In this proposal for competitive renewal of award RO1-NS-27321, there are two broad goals: (a) define the lymphocyte surface molecules responsible for permitting T-lymphoblasts rapid entry into the CNS (and other sites); and (b) characterize the changes occurring in areas of the CNS which are rendered susceptible to inflammation.
These aims are established based upon observations made under the present award. Two of these observations are: (a) T-cells readily enter the CNS regardless of MHC compatibility, antigen specificity, or phenotype if they are in the lymphoblast phase - resting/memory cells are excluded; and (b) a site specific model of Wallerian degeneration will alter a specific site in the CNS from be inflammation resistant to being inflammation susceptible within 24 hours. In reaching the stated goals, many convergent avenues of investigation of both T-cell membrane antigens and tissue molecular changes will be used. These will include both in vivo and in vitro studies. The methods to be employed are: in situ hybridization, monoclonal antibody production, T-cell tissue culture, FACS analysis, and in vivo systems of cytokine infusion, experimental allergic encephalomyelitis, Wallerian degeneration, Graft vs. Host disease, and T-lymphoblast transfer. The results of these studies should be readily applicable to any human illness in which the CNS is damaged by inflammation mediated by T-cells. Examples of such diseases are multiple sclerosis, viral encephalitis and post vaccinial encephalomyelitis.
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