Mucosal infections, especially those inducing diarrheal diseases, are common causes of morbidity and death worldwide. We hypothesize that the pattern of expression of key cytokines and costimulatory molecules during the initial interaction between pathogen or vaccine and the mucosal immune system is a critical determinant of healing and immunizing outcomes. The hypothesis will be tested in a swine model of mucosal immunity. The use of swine in this model is especially relevant since swine health is important to protection of the human food supply, and because of interest in pigs as donors for human xenotransplantation. The hypothesis will be tested in two parts. In part I, two types of mucosal adjuvants, cholera toxin (CT) and avirulent Salmonella (AS), will be used in combination with an orally administered model antigen, keyhole limpet hemocyanin (KLH) [1] to determine the pattern of expression of cytokines and costimulatory molecules induced in gut associated lymphoid tissues (GALT) following oral administration of CT or AS; and [2] to characterize the immune response to KLH delivered alone or coadministered with CT or AS. In part II, the casual relationship between the initial cytokine environment and immune outcome will be investigated [3] to characterize the patterns of type 1 and type 2 cytokines produced by T cells isolated from pigs immunized with KLH alone or with CT and AS; and [4] to determine if the differential expression of IL-10,IL-12 and CD 80/86 in GALT macrophages induces type 1 or type 2 responses in cocultured T cells. The PI holds a B.S. degree in Veterinary Science and a D.V.M. from the University of Minnesota, College of Veterinary Medicine. After 10 yrs in veterinary practice, he now is in his 4th yr of the Ph.D. program in the Department of Veterinary PathoBiology, University of Minnesota. The proposal will support further training and research in the areas of molecular biology and immunology leading to a career in biomedical research. It will be conducted in the Department of Veterinary PathoBiology, University of Minnesota. The graduate program has an emphasis on molecular mechanisms of disease pathogenesis and protective immunity. Members of the department and advisory committee will provide a wealth of expertise relative to the successful completion of the proposed research.
