Immuno-regulation of GI nematode infection

胃肠道线虫感染的免疫调节

• 批准号: 8413648
• 负责人: David Artis
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413648
• 关键词: Address; Adoptive Transfer; Antigens; Asthma; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chronic; Dendritic Cells; Development; Disease; Epithelial Cells; Event; Exhibits; Experimental Models; Functional disorder; Goals; Health; Helminths; Human; Hypersensitivity; Immune response; Immunity; Immunologics; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Knowledge; Laboratories; MHC Class II Genes; Maintenance; Memory; Mus; Nematode infections; Outcome; Parasites; Pathway interactions; Play; Predisposition; Prevention; Production; Regulation; Resistance; Role; Secondary to; Soil; Synapses; T cell response; T memory cell; Testing; Th2 Cells; Therapeutic; Trichuris; Vaccines; Work; adaptive immunity; base; congenic; cytokine; design; field study; gastrointestinal; human TSLP protein; in vivo; mouse model; novel; research study; response; treatment response

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.

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。田间和实验研究表明，感染个体的免疫力与辅助性T细胞2型（Th 2）细胞因子的表达相关，而持续的重度感染可导致促炎细胞因子的过度产生和严重肠道炎症的发展。该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力或感染易感性。采用鞭虫感染的实验模型，我们的初步研究确定了肠上皮细胞（IEC）在先天性感染反应中的关键作用。对IEC功能的操纵揭示了IEC可以调节抗寄生虫免疫应答的多个方面。首先，IEC中MHC II类的表达似乎对Th 2型细胞依赖性免疫的发展至关重要。其次，IEC分泌细胞因子胸腺基质淋巴细胞生成素（TSLP）似乎是影响驱虫和预防肠道炎症所需的树突状细胞和CD 4 + T细胞反应的重要早期事件。第三，TSLP-TSLPR相互作用似乎在继发性鞭虫感染的免疫中起关键作用，表明IEC衍生的细胞因子可能对Th 2记忆细胞的功能具有重要影响。利用MHC II类、TSLP或TSLPR中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类表达如何支配Th 2细胞因子应答的发展和调节，（ii）TSLP-TSLPR相互作用如何在Th 2细胞因子应答的发展和肠道炎症的预防中发挥双重作用，以及（iii）IEC衍生的TSLP如何调节鞭毛虫反应性Th 2记忆细胞的维持和功能。这些研究的结果将提供一个框架来测试操纵IEC应答在促进抗蠕虫Th 2应答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。此外，希望这些研究的结果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）的病理生理学和治疗产生更广泛的影响。公共卫生相关性：据估计，全球有20亿人感染了土壤传播的蠕虫寄生虫。虽然有强有力的证据表明，辅助性T细胞2型（Th 2）细胞因子是至关重要的免疫感染，早期先天免疫反应，促进保护性Th 2细胞因子的反应是不明确的。该提案的目标是了解肠上皮细胞在保护性免疫反应的发展中的作用，并将这些知识应用于成功的新型抗蠕虫疫苗的设计中。