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Critical Role of Macrophage Migration Inhibitory Factor Activity in Experimental Autoimmune Diabetes

Institute for Biological Research Sinisa Stankovic (I.C., D.M., D.M.-I., S.S.-G.), 11000 Belgrade, Serbia and Montenegro; New York University School of Medicine (Y.A.-A.), New York, New York 10016; Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System (Y.A.-A.), Manhasset, New York 11030; Department of Geriatric, North Shore Long Island Jewish Health System (J.R.), New York, New York 11040; Department of Neurology (M.B.), University of Bonn, 10016 Bonn, Germany; Department of Medicine-Nephrology, Baylor College of Medicine (H.Y.L.), Houston, Texas 77030; and Department of Biomedical Sciences, University of Catania (F.N.), Catania 95021, Italy

Address all correspondence and requests for reprints to: Dr. Yousef Al-Abed, New York School of Medicine, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, New York 11030. E-mail: yalabed{at}nshs.edu. Or to: Dr. Stanislava Stosic-Grujicic, Institute for Biological Research Sinisa Stankovic, 29 Novembra 142, 11000 Belgrade, Serbia and Montenegro. E-mail: duta{at}eunet.yu.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pivotal role in several immunoinflammatory and autoimmune diseases. In this study we examined the role of MIF in the development of immunoinflammatory diabetes induced in susceptible strains of mice by multiple low doses of streptozotocin. We found that MIF protein was significantly elevated in islet cells during the development of diabetes, and that targeting MIF activity with either neutralizing antibody or the pharmacological inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, markedly reduced clinical and histopathological features of the disease, such as hyperglycemia and insulitis. Lymphocytes from mice treated with the MIF inhibitors exhibited reduction of both islet antigen-specific proliferative responses and adhesive cell-cell interactions. Neutralization of MIF also down-regulated the ex vivo secretion of the proinflammatory mediators, TNF-, interferon-, and nitric oxide, while augmenting that of the antiinflammatory cytokine, IL-10. This study provides the first in vivo evidence for a critical role for MIF in the immune-mediated ß-cell destruction in an animal model of human type 1 diabetes mellitus and identifies a new therapeutic strategy for the prevention and treatment of this disease in humans that is based on the selective inhibition of MIF activity.

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