Multiple sclerosis (MS) is a primary disorder of myelin of uncertain etiology. Experimental Autoimmune Encephalomyelitis (EAE) is induced by sensitization with myelin basic protein (MBP) or derived encephalitogenic polypeptides (EPP). EAE is the best defined experimental model which is analogous to MS. This model has proven useful for testing new experimental approaches to demyelination which may be applicable to MS. These approaches are primarily based on the manipulation of the trimolecular complex. They are predicated on restricted T cell gene usage, genetic restriction, and precise epitopic definition. However, the practicality of these approaches is limited by the heterogeneity of human immune response. We propose to study a fusion toxin, DAB-IL-2. This mode of immunosuppression is no genetically restricted and preferentially attacks MBP of other antigen specific activated T cells. DAB-389 IL-2 is a Diphtheria toxin-IL-2 chimer protein. When MBP or other antigens activate T cells, these cells express the IL-2 high affinity receptor. The receptor binds the toxin and internalizes it. The cells are inactivated or killed and are no longer able to participate in the induction and/or maintenance of EAE pathology. This approach provides a model which is relatively independent of genetic restriction and precise epitopic definition. We will use DAB-IL-2 fusion toxin to prevent the development and/or promote the resolution of pathology due to EAE in the virus free Lewis rats. We will study the effects of DAB-IL-2 on EAE which is actively induced or passively transferred by sensitized T lymphocytes. In addition, we will determine the safety, toxicity, and optimal mode of therapy of DAB-IL-2. The mechanisms of suppression will be defined by studies on clonal deletion, anergy, and subpopulation regulation. These studies will provide an approach to the study of EAE which is relatively independent of the unique genetics of the host. DAB-IL-2 has been used safely and successfully in man to treat rheumatoid arthritis and juvenile onset diabetes mellitus. The immunopathology associated with these diseases has many analogies to the immunopathology of MS. Therefore, these studies will provide important insights into the genesis and treatment of multiple sclerosis and facilitate the targeted reduction of immunopathology in man.
| 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 |
