THU0027 INHIBITION OF TH17 CELLS IN PSORIATIC ARTHRITIS THROUGH ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR IS DEPENDENT UPON DISEASE ACTIVITY
Authors: Amara Ezeonyeji, Michael Ehrenstein
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Th17 cells have been implicated in the development of psoriatic arthritis (PsA) and psoriasis and are a major target for therapy. Th17 cells exhibit plasticity and can transdifferentiate to other effector cell types. Th17 cells that lose expression of IL-17 in favour of IFN-γ (nonclassical Th1 cells) contribute to the pathogenesis of autoimmune diseases and are found in the joints of patients with inflammatory arthritis. Conversely, induction of IL-10 in Th17 cells has been shown to suppress their pathogenic potential. The Aryl Hydrocarbon Receptor (AhR) is a nuclear receptor with pleiotropic effects on immune function. The AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ) has been shown to induce or suppress Th17 cell differentiation and promote generation of tolerogenic FoxP3+ T regs or Type 1 regulatory cells (Tr1) that produce IL-10. FICZ also reduces psoriaform inflammation in a model of skin inflammation through AhR activation<sup>1</sup>. FICZ could thus play a regulatory role to control inflammation in PsA. <h3>Objectives</h3> To evaluate the immunomodulatory effects of FICZ on IL-17, IL-10 and IFN-γ production from human CD4+ T cells in PsA and healthy controls (HCs) <h3>Methods</h3> Whole PBMCs and purified CD4+ T cells were isolated from HCs, untreated or DMARD treated (UNT/DMARD) PsA patients and anti-TNFα (adalimumab and etanercept) treated patients. Cells were stimulated with anti-CD3/CD28 (αCD3/28) (1μg/ml) and cultured for 3-5 days in the presence or absence of FICZ (250nM). To some cultures 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) (10nM) was used as a control AhR ligand, and IL-21 (30ng/ml) as a positive control for IL-10 production. Cells were then re-stimulated with PMA/ionomycin and intracellular production of IL-17, IFN-γ and IL-10 measured by FACS. <h3>Results</h3> The percentage of IL-17+ CD4+ T cells was reduced in the peripheral blood of HCs and PsA patients after 3 days (healthy p=0.0098, UNT/DMARD p=0.0004, anti-TNFα p=0.0012) and 5 days (healthy p=0.0005, UNT/DMARD p=0.0012, anti-TNFα p=0.0012). The percentage of IFN-γ+ CD4+ T cells was reduced in HCs and PsA patients (HC p=0.016, UNT/DMARD p=0.001, anti-TNFα p=0.001) after 3 days culture with FICZ but this effect was only sustained for HCs (p=0.02) and anti-TNFα treated patients (p=0.01) after 5 days of culture. No ligand specific difference in IL-17 suppression was seen between FICZ and TCCD. No difference in baseline IL-10 expression was seen between treatment groups. However, IL-10 production was significantly enhanced by FICZ in the anti-TNFα patients group (p=0.02). This effect was not seen with TCDD nor IL-21 alone. The addition of IL-21 to cultures from anti-TNFα patients treated with FICZ further enhanced IL-10 expression (p&lt;0.05). Increase in Il-10 by FICZ was associated with a reduction in IL-17. Upon stratifying patients by swollen joint count (SJC) and Psoriasis Area Severity Index (PASI) into high (SJC≥3, PASI≥5) and low (SJC&lt;3, PASI&lt;5) disease activity, the percentage of IL-17+ CD4+ T cells after 3 days culture with FICZ was reduced for patients with low PASI score (p=0.02). A similar trend was seen for those with low SJC (p=0.06). In contrast, stimulation with FICZ did not regulate Th17 cells in patients with high PASI score or SJC. <h3>Conclusion</h3> The AhR ligand FICZ suppresses IL-17 production in CD4+ T cells of PsA patients and HCs and IFN-γ in HCs and anti-TNFα treated patients. FICZ promotes IL-10 production in CD4+ T cells from anti-TNFα treated patients and this effect is enhanced in the presence of IL-21. CD4+ T cells from patients with high disease activity are more resistant to FICZ mediated IL-17 suppression. Use of AhR ligands may thus be a useful therapeutic adjunct to conventional and biological therapy in PsA. <h3>Reference</h3> [1] Di Meglio P, et al. Activation of the AhR dampens the severity of inflammatory skin conditions, Immunity, 2014, Jun 19;40(6):989-1001. <h3>Disclosure of Interests</h3> Amara Ezeonyeji: None declared, Michael Ehrenstein Grant/research support from: A different project receives support from GSK