The Journal of Immunology, Vol 157, Issue 10 4721-4725, Copyright © 1996 by American Association of Immunologists

ARTICLES

Prevention of autoimmune diabetes by linomide in nonobese diabetic (NOD) mice is associated with up-regulation of the TCR-mediated activation of p21(ras)

MJ Rapoport, L Weiss, A Mor, T Bistritzer, Y Ramot and S Slavin
Diabetes Unit, Assaf Harofeh Medical Center, Tel-Aviv University, Israel.

Oral therapy with linomide protects prediabetic nonobese diabetic (NOD) mice from insulin-dependent diabetes mellitus. The mechanisms by which linomide exerts its protective effect are not fully understood. A decreased TCR-mediated activity of the GTP-GDP binding p21(ras) proto- oncogene is associated with prediabetes in NOD mice. However, the role of this signal transduction defect in the pathogenesis of autoimmune diabetes is not known. The TCR-mediated and protein kinase C-induced activations of p21(ras) were determined in mononuclear cells from lymph nodes of linomide-treated and untreated prediabetic NOD mice. TCR cross- linking by Con A induced an increase of 13 +/- 6.8% and a decrease of 0.8 +/- 1.8% in p21(ras) activity in the linomide-treated group and the untreated controls, respectively. Cell stimulation with PMA resulted in a 15 +/- 2% increase in p21(ras) activity in the linomide-treated mice and a 10 +/- 11.4% decrease in the untreated mice. Protein levels of p21(ras) and its regulatory elements, the GTPase-activating protein and the guanine nucleotide-releasing factor, mSOS, were comparable in both groups. We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice.

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				M J Rapoport, A Mor, M Amit, R Rosenberg, Y Ramot, A Mizrachi, and A J Wysenbeek Decreased expression of the p21ras stimulatory factor hSOS in PBMC from inactive SLE patients Lupus, January 1, 1999; 8(1): 24 - 28. [Abstract] [PDF]