MUCOSAL IMMUNITY AND ORAL TOLERANCE--INNATE IMMUNITY

胃肠黏膜免疫系统已经进化出复杂和冗余的机制，以满足两个相互冲突的要求，既保护宿主免受侵袭性病原体的侵害，又确保对消化和正常菌群产生的无害但潜在的抗原物质的耐受性。本提案的长期目标是研究人体粘膜免疫系统中保护性免疫和耐受性之间的平衡取决于口服免疫原是在类似致病性入侵的环境中还是在非炎症、耐受性环境中遇到免疫系统的一般假设，部分取决于先天免疫系统的激活状态。在动物模型中有证据表明，调节先天免疫的许多途径之一涉及环加氧酶系统。不同抗原递送系统的影响，以及环加氧酶途径的药理学调节对粘膜免疫和耐受的影响尚未在人类中研究。该方法将包括系统测量人体对两种截然不同的口腔攻击的保护性免疫和耐受性，一种模仿侵入性病原体，另一种模仿对无害食物抗原的反应。我们将使用新的活重组肠道细菌载体（表达重组破伤风类毒素片段C的减毒伤寒沙门氏菌）和表达疫苗抗原的转基因植物食品（表达乙型肝炎表面抗原的转基因马铃薯）来评估保护性免疫，然后使用肠外免疫（破伤风类毒素或乙型肝炎表面抗原）来测试耐药性。为了研究前列腺素在粘膜免疫和耐受中的作用，志愿者将在口服免疫期间随机接受安慰剂、罗非昔布（一种选择性cox-2抑制剂）或米索前列醇（一种长效前列腺素E1类似物）。这项研究的结果将首次解决抗原递送方式和前列腺素水平调节人类口腔免疫和耐受之间平衡的假设。

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.