INTERLEUKIN-12 GENE-EXPRESSION IS ASSOCIATED WITH RAPID DEVELOPMENT OF DIABETES-MELLITUS IN NONOBESE DIABETIC MICE

A single dose of cyclophosphamide (250 mg/kg) is known to synchronize and accelerate development of diabetes in non-obese diabetic mice. We have reported previously that cyclophosphamide treatment of 10-week-ol d female non-obese diabetic mice induces a shift from T-helper type 2 to T-helper type 1 activity in islet lesions. We now show that this sh ift in regulatory T-cell function is preceded by the expression of int erleukin-12 in the islets as well as in the spleen. In the spleen macr ophages were identified as the interleukin-12 expressing cell type. At the same time there was little induction of tumour necrosis factor al pha gene expression by macrophages. Since interleukin-12 is well known to drive T-helper cell type 1 responses we assume that interleukin-12 released by macrophages mediates the accelerating effect of cyclophos phamide on islet inflammation in non-obese diabetic mice. mRNA express ion of the p40 chain of interleukin-12 in response to cyclophosphamide was not seen in macrophages of Balb/c mice and thus represents an imm une abnormality of non-obese diabetic mice favouring T-helper type 1 r eactions.