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

描述（由申请方提供）：胃肠道蛔虫寄生虫感染全球约10亿人，据信每年导致约100万人死亡。针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-4 R α多肽的受体结合。在小鼠中，IL-4 R α和Stat 6（一种当IL-4或IL-13与IL-4 R α结合时被激活的信号分子）的表达对于排出胃肠道线虫寄生虫是必不可少的。在感染巴西日本圆线虫和旋毛虫的小鼠中进行的研究表明，驱虫需要非骨髓来源的细胞表达IL-4 R α。IL-4和IL-13均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中排出;然而，没有证据表明这些作用或细胞类型中的任何一种对于蠕虫排出是足够的或必需的。该提议将通过产生在一种或多种这些细胞类型上选择性表达IL-4 R α或Stat 6的转基因小鼠，以及在一种或多种这些细胞类型上选择性不表达IL-4 R α的转基因小鼠，来检验一种或多种这些作用对于蠕虫驱逐是足够和/或必需的假设。结果表明，小鼠对IL-4和IL-13的生理反应及对N. brasiliensis和T.螺旋将被确定。识别参与蠕虫驱逐的细胞类型应有助于识别通过驱逐胃肠道蠕虫来保护脊椎动物宿主的IL-4/IL-13/IL-4 R α/Stat 6依赖性机制。这些信息对于预防或治疗胃肠道蠕虫感染的药物的合理设计是有用的。它也应该是有用的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.