Cytokine regulation of anti-helminth immunity

描述（由申请人提供）：全球估计有20亿人感染土壤传播的蠕虫，这组寄生虫感染代表了重大的公共卫生和经济问题。虽然以IL-4和IL-13产生为特征的CD 4 + T辅助2型（TH 2）细胞应答是对肠道蠕虫感染的保护性免疫所必需的，但促进体内TH 2细胞应答的先天性免疫应答仍不完全清楚。该建议的目的是询问上皮细胞衍生的细胞因子胸腺基质淋巴细胞生成素（TSLP）对调节嗜碱性粒细胞反应和TSLP反应性祖细胞群分化的影响，并评估这些细胞在肠道线虫感染后影响TH 2细胞因子依赖性宿主保护性免疫中的作用。采用小鼠鞭虫和旋毛虫，两个充分表征的实验小鼠模型的人蠕虫感染，我们的初步研究确定，TSLP选择性地促进嗜碱性粒细胞的反应和嗜碱性粒细胞限制性表达是足以部分恢复TH 2细胞的反应和宿主的保护性免疫力蠕虫感染后，在易感小鼠。此外，我们在外周中鉴定了TSLP诱导的祖细胞样细胞群，其表达TSLP受体（TSLPR），表现出多能潜能并分化为产生IL-4和IL-13的效应细胞。总的来说，这些数据提供了两个以前未被认识到的途径，TSLP依赖性嗜碱性粒细胞和外周祖细胞样群体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消除方法，本提案的目标1将利用实验性鞭虫或旋毛虫感染小鼠来确定TSLP如何调节宿主保护性免疫所需的先天免疫应答。该提案的目的2将利用小鼠中的类似过继转移研究，结合人类患者和人源化小鼠（hu-mice）中的前沿研究，以评估TSLP对外周祖细胞应答的影响。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中的治疗潜力。我们预计，确定TSLP诱导的嗜碱性粒细胞和祖细胞样细胞对抗蠕虫免疫的贡献将指导未来的努力，以设计和提高抗寄生虫口服疫苗的功效，并抑制哮喘和其他过敏性疾病背景下的TH 2烟碱相关炎症。

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.