The mucosal immune response to antigen stimulation has a number of specialized features which are quite different from the systemic immune response, such as the induction of IgA synthesis and oral tolerance. The hypothesis behind this proposal is that these features of immune responses in gut-associated lymphoid tissues (GALT) are due to differences in the composition of lymphocytes and accessory cells in GALT compared to peripheral lymphoid tissues. These differences may lead to unique patterns of cytokine production, and may alter the balance between lymphocyte activation and tolerance in response to antigen exposure. The long-term goal of this proposal is to improve our current understanding of the cellular mechanisms underlying the mucosal immune response.
The specific aims are: 1) Compare T cell responses to orally and systemically administered antigens, including cytokine secretion, proliferation, and helper function for B cells; 2) Derive antigen-specific T helper cell clones from the mucosal immune system, which will serve as tools to investigate interactions between T cells and APC of GALT; 3) Characterize the T cell responses in situations where mucosal immune response differs from normal adult mice, as in graft-versus-host disease and in the neonatal period; studies of the oral immune response in these conditions may shed light on the mechanisms underlying human conditions such as food allergies. T cells will be harvested from GALT(Peyer's patches and mesenteric nodes) and peripheral lymph nodes of orally and systemically immunized mice, respectively, and will be stimulated in vitro with the antigens. Cytokine activities, including IL-2, IL-3, IL-4, AND IFN-gamma will be detected by bioassays and by mRNAs expressed, using Northern and dot blot hybridizations with P-labelled cDNAs. Neutralizing antibodies that are cytokine-specific (e.g. against IL-2 receptor, IL-4, IFN-gamma, and TNF) will be added to cultures and administered in vivo to see if the GALT T cell responses will be affected.
