EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA ON INSULIN-DEPENDENT DIABETES-MELLITUS IN NOD MICE .1. THE EARLY DEVELOPMENT OF AUTOIMMUNITY AND THE DIABETOGENIC PROCESS

被引:296
作者
YANG, XD
TISCH, R
SINGER, SM
CAO, ZA
LIBLAU, RS
SCHREIBER, RD
MCDEVITT, HO
机构
[1] STANFORD UNIV,SCH MED,DEPT MED,STANFORD,CA 94305
[2] WASHINGTON UNIV,SCH MED,DEPT PATHOL,ST LOUIS,MO 63110
关键词
D O I
10.1084/jem.180.3.995
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical sole in the early development of autoimmunity towards beta-islet cells.
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页码:995 / 1004
页数:10
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