Cellular targets of IL-4 and IL-13 in worm expulsion

描述(由申请人提供)：胃肠道蛔虫寄生虫感染全世界约10亿人，据信每年导致约100万人死亡。对这些寄生虫的保护性免疫依赖于细胞因子IL-4和IL-13，这两种细胞因子都与含有IL-4Rα多肽的受体结合。在小鼠中，IL-4Rα和Stat6的表达对于驱除胃肠道线虫寄生虫是必不可少的。Stat6是一种信号分子，当IL-4或IL-13与IL-4Rα结合时被激活。在感染巴西拟青霉和旋毛虫的小鼠身上的研究表明，驱虫需要非骨髓来源的细胞表达IL-4Rα。IL-4和IL-13都影响非骨髓来源的细胞，包括肠上皮细胞、杯状细胞、潘氏细胞、平滑肌和血管内皮细胞，其作用方式可能有助于蠕虫从肠道中排出；然而，没有证据表明这些效应或细胞类型中的任何一种都足以或必不可少地驱除蠕虫。这项提议将通过产生在一个或多个这些细胞类型上选择性表达IL-4Rα或Stat6的转基因小鼠，以及在一个或多个这些细胞类型上选择性表达IL-4Rα的转基因小鼠，来检验这样的假设，即一个或多个或这些效应对于驱虫是充分和/或必要的。将测定这些小鼠对IL-4和IL-13的生理反应以及它们驱逐巴西奈瑟氏菌和旋毛虫的能力。识别参与驱虫的细胞类型将有助于识别IL-4/IL-13/IL-4Rα/Stat6依赖的机制，这些机制通过驱逐胃肠道蠕虫来保护脊椎动物宿主。这些信息应该有助于预防或治疗胃肠道蠕虫感染的药物的基本原理设计。它也应该有助于智能预测与抑制过敏性炎症的药物相关的风险。

DESCRIPTION (provided by the applicant): Gastrointestinal roundworm parasites infect approximately one billion people worldwide and are believed to cause approximately one million deaths annually. Protective immunity against these parasites is dependent upon the cytokines IL-4 and IL-13, which both bind to receptors that contain the IL-4R alpha polypeptide. In mice, the expression of both IL-4R alpha and Stat6, a signaling molecule that is activated when IL-4 or IL-13 bind to IL-4R alpha, are essential for expulsion of gastrointestinal nematode parasites. Studies in mice infected with Nippostrongylus brasiliensis and Trichinella spiralis demonstrate that worm expulsion requires IL-4R alpha expression by non-bone marrow-derived cells. Both IL-4 and IL-13 affect non-bone marrow-derived cells, including intestinal epithelium, goblet cells, Paneth cells, smooth muscle, and vascular endothelium, in ways that might contribute to worm expulsion from the gut; however, there is no evidence that any of these effects or cell types is sufficient or essential for worm expulsion. This proposal will test the hypothesis that one or more or these effects is sufficient and/or essential for worm expulsion by producing transgenic mice that selectively express IL-4R alpha or Stat6 on one or more of these cell types, as well as transgenic mice that selectively fail to express IL-4R alpha on one or more of these cell types. The physiological responses of these mice to IL-4 and IL-13 and their abilities to expel N. brasiliensis and T. spiralis will be determined. Identifying the cell types that participate in worm expulsion should facilitate identification of the IL-4/IL-13/IL-4R alpha/Stat6-dependent mechanisms that protect vertebrate hosts by expelling gastrointestinal worms. This information should be useful for the rationale design of pharmaceuticals that prevent or treat gastrointestinal worm infections. It should also be useful for the intelligent prediction of risks associated with agents that inhibit allergic inflammation.