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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001715-02
Application #
3218329
Study Section
Special Emphasis Panel (SRC (01))
Project Start
1992-07-01
Project End
1996-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Yamagishi, M; Getchell, M L; Takami, S et al. (1998) Increased density of olfactory receptor neurons immunoreactive for apolipoprotein E in patients with Alzheimer's disease. Ann Otol Rhinol Laryngol 107:421-6
Kulkarni-Narla, A; Getchell, T V; Getchell, M L (1997) Differential expression of manganese and copper-zinc superoxide dismutases in the olfactory and vomeronasal receptor neurons of rats during ontogeny. J Comp Neurol 381:31-40
Kulkarni-Narla, A; Getchell, T V; Schmitt, F A et al. (1996) Manganese and copper-zinc superoxide dismutases in the human olfactory mucosa: increased immunoreactivity in Alzheimer's disease. Exp Neurol 140:115-25
Takami, S; Getchell, M L; Albers, K M et al. (1996) An age-dependent novel hyperinnervation of circumvallate papillae by tyrosine hydroxylase-containing nerve fibers in NGF-overexpressing transgenic mice. Brain Res 707:303-7
Krishna, N S; Getchell, T V; Dhooper, N et al. (1995) Age- and gender-related trends in the expression of glutathione S-transferases in human nasal mucosa. Ann Otol Rhinol Laryngol 104:812-22
Getchell, T V; Krishna, N S; Dhooper, N et al. (1995) Human olfactory receptor neurons express heat shock protein 70: age-related trends. Ann Otol Rhinol Laryngol 104:47-56
Krishna, N S; Getchell, M L; Buiakova, O I et al. (1995) Human olfactory receptor neurons contain OMP mRNA in their dendritic and axonal processes. Neuroreport 6:817-21
Takami, S; Getchell, M L; Yamagishi, M et al. (1995) Enhanced extrinsic innervation of nasal and oral chemosensory mucosae in keratin 14-NGF transgenic mice. Cell Tissue Res 282:481-91
Takami, S; Getchell, M L; Getchell, T V (1995) Resolution of sensory and mucoid glycoconjugates with terminal alpha-galactose residues in the mucomicrovillar complex of the vomeronasal sensory epithelium by dual confocal laser scanning microscopy. Cell Tissue Res 280:211-6
Getchell, M L; Kulkarni-Narla, A; Takami, S et al. (1995) Age-dependent phenotypic switching of mast cells in NGF-transgenic mice. Neuroreport 6:1261-6

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