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Polyethylene Glycolated Recombinant TNF Receptor I Improves Insulitis and Reduces Incidence of Spontaneous and Cyclophosphamide-Accelerated Diabetes in Nonobese Diabetic Mice

Departments of Metabolic Disorders (J.-L.W., N.C., Z.-Q.S.), Inflammation (X.Q., L.E.T.), Pathology (G.C.), and Cancer Biology (J.L.), Amgen, Inc., Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Dr. Zhi-Qing Shi, Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, California 91320. E-mail: jshi{at}amgen.com.

We have conducted three studies to examine the role of TNF in islet destruction in female nonobese diabetic mouse (NOD) mice, a model of human autoimmune diabetes, using polyethylene glycolated (PEGylated) soluble TNF receptor type I (PEG sTNF-RI) as TNF antagonist. PEG sTNF-RI (3 mg/kg, sc) was given every other day to NOD mice from age wk 8 for 12 wk (study 1), from age wk 12 for 8 wk (study 2), or from age wk 8 for 3 wk, with cyclophosphamide (6 mg/mouse) injected at wk 9 to accelerate the onset of diabetes (study 3). Diabetic incidence was reduced (control vs. PEG sTNF-RI) from 68.7% (11 of 16) to 18.3% (3 of 16) in study 1, from 84.6% (11 of 13) to 28.5% (4 of 14) in study 2, and from 66.6% (8 of 12) to 23.1% (3 of 13) in study 3, respectively. The incidence of insulitis was also reduced from 91.6% (11 of 12) to 12.5% (2 of 16) in study 1 and from 100% (7 of 7) to 16.6% (2 of 12) in study 2 by PEG sTNF-RI. PEG sTNF-RI also largely preserved islet insulin content, reduced mRNA of inducible nitric oxide synthase and IL-6 in pancreases, and lowered plasma corticosterone, glycerol, and free fatty acid levels. These results confirm a pathogenic role of TNF in mediating insulitis in NOD mice and suggest the prophylactic and therapeutic potential of PEG sTNF-RI for human autoimmune diabetes.

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