MUCOSAL IMMUNITY AND ORAL TOLERANCE--INNATE IMMUNITY

粘膜免疫和口腔耐受性——先天免疫

• 批准号: 6374619
• 负责人: Carol Tacket
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374619
• 关键词: Salmonella typhi; antigen presentation; attenuated microorganism; clinical research; genetically modified plants; hepatitis B antigens; human subject; mucosal immunity; oral tolerance; prostaglandin analogs; prostaglandin inhibitors; prostaglandins; recombinant proteins; tetanus toxoid

The gastrointestinal mucosal immune system has evolved complex and redundant mechanisms to meet two conflicting requirements that both protect the host from invasive pathogens and ensure tolerance to innocuous but potentially antigenic materials that are the products of digestion and the normal flora. The long term goal of this proposal is to study the general hypothesis that the balance between protective immunity and tolerance in the human mucosal immune system is dependent on whether oral immunogens encounter the immune system in a milieu resembling pathogenic invasion or in a non-inflammatory, toleragenic milieu, determined in part by the state of activation of the innate immune system. There is evidence in animal models that one of the many pathways regulating innate immunity involves the cyclooxygenase system. The effects of varying antigen delivery systems, and the effects of pharmacologic modulation of cyclooxygenase pathways on both mucosal immunity and tolerance have not been studied in humans. The approach will encompass systematic measurements of protective immunity and tolerance in humans in response to two very different types of oral challenge, one mimicking an invasive pathogen and the second mimicking the response to harmless food antigens. We will use novel live recombinant enteric bacterial vectors (attenuated S. typhi expressing recombinant tetanus toxoid fragment C) and transgenic plant foods expressing vaccine antigens (transgenic potato expressing hepatitis B surface antigen) to evaluate protective immunity followed by parenteral immunization (tetanus toxoid or hepatitis B surface antigen) to test for tolerance. To study the role of prostaglandins in mucosal immunity and tolerance, volunteers will be randomized to receive either placebo, rofecoxib, a selective cox-2 inhibitor, or misoprostol, a long-acting prostaglandin E1 analog during oral immunization. The results of this study will be the first to address the hypothesis that the mode of antigen delivery and level of prostaglandins modulate the balance between oral immunity and tolerance in humans.

胃肠道粘膜免疫系统已经发展出复杂和冗余的机制，以满足两种矛盾的要求，这些要求既保护宿主免受侵入性病原体，又确保对无害但潜在的抗原材料的耐受性，这些材料是消化的产物和正常的植物群。该提案的长期目标是研究一个普遍的假设：人类粘膜免疫系统中的保护性免疫和宽容之间的平衡取决于口服免疫力是否遇到一种类似于致病性入侵或非炎症性，耐受性的，耐受性的环境的环境中的免疫系统，该系统是由一定程度地由Imbication Immune Immune Immune System Insation of Immune Systone确定的。在动物模型中有证据表明，调节先天免疫力的许多途径之一涉及环氧酶系统。在人类中尚未研究各种抗原递送系统的影响以及环氧酶途径的药理学调节对粘膜免疫和耐受性的影响。该方法将涵盖人类保护性免疫和耐受性的系统测量，以应对两种非常不同的口服挑战，一种模仿侵入性病原体，第二个模仿对无害食品抗原的反应。我们将使用新型的活细菌载体（表达重组的破伤风毒素碎片c）和表达疫苗抗原的转基因植物食品（转基因马铃薯表达肝炎乙型肝炎表面表面抗原），以评估替氏抗性的保护性免疫（tentanus toteriation）（tentanus tosofiatiation）。为了研究前列腺素在粘膜免疫和耐受性中的作用，志愿者将被随机地接受安慰剂，rofecoxib，一种选择性COX-2抑制剂或米索前列醇，或者是长效的前列腺素E1 AMANOG在口服免疫过程中。这项研究的结果将是第一个解决以下假设的结果：抗原递送方式和前列腺素水平调节了人类口服免疫和耐受性之间的平衡。