Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes
Andreas Holz, … , Kelly Brett, Michael B.A. Oldstone
Andreas Holz, … , Kelly Brett, Michael B.A. Oldstone
Published December 15, 2001
Citation Information: J Clin Invest. 2001;108(12):1749-1758. https://doi.org/10.1172/JCI13915.
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Article

Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes

Abstract

To analyze the function of the Th1-promoting cytokine IL-12 in vivo, we generated transgenic (tg) mice (RIP-IL12 mice) whose pancreatic β cells constitutively express bioactive IL-12 or one of its components, p35 or p40. In contrast to non-tg littermates or single-tg RIP-p35 and RIP-p40 mice, RIP-IL12 mice developed a marked pancreatic infiltration of lymphocytes and macrophages, mainly around islets. Expression of bioactive IL-12 primarily upregulated transcript levels of IFN-inducible protein-10 (IP-10), RANTES, IFN-γ, and TNF-α in the pancreas. Despite the substantial recruitment of mononuclear cells, no biochemical or clinical disease was evident in the exocrine or endocrine pancreas. Coexpression of lymphocytic choriomeningitis virus (LCMV) proteins with IL-12 in the β cells failed to spontaneously activate or expand antigen-specific anti-self/viral T cells in uninfected tg animals. However, when RIP-IL12 × RIP-LCMV tg mice were infected with LCMV, antigen-specific anti-self/viral T cells were induced, which led to an acceleration in the kinetics and severity of insulin-dependent diabetes mellitus (IDDM). Thus, the ectopic expression of IL-12 does not spontaneously break tolerance and activate antigen-specific T cells in the periphery, but it does worsen ongoing autoimmune disease.

Authors

Andreas Holz, Kelly Brett, Michael B.A. Oldstone

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Incidence of IDDM in RIP-LCMV and RIP-IL12 × RIP-LCMV tg mice after LCMV...
Incidence of IDDM in RIP-LCMV and RIP-IL12 × RIP-LCMV tg mice after LCMV infection. Incidence of IDDM for RIP-IL12 × RIP-GP (a) and RIP-IL12 × RIP-NP (b) mice following infection with 105 PFU of LCMV, administered IP. In the absence of viral infection, none of 70 RIP-GP mice, 43 RIP-IL12 × RIP-GP mice, 25 RIP-NP mice, or 19 RIP-IL12 × RIP-NP mice developed elevated blood glucose levels, including some of these mice that were observed for more than 6 months (n = 5 for each group). After LCMV infection, IDDM developed in all RIP-LCMV lines, but with different kinetics and severity. In rapid-onset IDDM RIP-GP mice, in which the viral transgene is expressed only in β cells of the islets of Langerhans, the incidence and kinetics of IDDM were roughly equivalent, although a quicker and more severe IDDM afflicted the double-tg RIP-IL12 × RIP-GP mice compared with single-tg RIP-GP mice. In the slow-onset IDDM RIP-NP mice, in which the viral transgene is expressed in the thymus as well as β cells, IDDM arose more quickly and severely in the RIP-IL12 × RIP-NP mice than in single-tg RIP-NP littermates. Mice in each experimental group were age- and sex-matched, and were infected with LCMV at 6–8 weeks of age.