Blockade of Interleukin-6 Signaling Suppresses Not Only Th17 but Also Interphotoreceptor Retinoid Binding Protein–Specific Th1 by Promoting Regulatory T Cells in Experimental Autoimmune Uveoretinitis

Abstract

PURPOSE. Both Th17 and Th1 cells contribute to experimental autoimmune uveoretinitis (EAU). Interleukin-6 (IL-6) blockade inhibits Th17 differentiation in EAU and potently suppresses ocular inflammation, although its effect on Th1 cells is unknown. To clarify the mechanism of IL-6 blockade, the authors investigated T helper cells with particular focus on Th1 and regulatory T cells (Treg) in EAU of IL-6 gene knockout (KO) mice. METHODS. EAU was induced in wild-type (WT) mice and in mice lacking IL-6 (IL-6KO), IL-17 (IL-17KO), and IFN-γ (GKO) on a C57BL/6 background. Clinical scores of EAU, cytokine levels in supernatants from ocular tissue homogenates, and T helper cell differentiation in lymph nodes in each mouse were examined. To study the roles of Treg cells, EAU was induced in IL-6KO mice treated with anti-CD25 monoclonal antibody (mAb) to deplete Treg cells in vivo. RESULTS. Inflammation was comparable between WT, IL-17KO, and GKO mice but was absent in IL-6KO mice. Th17 and interphotoreceptor retinoid binding protein (IRBP)-specific Th1 cells were increased in GKO and IL-17KO mice, respectively, whereas both populations were reduced in IL-6KO mice. Th1-dominant EAU in IL-17KO mice was suppressed by anti-IL-6R mAb treatment. Treg cell depletion in vivo induced EAU in IL-6KO mice. CONCLUSIONS. After the induction of EAU, IL-6 deficiency resulted in the inhibition of the IRBP-specific Th1 response and enhanced the generation of IRBP-specific Treg cells. Furthermore, Treg was needed to inhibit Th1 responses and ocular inflammation in IL-6KO mice. Protective effects of IL-6 signaling blockade in EAU involve not only Th17 cell inhibition but also IRBP-specific Treg cell promotion.

Treatment of Uveitis by In Situ Administration of Ex Vivo–Activated Polyclonal Regulatory T Cells

“…4). This cytokine profile suggests that uveitis was a Th1-or Th17-mediated disease, as previously described in other models (19)(20)(21)(22)(23). As expected, Treg cells produced very low amount of these different cytokines (Fig.…”

“…These findings suggest that uveitis suppression by donor Treg cells was not dependent on CTLA or ICOS. Surprisingly, Treg cell treatment had no effect at the peak of disease on Th1 or Th17 Teff cells that are pathogenic in uveitis (19)(20)(21)(22)(23)53). Rather, Treg cell-mediated uveitis control in mice was correlated with a decrease of ROS production in the eye, revealed by the level of myeloperoxidase and by ROS activity in infiltrating cells.…”

IL-6 in Inflammation, Immunity, and Disease

“…For example, IL-6 blockade resulted in a noticeable reduction in susceptibility to Castleman's diseaselike symptoms in IL-6 transgenic mice (Katsume et al 2002). Similar effects were observed in models of RA (Alonzi et al 1998;Ohshima et al 1998;Fujimoto et al 2008), systemic lupus erythematosus (Mihara et al 1998), systemic sclerosis (Kitaba et al 2012), inflammatory myopathies (Okiyama et al 2009), experimental autoimmune uveoretinitis (Haruta et al 2011), experimental autoimmune encephalomyelitis , and many other diseases.…”

Application of Novel Quantitative Proteomic Technologies to Identify New Serological Biomarkers in Autoimmune Diseases

“…Anti-IL-6R mAb treatment had a significant protective effect in experimental autoimmune uveoretinitis (EAU) mice, but either TNFR-Fc or anti-TNF mAb treatment did not (Hohki et al, 2010). Interestingly, in the EAU model, anti-IL-6R mAb not only suppressed Th17 cell differentiation but also suppressed autoantigen-specific Th1 cells via the generation of induced regulatory T cells, supporting the notion that IL-6 inhibitors act on initial phase of adoptive immune response (Haruta et al, 2011). Confusingly, biological agents may act differently on different autoimmune diseases.…”