The prevention and/or effective treatment of Multiple Sclerosis (MS) will ultimately depend on an understanding of etiology and pathogenesis. The two most popular theories include a disorder of immune regulation and an infectious agent theory but these are not mutually exclusive. Our working hypothesis states that MS is the result of unregulated immune responses (the result of defects in immune regulation in genetically susceptible individuals) directed at latent viral infections of the central nervous system (CNS) and resulting in damage to oligodendrocytes (OL). Previous reports of defects in immune regulation and the presence of viral genome sequences in the CNS of MS patients form the basis of this proposal. The functional studies of Antel et al. (1979) using an in vitro Con A suppressor cell assay indicates that an abnormality of cell mediated immunity exists and correlates with clinically determined disease activity. These results, confirmed by independent investigators, were interpreted as indicating an abnormality in T-suppressor cell subsets. Support for this interpretation came from the phenotypic studies of Reinherz et al. (1980) and Bach et al. (1980) in which specific peripheral blood lymphocyte (PBL) phenotypes (OKT5+, OKT8+) were altered in MS. Infectious agents have not consistently been recovered from the CNS of MS patients however recently viral genome sequences of measles (Haase et al. 1981) and Herpes simplex virus (Fraser et al. 1981) have been identified in the CNS of a number of MS patients. The long term objective of this proposal is to develop phenotypic and functional studies of the immune system in MS patients based on these original observations. The phenotypic studies will employ """"""""multicolor"""""""" microfluorometric analysis in which three or more cell surface antigens can be identified simultaneously by monoclonal antibodies and FACS IV. The study will define the PBL subsets which best correlate with MS disease and disease activity (defined clinically and by MRI) by further subdividing larger subsets with additional monoclonal antibodies. Ultimately, the functional properties of these subsets will be studied. Functional studies will employ standard assays (in-vitro NK cell assay using K562 cells as targets) but will also develop additional in-vitro assays using human OL (HOL) cultures as targets. HOL from controls and MS patients, along with control HOL latently infected with Herpes simplex virus 1 as a model of latent viral infection in the CNS will be used as targets.
