MUCOSAL IMMUNITY AND INFECTION

大多数感染涉及粘膜，无论是作为实际的网站， 感染或作为进入体内的门户。 本方案项目 目的是研究其性质、意义和预防， 粘膜免疫应答对感染性疾病的治疗潜力 病原体 总体目标是加深对以下方面的了解： 伊加介导的防御机制，被动免疫的治疗效果 特异性伊加抗体的施用，新疫苗的开发， 预防特定的粘膜感染和某些免疫病理学 粘膜对感染的免疫反应的并发症。 这项研究， 将由具有基础科学和临床 背景，将处理呼吸道感染， 由病毒、细菌和原生动物引起的胃肠道疾病。 的 四个项目将侧重于重要人类疾病的动物模型， 粘膜伊加抗体在宿主防御中的作用。 相关人力 阿米巴病、H.幽门胃炎（被认为占大多数 消化性溃疡病例），以及与粘膜病毒相关的疾病 感染，包括伊加肾病 虽然传统的保护 粘膜伊加的功能被认为是免疫排斥 屏障，基于体外研究新提出的功能，即 现在将中和粘膜上皮细胞内的病毒 在体内研究。 第一个项目是关于阿米巴病的， E.是有希望疫苗候选物 抗原，特别是半乳糖可降解粘附蛋白， 对发病机理至关重要。 这项研究将利用新的 狒狒肠道阿米巴病模型。 第二个项目，关于 螺杆菌引起的胃炎，也将调查有前途的候选人 疫苗抗原包括尿素酶 这项研究将利用 最近推出的H.无菌小鼠的猫感染。 在 第三个项目，伊加抗体中和病毒的能力 将在呼吸道感染中进行细胞内研究， 肝脏 对于呼吸道感染，仙台病毒，一种天然病原体， 小鼠和引起人类的副流感病毒的近亲 呼吸道疾病，将使用;肝炎的研究将使用 小鼠肝炎病毒，一种与人类冠状病毒相似的冠状病毒。 伊加单克隆抗体对病毒的细胞内中和作用将被证实。 在严重的气管上皮细胞和肝细胞中进行了评估， 免疫缺陷（SCID）小鼠。 由于伊加肾病，最常见的形式 肾小球肾炎，时间上与上呼吸道 疾病，第四个项目将寻求开发一种小鼠模型， 由呼吸道病毒（仙台）感染引起， 人类疾病的本质。 感染的特征和 导致伊加免疫复合物沉积在 肾脏和肾炎将被识别。

Most infections involve mucous membranes, either as the actual site of infection or as the portal of entry into the body. This Program Project is designed to investigate the nature, significance, and prophylactic and therapeutic potential of the mucosal immune response to infectious pathogens. The overall goals are to gain increasing insights into: mechanisms of defense mediated by IgA, therapeutic efficacy of passive administration of specific IgA antibody, development of new vaccines to prevent selected mucosal infections, and certain immunopathological complications of the mucosal immune response to infection. The research, to be performed by investigators with both basic science and clinical backgrounds, will deal with infections of the respiratory and gastrointestinal tracts caused by viruses, bacteria, and protozoa. The four projects will focus on animal models of important human diseases and the role of mucosal IgA antibodies in host defense. The relevant human diseases are amebiasis, H. pylori gastritis (thought to account for most cases of peptic ulcer disease), and diseases associated with mucosal viral infection, including IgA nephropathy. While the traditional protective function of mucosal IgA has been considered to act as an immune exclusion barrier, a newly proposed function based on studies in vitro, namely neutralization of viruses inside mucosal epithelial cells, will now be investigated in vivo. The first project, on amebiasis, seeks to exploit components of E. histolytica that are promising candidates for vaccine antigens, notably a galactose-inhibitable adherence protein that is critical to pathogenesis. This research will take advantage of a new baboon model of intestinal amebiasis. The second project, on Helicobacter-induced gastritis, will also investigate promising candidate vaccine antigens, including urease. The research will exploit the recently available model of H. felis infection of germ-free mice. In the third project, the ability of IgA antibodies to neutralize viruses intracellularly will be studied in infections of the respiratory tract and liver. For respiratory infection, Sendai virus, a natural pathogen of mice and a close relative of the parainfluenza viruses that cause human respiratory illnesses, will be used; the studies in hepatitis will employ mouse hepatitis virus, a coronavirus similar to human coronaviruses. Intracellular neutralization of virus by IgA monoclonal antibodies will be assessed in tracheal epithelial cells and hepatocytes in severe combined immunodeficient (SCID) mice. Since IgA nephropathy, the most common form of glomerulonephritis, is associated temporally with upper respiratory illness, the fourth project will seek to develop a mouse model that is induced by a respiratory viral (Sendai) infection and that mimics the essentials of the human disease. Those features of the infection and of the host response that lead to deposition of IgA immune complexes in the kidney and to nephritis will identified.