NIH Research Festival
Autoimmune uveitis is a complex group of sight-threatening CNS diseases caused by activated retina-specific Th1 or Th17 cells, but their respective contribution to disease is still unclear. Previous studies showed that IL-17A neutralization prevents and reverses experimental autoimmune uveitis (EAU), and that the intensity of Th17 response correlates with disease severity (PMID 18391061). Furthermore, it has been proposed that IL-17/IFN-γ double-producer T cells are the actual pathogenic effectors in CNS disease (PMID 21278737). Paradoxically, however, IFN-γ KO (GKO) mice develop exacerbated autoimmunity compared to WT controls and EAU could develop in IL-17A KO mice, suggesting that diverse pathways can lead to pathology. We hypothesized that concurrent absence of IFN-γ and IL-17A would trigger alternative disease pathways. To test this, we immunized IL-17A and IFN-γ double KO (DKO) mice with the retinal autoantigen IRBP to induce EAU. We found that DKO mice were fully susceptible to EAU similarly to WT controls and displayed an eosinophil-dominant (as opposed to mononuclear) eye infiltrate as well as enhancement of IL-17F, Th2 and pro-inflammatory cytokines (IL-6, TNF- and IL-1). To rule out a protective role of IFN-γ that might have contributed to EAU development in DKO mice, we blocked IFN-γ at the effector phase of disease, when its pathogenic role is presumably dominant, in WT and IL-17A/IL-17F (17AF) KO mice. While effector stage blockade of IFN- γ ameliorated EAU in WT mice, it exacerbated EAU in 17AF KO mice. Moreover, IFN-γ Ab treated 17AF KO mice showed enhanced production of GM-CSF and massive infiltration of eosinophils in their eyes. To test whether GM-CSF contributes to pathology of EAU in the absence of Th1 and Th17, we administered an anti-GM-CSF antibody to EAU-challenged IL-17/IFN-γ DKO mice. Treatment with an anti-GM-CSF antibody during either induction or expression stage of EAU significantly suppressed disease severity and decreased eosinophil infiltration in DKO mice. Importantly, a single intravitreal injection of an anti-GM-CSF antibody immediately after the disease onset reduced EAU severity. These results support the interpretation that, in the concurrent absence of IFN-γ and IL-17A, GM-CSF plays a major and nonredundant role as a pathogenic effector cytokine.
Scientific Focus Area: Immunology
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