Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.
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.


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.
Emamaullee
Juliet A
JA
Department of Surgery, University of Alberta, Edmonton, Alberta,Canada. juliete@ualberta.ca
Davis
Joy
J
Merani
Shaheed
S
Toso
Christian
C
Elliott
John F
JF
Thiesen
Aducio
A
Shapiro
A M James
AM
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000637:transplantation*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D018398:Homeodomain Proteins; D011994:Recombinant Proteins; C064658:RAG-1 protein; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2