Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice

  1. Juliet A. Emamaullee1,
  2. Joy Davis1,
  3. Shaheed Merani1,
  4. Christian Toso1,
  5. John F. Elliott2,
  6. Aducio Thiesen3 and
  7. A.M. James Shapiro1,4
  1. 1Department of Surgery, University of Alberta, Edmonton, Alberta, Canada;
  2. 2Departments of Medicine and of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada;
  3. 3Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada;
  4. 4Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
  1. Corresponding author: Juliet Emamaullee, juliete{at}


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.


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    • Received August 14, 2008.
    • Accepted March 3, 2009.
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  1. Diabetes vol. 58 no. 6 1302-1311
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