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More MS news articles for November 2002

Glycosylation processing inhibition by castanospermine prevents experimental autoimmune encephalomyelitis by interference with IL-2 receptor signal transduction

http://www.elsevier.com/gej-ng/10/27/37/137/25/26/abstract.html

Journal of Neuroimmunology, Vol. 132 (1-2) (2002) pp. 1-10
Silke Walter a, Klaus Fassbender a, Erich Gulbins b, Yang Liu a, Monika Rieschel c,d, Monika Herten e, Thomas Bertsch f and Britta Engelhardt d
a Department of Neurology, University of Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany
b Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 2794, USA
c Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Germany
d Max-Planck-Institute for Vascular Biology, Münster, Germany
e German Diabetes Research Institute at the University of Düsseldorf, Düsseldorf, Germany
f Institute of Clinical Chemistry, Klinikum Mannheim, University of Heidelberg, Heidelberg, Germany

In this study, we explored the therapeutic targets of the glycosylation processing inhibitor, castanospermine (CAST), in murine passive transfer experimental autoimmune encephalomyelitis (EAE), a model disease of multiple sclerosis. By using lymphocytic-endothelial adhesion and transmigration assays, FACScan and Western blotting, we defined the effects of CAST on expression, function and signal transduction of glycoproteins crucial in the pathophysiology of this disease. CAST prevented clinical signs of EAE and completely inhibited inflammatory CNS infiltrates associated with this disease. Here, we showed that CAST blocks antigen-induced lymphocytic activation and clonal expansion in a dose-dependent manner. Importantly, we observed that CAST strongly impairs IL-2-induced signal transduction of the IL-2 receptor. In contrast, neither expression nor binding ability of the IL-2 receptor was affected by this drug. In addition, we were able to exclude major effects of CAST on expression and function of different glycoproteins important in antigen presentation as well as lymphocytic-endothelial adhesion and transmigration. In conclusion, CAST strongly interferes in the signal transduction of the IL-2 receptor. This could explain both inhibitory effects of CAST in clonal T cell expansion and development of transfer EAE. This relatively selective pharmacological effect of CAST highlights its potential as a novel immunomodulatory approach in multiple sclerosis.