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Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18

Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; and
^* The Open University, Tel-Aviv 61392, Israel

²Correspondence: Department of Immunology, The Weizmann Institute of Science, Wolfson Bldg., Room 404, Rehovot 76100, Israel. E-mail: sara.fuchs{at}weizmann.ac.il

Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine that plays an important role in interferon gamma (IFN-) production and IL-12-driven Th1 phenotype polarization. Increased expression of IL-18 has been observed in several autoimmune diseases. In this study we have analyzed the role of IL-18 in an antibody-mediated autoimmune disease and elucidated the mechanisms involved in disease suppression mediated by blockade of IL-18, using experimental autoimmune myasthenia gravis (EAMG) as a model. EAMG is a T cell-regulated, antibody-mediated autoimmune disease in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1- and Th2-type responses are both implicated in EAMG development. We show that treatment by anti-IL-18 during ongoing EAMG suppresses disease progression. The protective effect can be adoptively transferred to naive recipients and is mediated by increased levels of the immunosuppressive Th3-type cytokine TGF-ß and decreased AChR-specific Th1-type cellular responses. Suppression of EAMG is accompanied by down-regulation of the costimulatory factor CD40L and up-regulation of CTLA-4, a key negative immunomodulator. Our results suggest that IL-18 blockade may potentially be applied for immunointervention in myasthenia gravis.—Im, S.-H., Barchan, D., Maiti, P. K., Raveh, L., Souroujon, M. C., Fuchs, S. Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18.

Key Words: autoimmunity • interleukin 18 • cytokines and costimulatory factors • immunotherapy • MG

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