This ongoing research program, in its eleventh year, has utilized respiratory/enteric orphan (REO) viruses as model probes of the mucosal immune system. Thusfar we have confined our studies to the gut and liver of various mouse hosts: immunocompetent or severe-combined immunodeficient neonates and adults. We have made a number of original fundamental findings concerning the host's mucosal immune response in the gut: especially ato elucidate the role of the Peyer's patch microenvironment in mediating preferred isotype switching of B cells to IgA (SecretaryAb) expression and in generating cytotoxic T cells (CTLs) that accumulate in intraepithelial spaces to contain enteric virus infections in the gut. Our studies have provided the functional bases for a 'cellular mucosal immune system' including both natural killer cells and cytotoxic T cells. We now propose to use reoviruses - which also display a tropism for respiratory epithelial cells - to address certain major, unresolved, fundamental questions concerning the 'mucosal' component of the immune system which functions in the respiratory tract (RALT). We plan to use assays which we have originally developed - the T dependent, clonal B cell microculture and organ fragment cultures for mucosal tissues - and the limiting dilution analyses for CTLs plus MAbs vs. mucosal 'homing' receptors, in these attempts: l) to determine whether RALT contains inductive sites analogous to those in Peyer's patches where preferred isotype switching to IgA occurs; 2) to assess whether CTLs with 'mucosal' homing propensities can be generated in the gut or RALT, and whether these can contribute effective protection to the respiratory tract; and 3) whether effective 'cross-priming' between gut and RALT can occur. The results of these analyses should be extremely relevant for the development of efficacious vaccines vs. respiratory pathogens.
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