Cytokine regulation of anti-helminth immunity

描述(申请人提供)：据估计，全世界有20亿人感染了土源性蠕虫，这组寄生虫感染是一个重大的公共卫生和经济问题。尽管肠道蠕虫感染的保护性免疫需要以IL-4和IL-13产生为特征的CD4+T辅助细胞2型(TH2)细胞反应，但体内促进TH2细胞反应的先天免疫反应仍不完全清楚。本研究的目的是探讨上皮细胞衍生细胞因子胸腺基质淋巴生成素(TSLP)对调节嗜碱性细胞反应和TSLP反应性前体细胞群分化的影响，并评估这些细胞在影响肠道线虫感染后TH2细胞因子依赖的宿主保护性免疫中的作用。我们的初步研究表明，TSLP能选择性地促进小鼠嗜碱性粒细胞的应答，而嗜碱性粒细胞的限制性表达足以部分恢复易感小鼠的TH2细胞应答和宿主保护性免疫。此外，我们在外周发现了一组TSLP诱导的祖细胞样细胞，它们表达TSLP受体(TSLPR)，显示出多潜能，并分化为产生IL-4和IL-13的效应细胞。总而言之，这些数据提供了两条以前未被认识的途径，通过这两条途径，依赖TSLP的嗜碱性粒细胞和外周血祖细胞样群是抗蠕虫免疫的关键调节因子。采用一系列新的过继转移和体内耗尽方法，该提案的目标1将利用小鼠的实验性旋毛虫或旋毛虫感染来确定TSLP如何调节宿主保护性免疫所需的先天免疫反应。这项建议的目的2将利用类似的小鼠过继转移研究，结合在人类患者和人源化小鼠(HU-小鼠)上的尖端研究，评估TSLP对外周血祖细胞反应的影响。这些研究的结果将提供一个框架，以测试操纵TSLP诱导的嗜碱性粒细胞或TSLP诱导的祖细胞样细胞在促进抗蠕虫免疫方面的治疗潜力。我们预计，确定TSLP诱导的嗜碱性粒细胞和祖细胞样细胞在抗蠕虫免疫中的作用将指导未来的努力，设计和改进抗寄生虫口服疫苗的效力，并在哮喘和其他过敏性疾病的背景下抑制TH2细胞因子相关的炎症。 公共卫生相关性：土壤传播的蠕虫寄生虫是一个重大的公共卫生问题，全世界约有20亿人感染。这项建议的目的是了解免疫系统中一种名为胸腺基质淋巴生成素(TSLP)的可溶性分子对调节免疫细胞发育和保护这些寄生虫感染所需的功能的影响。这些研究的结果将有助于设计成功的新的抗寄生虫药物、疫苗和免疫疗法来对抗这些传染病。

DESCRIPTION (provided by applicant): With an estimated two billion people infected with soil-transmitted helminthes worldwide, this group of parasitic infections represents a significant public health and economic concern. While CD4+ T helper type 2 (TH2) cell responses characterized by IL-4 and IL-13 production are required for protective immunity to intestinal helminth infection, the innate immune responses that promote TH2 cell responses in vivo remain incompletely understood. The goals of this proposal are to interrogate the influence of the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) on regulating basophil responses and the differentiation of TSLP- responsive progenitor cell populations and to assess the role of these cells in influencing TH2 cytokine- dependent host protective immunity following intestinal nematode infection. Employing Trichuris muris and Trichinella spiralis, two well-characterized experimental murine models of human helminth infections, our preliminary studies identified that TSLP selectively promotes basophil responses and basophil-restricted expression was sufficient to partially restore TH2 cell responses and host protective immunity following helminth infection in susceptible mice. In addition, we identified a population of TSLP-elicited progenitor-like cells in the periphery that express the TSLP receptor (TSLPR), exhibit multipotent potential and differentiate to effector cells that produce IL-4 and IL-13. Collectively these data provide insight into two previously unrecognized pathways by which TSLP-dependent basophils and peripheral progenitor-like populations are critical regulators of anti-helminth immunity. Employing a series of novel adoptive transfers and in vivo depletion approaches, Aim 1 of this proposal will utilize experimental Trichuris or Trichinella infection in mice to determine how TSLP regulates innate immune responses required for host protective immunity. Aim 2 of this proposal will utilize similar adoptive transfer studies in mice, in conjunction with cutting edge studies in human patients and humanized mice (hu-mice), to assess the influence of TSLP on progenitor cell responses in the periphery. The results of these studies will provide a framework to test the therapeutic potential of manipulating TSLP-elicited basophils or TSLP-elicited progenitor-like cells in the promotion of anti-helminth immunity. We anticipate that defining the contribution of TSLP-elicited basophils and progenitor-like cells to anti-helminth immunity will direct future efforts to design and improve the efficacy of anti-parasitic oral vaccines and to dampen TH2 cytokine-associated inflammation in the context of asthma and other allergic diseases. PUBLIC HEALTH RELEVANCE: Soil transmitted helminth parasites are a significant public health concern, with approximately two billion people infected worldwide. The goals of this proposal are to understand the influence of a soluble molecule of the immune system called thymic stromal lymphopoietin (TSLP) on regulating immune cell development and function required for protective immunity to these parasitic infections. The results of these studies will help to inform the design of successful new anti-parasitic drugs, vaccines and immunotherapies to fight these infectious diseases.