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

• Published in: Endocrinology (Philadelphia) 2002-09, Vol.143 (9), p.3490-3497
• Main Authors: Wang, Jin-Lin, Qian, Xueming, Chinookoswong, Narumol, Lu, John, Chow, Gwyneth, Theill, Lars E, Shi, Zhi-Qing
• Format: Article
• Language: English
• Subjects: Age; Animals; Autoimmune diseases; Autoimmune Diseases - prevention & control; Corticosterone; Corticosterone - blood; Cyclophosphamide; Cyclophosphamide - administration & dosage; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Fatty Acids, Nonesterified - blood; Female; Gene Expression - drug effects; Glycerol - blood; Insulin - analysis; Insulitis; Interleukin-6 - genetics; Islets of Langerhans - chemistry; Islets of Langerhans - pathology; Lymphocytes - pathology; Mice; Mice, Inbred NOD; mRNA; Necrosis; Nitric oxide; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Nitric-oxide synthase; Pancreatitis - pathology; Pancreatitis - prevention & control; Polyethylene; Polyethylene glycol; Receptors; Receptors, Tumor Necrosis Factor - physiology; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; RNA, Messenger - analysis; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - physiology; Tumor necrosis factor-α
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2002-220412

We have conducted three studies to examine the role of TNFα 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 TNFα 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 TNFα in mediating insulitis in NOD mice and suggest the prophylactic and therapeutic potential of PEG sTNF-RI for human autoimmune diabetes.