The objective of this proposal is to clarify the cellular mechanisms which lead to antigen specific immunity and systemic hyporesponsiveness after oral antigen exposure. It is important to delineate these mechanisms in the normal state to understand the pathophysiology of intestinal diseases associated with immune abnormalities. The long-term objective is to develop effective strategies for manipulating the systemic and intestinal immune response to oral antigen, thereby reversing pathology seen in disease states. More specifically, the aims of this proposal are to characterize the immune cellular interactions in the Peyer's patch (PP), mesenteric lymph mode (MLN), and spleen that normally occur in response to enteric antigen exposure. The antigen presenting cells (APCs) in the systemic system play a role in initiating the immune response, and in fact, it may be the efficacy of antigen presentation that dictates the type of response induced. These cells will be characterized in the PP and MLN and attempts will be made to modulate the immune response by manipulation of the APC. The rpesence or absence of suppressor T cell subsets will be delineated, as well as the pattern of lymphocyte migration leading to systemic hyporesponsiveness. To investigate cellular immune interactions in pathologic conditions, a model of antigen specific granuloma formation will be studied with regards to the manner in which antigen processing relates to the generation of granulomas. To achieve these goals, the immune response to the hapten azobenzenearsonate (ABA), will be studied since much is known regarding the cellular immune response to this hapten. Agents such as monoclonal antibodies, hybridoma supressor factors, leukocytosis promoting factor and chemotherapeutic reagents will be used to manipulate and modulate the normal immune response to ABA. Both in vivo and in vitro, responses will be assayed by means of measuring delayed type hypersensitivity responses or cytotoxic T cell lysis. In addition, studies on reovirus will be performed since oral inoculation of specific types of virus lead to systemic suppression. By using monoclonal anti-idiotypic antibodies, specific for idiotypes reactive to certain domains of the reovirus hemagglutinin, manipulation of the immune response may be possible. Further characterization of an antigen specific T cell dependent model of granuloma formation will be investigated as will new methods to inhibit this lesion. Only by delineating the cellular interactions that occur in the GI tract in normal and disease states, will rational strategies for therapeutic intervention be devised.
| Ginsburg, C H; Wisniewski, E; Greene, M I (1987) The role of an anti-idiotype antibody in regulating hapten (azobenzenearsonate)-specific granuloma formation. Immunology 62:335-40 |
