IMMUNITY TO PARASITIC INFECTION

这一建议将推进获得性肠道免疫的研究 旋毛虫在模型系统中使用大鼠。的重点 研究涉及对T.旋毛虫 被动地从一个特定免疫的母亲转移到她身上， 年轻该模型的新颖之处在于， 通过肠胃外免疫诱导。此外，一个戏剧性的和直接的 寄生虫的排出（“快速排出”）在肠中表达 被动免疫单克隆IgG抗体的幼崽。这些 抗体结合存在于幼虫表面以及 在它们的分泌物中发现的糖蛋白。保护性抗体不 阻止寄生虫进入其肠道生态位， 将其从该地点驱逐，以便实施驱逐。在某些 在某些情况下，抗体会影响幼虫在水中自由移动的能力。 上皮，但不驱逐它们。我们的目标是阐明 抗体通过其抑制和/或驱逐幼虫的机制， 他们的上皮生态位，并确定和功能特点， 这些抗体的分子靶标。 单克隆抗体可以抑制和驱逐T。旋毛虫幼虫 将在体内和体外使用， 研究抗体扰乱维持平衡的机制， 寄生虫和宿主在上皮中。实验提出了测试一个 提出了一系列与T.螺旋在 上皮以及寄生虫和 主持人这些假设表明，保护性抗体：1）影响 通过结合分泌的而非表面抗原的免疫; 2）干扰 随着幼虫通过上皮的迁移; 3）将幼虫从 阻断寄生虫抗原与宿主细胞的相互作用 依赖于肠上皮细胞上表达的Fc受体 在新生和成年大鼠和小鼠中。我们将把我们的发现应用于 针对另一种线虫-小鼠鞭虫的保护性免疫研究。 靶抗原的组成将在生物化学中揭示。 基因调查。结合的聚糖的结构 保护性抗体将被确定， 合成，以剖析其在寄生虫建立中的作用。我们 将继续克隆和表达编码肽的基因 部分抗原性糖蛋白，测试重组抗原， 免疫原性这些调查旨在查明和 表征寄生虫和宿主产生的分子， 是肠道线虫成功寄生所必需的

This proposal would carry forward studies of acquired intestinal immunity to Trichinella spiralis in a model system using rats. The focus of the inquiry has concerned the antibody dependent resistance to T. spiralis that is transferred passively from a specifically immunized mother to her young. This model is novel in that protective intestinal immunity is induced by parenteral immunization. Furthermore, a dramatic and immediate expulsion ("rapid expulsion") of parasites is expressed in the intestines of pups passively immunized with monoclonal IgG antibodies. These antibodies bind glycans presented on the surfaces of larvae and also on glycoproteins found in their secretions. Protective antibodies do not prevent the parasite from entering its intestinal niche, but rather dislodge it from that site, in order to effect expulsion. In certain instances, antibodies affect the ability of larvae to move freely in the epithelium, but do not expel them. Our objectives are to elucidate the mechanisms by which antibodies immobilize and/or dislodge larvae from their epithelial niche and to identify and functionally characterize the molecular target(s) of these antibodies. Monoclonal antibodies which immobilize and dislodge T. spiralis larvae from intestinal epithelia would be used in vivo and in vitro in order to study the mechanism by which antibodies perturb the balance maintained by parasite and host in the epithelium. Experiments are proposed to test a series of hypotheses which concern the behavior of T. spiralis in the epithelium as well as the essential interactions between parasite and host. These hypotheses state that protective antibodies: 1) effect immunity by binding to secreted and not surface antigens; 2) interfere with the migration of larvae through the epithelium; 3) divert larvae from their niche; 4) block interaction of parasite antigens with host cell components; 5) depend upon Fc receptors expressed on intestinal epithelia in neonatal and adult rats and mice. We would apply our findings to studies of protective immunity against another nematode, Trichuris muris. The composition of the target antigen(s) would be revealed in biochemical and genetic investigations. The structures of the glycans bound by protective antibodies would be determined and fragments of the glycans synthesized in order to dissect their role in parasite establishment. We would continue to clone and express the genes which encode peptide portions of antigenic glycoproteins, testing recombinant antigens for immunogenicity. These investigations are designed to identify and characterize the molecules produced by the parasite and the host that are required for successful parasitism by an intestinal nematode.