© The Rockefeller University Press, 0022-1007/1999/4/1053/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 7, April 5, 1999 1053-1062
In Autoimmune Diabetes the Transition from Benign to Pernicious Insulitis Requires an Islet Cell Response to Tumor Necrosis Factor
Syamasundar V. Pakala,
Marylee Chivetta,
Colleen B. Kelly, and
Jonathan D. Katz
From the Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1β, tumor necrosis factor (TNF)-
, and interferon (IFN)-
are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to β cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-
receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF-
receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4+ T cells to establish insulitis and subsequently destroy islet β cells. These results argue that islet cells play a TNF-
–dependent role in their own demise.
Key Words: autoimmunity diabetes tumor necrosis factor
receptor T cells insulitis
Address correspondence to J.D. Katz, Center for Immunology and Department of Pathology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Phone: 314-747-1221; Fax: 314-747-0728; E-mail: jkatz{at}immunology.wustl.edu
We particularly wish to thank Dr. Charles Kilo and his Kilo Diabetes and Vascular Research Foundation for their generous financial support. In addition, this work was supported by grants to J.D. Katz from the Juvenile Diabetes Foundation International (JDFI; No. 197030), the Washington University Diabetes Research and Training Center, the National Institutes of Health (R01 AI44416), and a joint NIH/JDFI program project grant (P01 AI39676/995012; Dr. E.R. Unanue, program director). J.D. Katz is a recipient of an American Diabetes Association Career Development Award.
Abbreviations used: CFSE, 5,6-carboxy-succinimidyl-fluorescein-ester; IDDM, insulin-dependent diabetes mellitus; iNOS, inducible NO synthase; NO, nitric oxide; NOD, nonobese diabetic.

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