IL-23 and IL-17 in pathogenesis of experimental ocular autoimmunity: requirement for IL–23 may extend beyond its role in sustaining the IL-17 effector response (129.26)

Abstract

Abstract Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. Here we examined the role of the IL-23/IL-17 pathway in EAU. We immunized IL-23p19, IL-12p35, IL-12p40, IFN-γ and IL-17 KO mice with the uveitogenic Ag IRBP. Alternatively, we treated wild type mice immunized for EAU with Abs to IL-23p19 or to IL-17 throughout the disease course (prevention), or only during the effector phase (reversal). IL-23p19 KO were resistant to EAU, showing reduced Ag-specific DTH, IL-2, IFN-γ, IL-17, IL-1β, IL-6 and IL-5. In contrast, IL-12p35 and IFN-γ KO mice developed exacerbated EAU, DTH and IL-17 responses. Treatment with anti-IL-23p19 protected from EAU and reduced immunological responses, but was unable to reverse disease, indicating that EAU is dependent on early availability of IL-23. In contrast, anti-IL-17 prevented as well as reversed EAU. Interestingly, severe EAU could be induced with a Th1 cell line that does not produce IL-17. In vivo cytokine neutralization revealed requirement for IFN-γ and TNF-α, but not for IL-17, suggesting that under some conditions an antigen-specific Th1 effector is sufficient to induce EAU. In keeping with this, IL-17 KO mice were still susceptible to disease. These data raise the possibility that the nonredundant need for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and point to IL-23 and IL-17 as new therapeutic targets for uveitis.