Prevention of autoimmune diabetes mellitus in NOD mice by transgenic expression of soluble tumor necrosis factor receptor p55.
The non-obese diabetic (NOD) mouse represents a relevant animal model of autoimmunity for insulin-dependent diabetes mellitus. The pathogenic role of tumor necrosis factor (TNF) in insulitis and beta cell destruction observed in these mice remains controversial, since injections of TNF or of anti-TNF antibodies have been reported to exert protection or acceleration of diabetes, depending on the timing of administration. In this study, we demonstrate that, in contrast to the non-transgenic littermates, NOD mice with permanent neutralization of TNF by high blood levels of soluble TNF receptor p55-human FcIgG3-fusion molecules resulting from the expression of a transgene are protected from spontaneous diabetes. They are also protected from accelerated forms of disease caused by transfer of NOD spleen cells or cyclophosphamide injections. This protection is associated with a marked decrease in the severity and incidence of insulitis and in the expression of the adhesion molecules MAdCAM-1 and ICAM-1 on the venules of pancreatic islets. These data suggest a central role for TNF-alpha in the mediation of insulitis and of the subsequent destruction of insulin-secreting beta-cells observed in NOD mice. They may be relevant to cell-mediated autoimmune diseases in general, in which treatment with soluble TNF receptors might be beneficial.
Hunger
R E
RE
Department of Pathology, University of Bern, Switzerland.
Carnaud
C
C
Garcia
I
I
Vassalli
P
P
Mueller
C
C
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD / Q000276:immunology*; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000502:physiology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha