Our program focuses on attempts to understand the pathogenesis of multiple sclerosis. The central hypothesis of this application is: T cell react to central nervous system antigen(s) and damage myelin/oligodendrocytes, leading to inflammation and demyelination. We propose three specific projects to test some aspects of this hypothesis, using, as a model system, Experimental Autoimmune Encephalomyelitis (EAE). We will study the T cell receptors involved in the induction of EAE, investigate the effects of elimination of autoreactive T cells, and seek ways to rescue injured oligodendocytes. The first Project will use a novel cytotoxic fusion toxin, DAB-IL-2, to inhibit the development of EAE. The detailed analysis of the dosimetry and toxicity mechanisms of action of this molecule on active and passive EAE are the focus of this project. These studies will pave the way for the possible application of this immunotherapeutic approach to multiple sclerosis. The second Project investigates the implication of restricted T cell Receptor gene usage for the generation of EAE. The analysis of how Vbeta8 restricted T cells are generated and escape elimination by immune surveillance are the focus of this project. These studies will provide essential information relating to the influence of the T cell repertoire on the generation of autoimmune diseases such as EAE and MS. The third Project studies basic mechanisms of the regulation of oligodendrocyte development and maturation. An investigation of the role of two receptors, p185c-neu and p65/95, containing tyrosine kinase activity, is the focus of this project. These receptors are relevant to the growth and maturation of oligodendrocytes and the ligands, which bind the receptors may be relevant to oligodendrocyte injury or enhancement of remyelination in MS.
|Cowan, David A; Gay, Denise; Bieler, Bert M et al. (2002) Characterization of mouse tGolgin-1 (golgin-245/trans-golgi p230/256 kD golgin) and its upregulation during oligodendrocyte development. DNA Cell Biol 21:505-17|
|Kawai, K; Ito, K; Imamura, K et al. (1993) Enhancing effects of irrelevant lymphocytes on adoptive transferred experimental allergic encephalomyelitis. J Neuroimmunol 42:39-45|
|Kawai, K; Heber-Katz, E; Zweiman, B (1991) Cytotoxic effects of myelin basic protein-reactive T cell hybridoma cells on oligodendrocytes. J Neuroimmunol 32:75-81|
|Kawai, K; Zweiman, B (1990) Characteristics of in vitro cytotoxic effects of myelin basic protein-reactive T cell lines on syngeneic oligodendrocytes. J Neuroimmunol 26:57-67|
|Zweiman, B; Lisak, R P (1986) Cell-mediated immunity in neurologic disease. Hum Pathol 17:234-45|