现将对理解与细胞因子产生失调相关的多种炎症性疾病（包括哮喘、过敏和炎症性肠病）的病理生理和治疗具有更广泛的意义。公共卫生相关性：全世界估计有20亿人感染了土壤传播的蠕虫寄生虫。尽管有强有力的证据表明辅助性T型2 （Th2）细胞因子对感染免疫至关重要，但促进保护性Th2细胞因子反应的早期先天免疫反应尚不明确。本建议的目标是了解肠上皮细胞在保护性免疫反应发展中的作用，并将这一知识应用于设计成功的新型抗蠕虫疫苗。

DESCRIPTION (provided by applicant): Soil transmitted helminths remain the most prevalent of all chronic human infections, with an estimated two billion people infected worldwide. Field and experimental studies indicate that immunity in infected individuals is associated with expression of T helper type 2 (Th2) cytokines, while persistent heavy infections can result in overproduction of proinflammatory cytokines and the development of severe intestinal inflammation. The goal of this proposal is to identify the innate immunologic events that occur following infection and interrogate how these responses influence T helper cell differentiation and subsequent resistance or susceptibility to infection. Employing an experimental model of Trichuris infection, our preliminary studies identified a critical role for intestinal epithelial cells (IECs) in the innate response to infection. Manipulation of IEC functions revealed that IECs can regulates multiple aspects of the anti-parasite immune response. First, expression of MHC class II in IECs appears to be critical for the development of Th2 cytokine-dependent immunity. Second, secretion of the cytokine thymic stromal lymphopoietin (TSLP) by IECs appears to be an important early event in influencing dendritic cell and CD4+ T cell responses required for worm expulsion and prevention of intestinal inflammation. Third, TSLP-TSLPR interactions appear to play a critical role in immunity to secondary Trichuris infection, suggesting IEC-derived cytokines may have an important influence on the function of Th2 memory cells. Employing cell lineage- specific deletions in MHC class II, TSLP or TSLPR, three specific aims of this project will determine (i) how IEC-intrinsic MHC class II expression governs the development and regulation Th2 cytokine responses, (ii) how TSLP-TSLPR interactions play a dual role in the development of Th2 cytokine responses and prevention of intestinal inflammation, and (iii) how IEC-derived TSLP regulates the maintenance and function of Trichuris-responsive Th2 memory cells. The results of these studies will provide a framework to test the therapeutic potential of manipulating IEC responses in the promotion of anti- helminth Th2 responses and treatment of infection-induced intestinal inflammation following gastrointestinal nematode infection. In addition, it is hoped that the findings of these studies will have broader implications for understanding the pathophysiology and treatment of multiple inflammatory diseases associated with dysregulated cytokine production including asthma, allergy and inflammatory bowel disease. PUBLIC HEALTH RELEVANCE: An estimated two billion people worldwide are infected with soil transmitted helminth parasites. Although there is strong evidence that T helper type 2 (Th2) cytokines are critical for immunity to infection, the early innate immune responses that promote protective Th2 cytokine responses are poorly defined. The goals of this proposal are to understand the role of intestinal epithelial cells in the development of protective immune responses and apply this knowledge in the design of successful new anti-helminth vaccines.