Tumor necrosis factor-alpha and the progression of diabetes in non-obese diabetic mice.
In the past decade, a wealth of information has accumulated through studies in non-obese diabetic (NOD) mice regarding the molecular and cellular events that participate in the progression to diabetes in insulin-dependent diabetes mellitus (IDDM). One molecule that has received considerable attention is the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). TNF-alpha has been demonstrated to have a positive or negative effect on the progression to diabetes in NOD mice, although the mechanism by which TNF-alpha exerts these differential outcomes is unknown. Here we describe a new NOD model for analyzing the role of TNF-alpha in IDDM, TNF-alpha-NOD mice. TNF-alpha-NOD mice express TNF-alpha solely in their islets from neonatal life onwards, and develop accelerated progression to diabetes. This rapid progression to diabetes is related to earlier and more aggressive infiltration of the islets with immune cells and an enhancement in the presentation of islet antigen in situ in the islets by islet-infiltrating antigen-presenting cells to T cells. Although adoptive transfer studies demonstrated that TNF-alpha can enhance presentation of islet antigen to both effector CD4+ and CD8+ T cells, further investigations in TNF-alpha-NOD mice deficient in either CD4+ or CD8+ T cells demonstrated that diabetes progression is dependent on CD8+ T cells, with CD4+ T cells playing a lesser role. The data accumulating from TNF-alpha-NOD mice, described in this review, indicates novel pathways by which inflammatory stimuli can precipitate autoimmunity, and suggests newer approaches in the design of therapeutic treatments that prevent beta-cell destruction in IDDM.
Green
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EA
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Flavell
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RA
D000818:Animals; D000831:Animals, Newborn; D017951:Antigen Presentation; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D007515:Islets of Langerhans / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
D014409:Tumor Necrosis Factor-alpha