MUCOSAL IMMUNITY AND ORAL TOLERANCE--INNATE IMMUNITY

胃肠道粘膜免疫系统进化出复杂而冗余的机制，以满足两个相互冲突的要求，即保护宿主免受侵袭性病原体的侵袭，并确保对无害但潜在的抗原性物质的耐受性，这些物质是消化和正常菌群的产物。这一建议的长期目标是研究一般假设，即人类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病原体入侵的环境中遇到免疫系统，还是在非炎症性、耐受性环境中遇到免疫系统，这在一定程度上由天然免疫系统的激活状态决定。在动物模型中有证据表明，调节先天免疫的众多途径之一涉及环氧合酶系统。在人类中，不同的抗原递送系统的影响，以及环氧合酶通路的药物调节对粘膜免疫和耐受性的影响尚未被研究。该方法将包括系统地测量人类的保护性免疫和耐受性，以应对两种截然不同的口腔挑战，一种模仿侵袭性病原体，另一种模仿对无害食物抗原的反应。我们将使用新型重组肠道细菌载体(表达重组破伤风类毒素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(表达乙肝表面抗原的转基因土豆)来评估保护性免疫，然后进行肠外免疫(破伤风类毒素或乙肝表面抗原)以测试耐受性。为了研究前列腺素在粘膜免疫和耐受中的作用，志愿者将被随机分为两组，一组在口服免疫期间接受安慰剂、罗非昔布(一种选择性的COX-2抑制剂)，另一组是米索前列醇(一种长效前列腺素E1类似物)。这项研究的结果将首次解决这一假设，即抗原递送方式和前列腺素水平调节人类口服免疫和耐受之间的平衡。

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.