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球约10亿人，据信每年造成约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，它们都与含有IL-4R α多肽的受体结合。在小鼠中，IL-4R α和Stat6（一种信号分子，当IL-4或IL-13与IL-4R α结合时被激活）的表达对胃肠道线虫寄生虫的驱逐至关重要。对感染巴西尼波圆线虫和旋毛虫的小鼠的研究表明，蠕虫的排出需要非骨髓源性细胞表达IL-4R α。IL-4和IL-13都影响非骨髓来源的细胞，包括肠上皮、杯状细胞、潘氏细胞、平滑肌和血管内皮，其方式可能有助于蠕虫从肠道排出；然而，没有证据表明这些作用或细胞类型对蠕虫的排出是充分或必要的。该提案将通过生产在一种或多种细胞类型上选择性表达IL-4R α或Stat6的转基因小鼠，以及在一种或多种细胞类型上选择性不表达IL-4R α的转基因小鼠，来验证一种或多种影响对蠕虫驱逐是充分和/或必要的假设。这些小鼠对IL-4和IL-13的生理反应及其对巴西奈瑟螨和螺旋体的驱逐能力将被确定。识别参与蠕虫驱逐的细胞类型将有助于识别IL-4/IL-13/IL-4R α / stat6依赖机制，这些机制通过驱逐胃肠道蠕虫来保护脊椎动物宿主。这一信息应该对预防或治疗胃肠道蠕虫感染的药物的基本原理设计有用。它还可以用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.