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.
