Immunity to Parasitic Infection

描述（由申请人提供）：肠上皮屏障对存活至关重要。肠道线虫部署了新的工具来生活在这个地方。反过来，对寄生线虫的免疫有一组新的参数。我们的目的是阐明对寄生线虫的保护性肠道免疫机制。快速驱逐是一种有效的免疫现象，可以保护大鼠免受旋毛虫的继发感染。我们已经证明，IgG抗体，对幼虫排泄-分泌产物上的tyvelos -capped glycans具有特异性，可以驱逐哺乳大鼠的幼虫。成年大鼠的驱逐也依赖于抗tyvelose IgG，但需要与一种未知的先天成分合作。有证据表明，主要的先天成分是粘膜肥大细胞。免疫机制尚不清楚。我们在体外复制螺旋体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。我们的具体目标将检验以下假设：1。免疫复合物对粘膜肥大细胞的激活是同型依赖性的。用单克隆抗tyvelose igg形成的免疫复合物将在大鼠粘膜肥大细胞中进行受体结合、脱颗粒和细胞因子诱导试验。肥大细胞将在感染期间局部产生细胞因子，以诱导可能有助于肠道免疫的细胞特性。2. 粘膜肥大细胞的激活破坏了螺旋体的上皮栖息地。螺旋体的肠道栖息地将在体外建模，以解剖肥大细胞的活动，促进寄生虫驱逐。将定义损害螺旋体上皮栖息地的特异性和非特异性介质的作用。3. 肥大细胞和抗tyvelose IgG介导体内快速排出。将感染肥大细胞缺陷大鼠，以测试肥大细胞对体内快速排出的贡献。我们将在不依赖肠螺旋体的大鼠体内诱导肥大细胞增生，然后用tyvelose特异性抗体对大鼠进行被动免疫，从而重建免疫肠。我们提出的工作将阐明肠道免疫的有效机制，并将提高我们开发肠道病原体新疫苗的能力。

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.