ENDOGENOUS TNF PRODUCTION DIFFERS BETWEEN HIGH AND LOW DIABETES INCIDENCE NONOBESE DIABETIC (NOD) MICE

Tumour necrosis factor (TNF) has been implicated in the pathogenesis o f insulin-dependent diabetes mellitus (IDDM). To investigate a possibl e role for TNF in IDDM we compared endogenous TNF production in two li nes of non-obese diabetic (NOD) mice, NOD/Lt and NOD/WEHI, that have a high and low incidence of diabetes, respectively. Preliminary experim ents had shown that the lower syngeneic mixed lymphocyte reaction (SML R) in NOD/Lt mice could be corrected by TNF-alpha. Plasma TNF-alpha wa s measured in 8 week-old female non-diabetic mice primed with 1000 uni ts IV of murine interferon gamma (IFN-gamma) followed after 3 hours by 5 mu g IV of lipopolysaccharide (LPS). Two hours later plasma was col lected and TNF measured by ELISA. Plasma TNF in NOD/Lt mice was 9.2 +/ - 2.4 ng/ml (mean +/- SEM, n = 16) compared to 2.5 +/- 0.5 ng/ml in NO D/WEHI mice (n = 15) and 7.6 +/- 1.0 ng/ml in BALB/c mice (n = 14). Ti me course studies demonstrated higher levels of both immunoreactive an d bioactive TNF in NOD/Lt compared to NOD/WEHI mice up to 4 hours post -stimulation. A separate group of female NOD/Lt mice had IFN-gamma/LPS -stimulated plasma TNF-alpha measured at 10 weeks and were followed to age 30 weeks. The mean stimulated plasma TNF-alpha level was consiste ntly higher in those mice that developed diabetes compared to those th at remained non-diabetic, the difference being significant when mice w ere 21 weeks of age. These results suggest that endogenous TNF-alpha p roduction may be a trait marker of IDDM susceptibility.