The long-term objectives of the experiments described in this application are to delineate the local interactions between the cells of the olfactory mucosa and the cells of the immune system that are resident in this sensory neuroepithelium in animal models; to characterize the response of the olfactory immune barrier to pathogen invasion, particularly by viruses that gain access to the central nervous system through the olfactory nerves; and to apply the insights gained from these experiments to the investigation of the immunobiology of the human olfactory mucosa.
The specific aims are: 1) to describe the distribution of functional subsets of T lymphocytes in the olfactory mucosa of healthy and virus inoculated animals; 2) to identity and describe the distribution of macrophages, neutrophils, eosinophils and mast cells, agents of cell-mediated immunity, in the olfactory mucosa of healthy and virus-inoculated animals; 3) to characterize the effects of inflammatory mediators, released as a result of viral infections, on mucus secretion by Bowman's glands and on mucosal histology; 4) to characterize changes, resulting from intranasal virus inoculation, in the expression and distribution of constituents of the secretory immune system (i.e., secretory IgA, J. chain and secretory component) in the olfactory mucosa; 5) to compare the immune response to intranasal virus inoculation in animals with well-characterized mutations affecting the immune system with those of normal animals; and 6) to determine the effect of substance P/calcitonin gene-related peptide depletion from nerves of the extrinsic mucosa] innervation on virus-. Induced immune responses as characterized by the preceding experiments. A neurotropic virus, herpes simplex type 1, will be intranasally inoculated into healthy rats and mice. The development of the mucosal immune response will be analyzed using cell-specific antibodies and immunohistochemical techniques to identify the types, numbers, and distribution of specific cells of the immune system that infiltrate the olfactory mucosa at varying post-inoculation intervals. Computerized video image analysis will be used to quantify and compare the data obtained from healthy and virus-inoculated animals. The results of this work will be applied to an analysis of the immune barrier of the human olfactory mucosa and may have implications for the treatment of viral infections of the upper respiratory tract as well as for the design and development of mucosal vaccines against pathogenic organisms.
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