Polyethylene glycolated recombinant TNF receptor I improves insulitis and reduces incidence of spontaneous and cyclophosphamide-accelerated diabetes in nonobese diabetic mice.
We have conducted three studies to examine the role of TNFalpha 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 TNFalpha 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 TNFalpha in mediating insulitis in NOD mice and suggest the prophylactic and therapeutic potential of PEG sTNF-RI for human autoimmune diabetes.
Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, California 91320, USA.
Jin-Lin
JL
Wang
Xueming
X
Qian
Narumol
N
Chinookoswong
John
J
Lu
Gwyneth
G
Chow
Lars E
LE
Theill
Zhi-Qing
ZQ
Shi
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control; D003345:Corticosterone / Q000097:blood; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005990:Glycerol / Q000097:blood; D007328:Insulin / Q000032:analysis; D015850:Interleukin-6 / Q000235:genetics; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009336:Necrosis; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010195:Pancreatitis / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D015850:Interleukin-6; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005990:Glycerol; D003345:Corticosterone