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Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice

Emamaullee, Juliet A.
Davis, Joy
Merani, Shaheed
Elliott, John F.
Thiesen, Aducio
Shapiro, A M James
Published in Diabetes. 2009, vol. 58, no. 6, p. 1302-1311
Abstract OBJECTIVE: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. RESEARCH DESIGN AND METHODS AND RESULTS: Although treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti-IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity. CONCLUSIONS: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.
Keywords Adoptive TransferAnimalsAntibodies, MonoclonalAutoantibodies/analysisDiabetes Mellitus, Type 1/*immunologyDisease ProgressionEnzyme-Linked Immunosorbent AssayFlow CytometryGlutamate Decarboxylase/genetics/immunologyHomeodomain Proteins/geneticsIslets of Langerhans TransplantationMiceMice, Inbred NODMice, KnockoutRecombinant Proteins/immunologyT-Lymphocytes, Helper-Inducer/*immunology/*transplantation
PMID: 19289457
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Research group Transplantation et hépatologie (905)
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EMAMAULLEE, Juliet A. et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. In: Diabetes, 2009, vol. 58, n° 6, p. 1302-1311. https://archive-ouverte.unige.ch/unige:19796

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Deposited on : 2012-04-23

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