Summary
The macrophage product interleukin (IL)-12 is known to drive Th1 reactions in physiological and pathological immune responses. Here we report that treatment with the homodimeric IL-12p40 subunit, an antagonist of the bioactive IL-12p35/p40 heterodimer, suppresses diabetes development in cyclophosphamide-injected NOD mice. Female mice of 70 days old received cyclophosphamide (250 mg/kg) to accelerate and synchronize diabetes development, and daily injections of 1 μg IL-12(p40)2. While there was no delay of the first diabetes cases, the incidence of overt diabetes was significantly decreased in treated mice (46 vs 23 %, p < 0.05). Analysis of mRNA expression in the pancreas showed that administration of the IL-12 antagonist had dampened interferon-gamma gene expression, decreased the ratio of interferon-gamma/IL-10 mRNA levels and in parallel suppressed the expression of the inducible nitric oxide synthase. At the same time intra-islet infiltration was significantly decreased (p < 0.001). Interestingly, the administration of IL-12(p40)2 also affected IL-12 gene expression, by downregulation of p35 mRNA. We conclude that IL-12 p40 homodimer suppresses diabetes development in the NOD mouse by dampening islet inflammation via selective downregulation of Th1 type responses. The naturally occurring IL-12 antagonist IL-12(p40)2 represents a new and specific Th1 directed approach to prevent autoimmune diabetes. [Diabetologia (1997) 40: 641–646]
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Received: 7 January 1997 and in revised form: 10 March 1997
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Rothe, H., O'Hara, R., Martin, S. et al. Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2. Diabetologia 40, 641–646 (1997). https://doi.org/10.1007/s001250050728
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DOI: https://doi.org/10.1007/s001250050728