Immunization of two (of four) inbred murine strains with purified syngeneic intestinal epithelial antigens elicits an inflammatory gut lesion. The immune response is implicated in lesion pathogenesis since the level of sensitization toward the immunizing antigen correlates with the incidence of lesion development. Patients with a chronic inflammatory bowel disease appear to be sensitized to the same set of macromolecules. These apparent autoreactive events directed at specific antigens on epithelial surfaces need, however, to be better understood through a more precise knowledge of the immunoregulatory factors which differentiate susceptible from non-susceptible strains and individuals. The importance of these studies derives from the extent to which mucosal epithelium covers internal body surfaces, the acute/chronic inflammatory diseases of unknown etiology which occur there, and the paucity of defined systems for studying the relevant immune responses.
The specific aim of this research is to test the hypothesis that immune sensitization to syngeneic intestinal epithelial cell-associated antigens (ECAC) in inbred murine strains is dependent upon a defect in antigen-specific immunoregulation which is genetically inherited; to determine whether such an immunoregulatory defect is single and dominant within each susceptible strain as well as in patients (index cases and first degree relatives) within families in which a genetic predisposition to chronic mucosal inflammation has been shown; and to study, in vitro, immunomodulation of the ECAC-specific cytotoxicity of human intestinal lamina propria mononuclear cells, through investigation of the possible regulatory effects of specific antibody, ECAC-specific suppressor cell populations, circulating ECAC-like antigenic fragments and anti-idiotypic antibody. Methods to be employed will include elicitation, then passive transfer of ECAC-specific antibody, Tsuppressor cells, and anti-idiotypic antibody-- to determine whether these macromolecules/cells can modulate the immune response/lesion development in ECAC/adjuvant challenged animals; quantitative radioimmunoassays--to detect ng/pg amounts of ECAC-specific antibody or ECAC itself in the circulation of patients, and 51Cr release microcytotoxicity assays to rigorously test whether selected macromolecules/cells may suppress the anti-ECAC reactivity of human lamina propria mononuclear cells.
