ALTERED RESPONSES TO FOOD PROTEINS IN ENTERIC INFECTION

肠道感染中食物蛋白质反应的改变

• 批准号: 7032855
• 负责人: CATHRYN R NAGLER
• 金额: $ 8.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032855
• 关键词: antigen antibody reaction; food hypersensitivity; genetically modified animals; helminthiasis; helper T lymphocyte; laboratory mouse; mucosal immunity; oral administration; oral tolerance; ovalbumin; parasitic gastrointestinal disorder; passive immunization

Oral administration of soluble protein antigens typically induces antigen specific systemic nonresponsiveness. However, the PI has found that when a model food protein, ovalbumin (OVA), is orally administered to mice infected with a nematode parasite (Heligmosomoides polygyrus), this normally tolerogenic stimulus primes for a systemic OVA specific Th2 response. We have shown that the polarized Th2 cytokine response induced by this enteric infection plays a central role in determining whether or not tolerance to OVA is induced. We have also found that H. polygyrus infection potentates the response to oral antigen by enhancing T cell clonal expansion and upregulating costimulatory molecule expression on mucosal antigen presenting cells (APC). In Specific Aim 1,we will further explore the mechanistic basis for this effect by examining the influence of infection on various APC populations which can present orally administered antigens in mucosal and peripheral lymphoid tissue. To examine the ways in which helminth infection alters the OVA specific T cell response, T cells from OVA specific TCR transgenic mice will be adaptively transferred into normal BALB/c mice and their response will be tracked in vivo. In addition to providing insight into the ability of an infection to bias the response to other antigens, these experiments will provide basic information on antigen presentation in the mucosal immune system and the means by which it orchestrates decisions concerning tolerance and immunity. Since parasitic infection is endemic in many parts of the Third World, our observations have important clinical implications. The ability of Th2 biased infections to deviate the immune response to other antigens is well documented. Our model extends these findings in a novel direction by showing that enteric infection can elicit a Th2-biased immune response to a normally tolerogenic form of antigen. This suggests that helminth infection may pre-dispose for allergic phenomena and may affect the response to oral vaccines. In Specific Aim 2, we will therefore examine the ability of helminth infection to prime for an allergic response to a food antigen and explore the relevance of these findings to clinical food allergy. We will also examine the practical implications of mucosal parasitic infection for oral vaccination. If helminth infection biases for a Th2 response to oral vaccination, the success of oral vaccination campaigns in developing countries may hinge upon controlling the ability of these infections to alter responses to vaccine antigens. Characterization of the influence of mucosal infection on the response to oral vaccination using this murine model may suggest methods for maximizing the desired response to oral vaccines.

口服施用可溶性蛋白抗原通常诱导 抗原特异性全身无反应性。然而，PI发现， 当将模型食物蛋白卵清蛋白（OVA）口服给药于小鼠时 感染了线虫寄生虫（Heligmosomoides polygyrus），这通常 致耐受性刺激引发系统性OVA特异性Th 2应答。我们有 显示了由这种细胞因子诱导的极化Th 2细胞因子应答， 肠道感染在决定耐受性是否 OVA是诱导的。 我们还发现H.多脑回感染 通过增强T细胞克隆扩增对口服抗原的应答， 上调粘膜抗原呈递上的共刺激分子表达 细胞（APC）。在具体目标1中，我们将进一步探讨 通过检查感染对各种APC的影响， 可以在粘膜中呈递口服给药抗原的群体， 外周淋巴组织研究寄生虫感染 改变OVA特异性T细胞应答，T细胞从OVA特异性TCR 将转基因小鼠适应性地转移到正常BALB/c小鼠中， 将在体内追踪它们的反应。除了深入了解 感染使对其他抗原的反应偏向的能力，这些抗原 实验将提供关于抗原呈递的基本信息， 粘膜免疫系统及其协调决策的手段 关于宽容和豁免。由于寄生虫感染是许多国家的地方病， 在第三世界的部分地区，我们的观察具有重要的临床意义。 影响Th 2偏向性感染偏离免疫系统的能力 对其它抗原的应答是有据可查的。我们的模型扩展了这些 一个新的方向的发现表明，肠道感染可以引起一个新的方向， 对正常致耐受性形式的抗原的Th 2偏向性免疫应答。这 提示蠕虫感染可能易诱发过敏现象， 影响对口服疫苗的反应。在具体目标2中， 检查蠕虫感染引发过敏反应的能力， 食物抗原，并探讨这些发现与临床食物的相关性 过敏我们还将研究粘膜寄生虫的实际意义 口服疫苗的感染。如果蠕虫感染偏向于Th 2应答， 口服疫苗，口服疫苗运动的成功， 各国可能取决于控制这些感染的能力， 对疫苗抗原的反应。粘膜影响的表征 感染对使用该鼠模型的口服疫苗接种的应答的影响可以 提出了使口服疫苗的预期应答最大化的方法。