Immunity to Parasitic Infection

描述(由申请人提供)：肠道上皮屏障对生存至关重要。肠道线虫利用新的工具在这个地方生活。反过来，对寄生线虫的免疫力有一套新的参数。我们的目标是阐明肠道免疫对寄生线虫的保护机制。快速排泄是一种有效的免疫现象，可以保护大鼠免受旋毛虫的二次感染。我们已经证明，针对幼虫排泄分泌产物上的酪氨酸糖封端的糖链的抗体，可以将幼虫从乳鼠体内驱逐出去。成年大鼠的排泄也依赖于抗酪糖免疫球蛋白，但需要与一种未知的先天成分合作。有证据表明，粘膜肥大细胞是粘膜肥大细胞的基本先天成分。免疫机制尚不清楚。我们在体外复制旋毛虫上皮栖息地的能力为我们提供了一个独特的机会来研究细胞和抗体的合作保护活性。我们的特定目标将检验以下假设：1.免疫复合体激活粘膜肥大细胞是同型依赖的。用抗酪氨酸单抗形成的免疫复合体将测试受体结合、脱颗粒和与大鼠粘膜肥大细胞的细胞因子诱导。肥大细胞将用感染过程中局部产生的细胞因子进行处理，以诱导可能有助于肠道免疫的细胞特性。2.黏膜肥大细胞的激活破坏了旋毛虫的上皮生境。旋毛虫的肠道栖息地将在体外模拟，以剖析促进寄生虫排出的肥大细胞活动。危害旋毛虫上皮栖息地的特定和非特定介体的工作机制将被定义。3.肥大细胞和抗酪糖抗体在体内介导快速排泄。将肥大细胞缺陷的大鼠感染，以测试肥大细胞在体内快速排出的贡献。我们将通过诱导不依赖于旋毛虫的大鼠肥大细胞增多来重建免疫肠道，然后用酪氨酸特异性抗体被动免疫大鼠。我们提出的工作将阐明一种有效的肠道免疫机制，并将提高我们开发针对肠道病原体的新型疫苗的能力。

DESCRIPTION (provided by the applicant): The epithelial barrier in the intestine is crucial to survival. Intestinal nematodes deploy novel tools to live in this site. In turn, immunity to parasitic nematodes has a set of novel parameters. Our objective is to elucidate mechanisms of protective, intestinal immunity against parasitic nematodes. Rapid expulsion is a potent immune phenomenon that protects rats against secondary infection by Trichinella spiralis. We have shown that IgG antibodies, specific for tyvelose-capped glycans on larval excretory-secretory products, expel larvae from suckling rats. Expulsion by adult rats is also dependent upon anti-tyvelose IgG but requires cooperation with an unidentified innate component. Evidence suggests that the essential innate constituent is the mucosal mast cell. The mechanism of immunity is unknown. Our ability to reproduce the epithelial habitat of T. spiralis in vitro affords us a unique opportunity to investigate the cooperative, protective activities of cells and antibodies. Our specific aims will test the following hypotheses: 1. Activation of mucosal mast cells by immune complexes is isotype dependent. Immune complexes formed with monoclonal anti-tyvelose IgGs will be tested for receptor binding, degranulation and cytokine induction with rat mucosal mast cells. Mast cells will be treated with cytokines that are produced locally during infection in order to induce cellular properties that may contribute to intestinal immunity. 2. Activation of mucosal mast cells disrupts the epithelial habitat of T. spiralis. The intestinal habitat of T. spiralis will be modeled in vitro in order to dissect mast cell activities that promote parasite expulsion. The workings of specific and non-specific mediators that compromise the epithelial habitat of T. spiralis will be defined. 3. Mast cells and anti-tyvelose IgG mediate rapid expulsion in vivo. Mast cell deficient rats will be infected to test the contribution of mast cells to rapid expulsion in vivo. We will recreate the immune intestine by eliciting mastocytosis in rats independently of intestinal T. spiralis, and then passively immunizing rats with tyvelose specific antibodies. The work we propose will elucidate a potent mechanism of intestinal immunity and will improve our ability to develop novel vaccines for intestinal pathogens.