The gastrointestinal tract contains the largest number of lymphocytes in the body that experience the greatest exposure to antigen. Central to our well being is the ability of the gastrointestinal immune system to mount an effective immune response to pathogenic bacteria and viruses, and at the same time display an immunologic hyporesponsiveness, or tolerance, to absorbed nutrients. The occurrence of tolerance to ingested antigens is well documented, however the mechanisms by which this tolerance occurs remain a mystery. Breakdown in the mechanisms of tolerance in the gastrointestinal immune system may result in diseases such as inflammatory bowel disease or celiac sprue. We believe that the intestinal lamina propria represents a specialized environment for the development and maintenance of a subset of immunoregulatory T- lymphocytes responsible for tolerance to ingested soluble antigens. We believe that macrophage tolerance to lipopolysaccharide and the immunoregulatory cytokines interleukin 10 and transforming growth factor beta are crucial to the induction and maintenance of tolerance in the gastrointestinal tract. Our preliminary data supports the hypothesis that when T lymphocytes in the lamina propria, in contrast to T lymphocytes from classical secondary lymphoid tissues, are stimulated by antigen, they exert a down regulatory effect on the immune response. We further hypothesize that development and maintenance of these immunoregulatory T lymphocytes is dependent upon the specialized environment of the intestinal lamina propria. To gain a better understanding of how the T-lymphocytes and antigen presenting cells in the lamina propria may regulate the immune response to ingested soluble antigens we propose the following specific aims: 1) Determine the role of macrophage tolerance to LPS in the induction and maintenance of tolerance in the gastrointestinal immune system. 2) Investigate the in vitro immunoregulatory capacity of the lamina propria lymphocytes. 3) Assess the ability of lamina propria lymphocytes to act in an immunoregulatory capacity in vivo in models of intestinal inflammation, lamina propria lymphocytes. We believe that understanding how the gastrointestinal immune system maintains a state of tolerance to ingested soluble antigens is of paramount importance in understanding the pathogenesis of gastrointestinal inflammatory diseases.
|Newberry, Rodney D; Lorenz, Robin G (2005) Organizing a mucosal defense. Immunol Rev 206:6-21|
|Lorenz, Robin G; Newberry, Rodney D (2004) Isolated lymphoid follicles can function as sites for induction of mucosal immune responses. Ann N Y Acad Sci 1029:44-57|
|Lorenz, Robin G; Chaplin, David D; McDonald, Keely G et al. (2003) Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J Immunol 170:5475-82|
|Newberry, Rodney D; McDonough, Jacquelyn S; McDonald, Keely G et al. (2002) Postgestational lymphotoxin/lymphotoxin beta receptor interactions are essential for the presence of intestinal B lymphocytes. J Immunol 168:4988-97|
|Newberry, R D; McDonough, J S; Stenson, W F et al. (2001) Spontaneous and continuous cyclooxygenase-2-dependent prostaglandin E2 production by stromal cells in the murine small intestine lamina propria: directing the tone of the intestinal immune response. J Immunol 166:4465-72|