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Submitted on October 22, 2004
Accepted on March 18, 2005
Institute for Biological Research "Sinisa Stankovic", Belgrade, Serbia and Montenegro; New York School of Medicine, NY and Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, New York, USA; Department of Geriatric, North Shore Long Island Jewish Health System, New York, USA; Department of Immunology, Philipps University, Marburg, Germany; Department of Medicine-Nephrology, Baylor College of Medicine, Houston, Texas, USA; Department of Biomedical Sciences, University of Catania, Italy
* To whom correspondence should be addressed. E-mail: yalabed{at}nshs.edu or DUTA{at}EUnet.yu.
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which plays a pivotal role in several immunoinflammatory and autoimmune diseases. In this study we have examined the role of MIF on the development of immunoinflammatory diabetes induced in susceptible strains of mice by multiple low doses of streptozotocin (MLD-STZ). 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 (ISO-1), markedly reduced clinical and histopathological features of the disease such as hyperglycaemia and insulitis. Lymphocytes from the mice treated with the MIF inhibitors exhibited reduction of both islet-Ag specific proliferative responses and adhesive cell-cell interactions. Neutralization of MIF also down-regulated the ex vivo secretion of the pro-inflammatory mediators TNF-
, IFN-
and nitric oxide while augmenting that of the anti-inflammatory cytokine, IL-10. This study provides the first in vivo evidence for a critical role for MIF in the immune-mediated 
cell destruction in an animal model of human T1D and identifies a new therapeutic strategy for the prevention and treatment of the disease in humans that is based on the selective inhibition of MIF activity.
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