Treatment with neutralizing antibodies specific for IL-1beta prevents cyclophosphamide-induced diabetes in nonobese diabetic mice.
Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of IDDM, but it is not clear which form, IL-1alpha or IL-1beta, is predominantly implicated. In this study, we have evaluated the contribution of IL-1beta by treating diabetes-prone nonobese diabetic (NOD) mice with specific neutralizing antibodies. First, we assessed the neutralizing potential of these antibodies in C57BL/6 mice under acute septic shock by measuring IL-1beta in sera 4 h after lipopolysaccharide injection. One milligram and 0.1 mg of anti-IL-1beta antibodies (Abs) were capable of neutralizing the IL-1beta produced, and the effect persisted for at least 5 days. Second, we evaluated the role of IL-1beta in the cyclophosphamide (CY)-accelerated model of diabetes. Nondiabetic male NOD mice were injected with 200 mg/kg CY and treated twice weekly with anti-IL-1beta Ab. The incidence of diabetes reached 76 and 100% in the control groups treated with 0.25 and 0.1 mg rabbit IgG, respectively. In contrast, only 34% of mice treated with 0.25 mg of anti-IL-1beta Ab became diabetic. In the group treated with 0.1 mg of anti-IL-1beta Ab, 89% of the mice became diabetic in the same period of time, demonstrating that the protective effect was dose dependent. Our results show that IL-1beta is a critical effector molecule in this model of IDDM and that its specific inhibition could be an attractive target for therapeutic intervention.
Cailleau
C
C
INSERM U25, Hôpital Necker, Paris, France.
Diu-Hercend
A
A
Ruuth
E
E
Westwood
R
R
Carnaud
C
C
D000818:Animals; D001681:Biological Assay; D003520:Cyclophosphamide / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000737:chemistry / Q000472:pathogenicity; D007106:Immune Sera / Q000276:immunology / Q000494:pharmacology*; D015994:Incidence; D007375:Interleukin-1 / Q000097:blood / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009500:Neutralization Tests; D011817:Rabbits; D011994:Recombinant Proteins / Q000276:immunology; D012772:Shock, Septic / Q000097:blood* / Q000139:chemically induced; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
D007106:Immune Sera; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D003520:Cyclophosphamide