025 Imiquimod-induced psoriatic inflammation can be attenuated by the application of a Liver X receptor agonist through the production of pro-resolution molecule M Otsuka 1 , T Okuno 2 , T Yokomizo 2 , G Egawa 1 , T Dainichi 1 and K Kabashima 1 1 Department of Dermatology, Kyoto University, Kyoto, Japan and 2 Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan Psoriasis is a common skin inflammatory disorder known for its hallmark of having abnormal keratinocyte differentiation. In psoriatic skin, the expression of liver X receptors (LXRa and LXRb), a nuclear receptor family of transcription factors has shown to be down-regulated. In addition, LXR plays an integral part in the control of keratinocyte differentiation. However, very few studies have been conducted to understand the role of LXRs during skin inflam- mation. We hypothesized that LXRs in the skin can interfere the immune cascade in the induction of psoriatic inflammation. We first evaluated imiquimod (IMQ)-induced psoriatic inflammation in murine ear skin that was simultaneously treated with or without an LXR agonist (GW3965) for 11 days. We found that IMQ-induced skin inflammation was milder in mice treated with GW3965 than in mice treated with its vehicle. In addition, qPCR analysis demonstrated that the gene expression levels of pro-resolution mediators (ABCA1, MerTK and TGF-b) in the IMQ-treated skin were higher in the LXR agonist-treated group than in the control group. We also performed lipidomics analysis to understand the role of the LXR agonist for the generation of lipid mediators in the skin. The levels of key immune recruitment lipid mediators (leukotriene D4 and prostaglandin E2) in the skin lesions were lower in the LXR agonist-treated group than in the control group. To further illustrate the role of LXRs for the immune cell recruitment in psoriatic skin inflammation, we performed whole mount skin imaging. We observed that neutrophil recruitment in the IMQ-treated skin were markedly lower in the LXR agonist-treated group compared to the control group. These results suggest that the activation of LXRs can alleviate psoriatic skin inflammation via the generation of pro- resolving molecules and the regulation of the synthesis of lipid mediators. 026 The impaired suppressive activity and altered response to IL-33 of regulatory T cells in a psoriasis model may be due to decreased ST2 expression A Schwarz, R Philippsen and T Schwarz Department of Dermatology, University Kiel, Kiel, Germany Interleukin 33 (IL-33), initially described as an alarmin, is released by cells following cell damage. It fulfills numerous functions in infections and inflammatory diseases by modulating both the innate and the adaptive immune system. IL-33, however, can also act in an immunosuppressive fashion by inducing regulatory T cells (Treg). Enhanced IL-33 levels are found both in the skin and the serum of psoriatic patients. On the other hand, in psoriasis Treg appear to be impaired in their suppressive function. To study whether “psoriatic” Treg are impaired in their response to IL-33, we utilized the imiquimod (IMQ)-induced psoriasis like model. IL-33 expression was elevated in both skin and serum of IMQ-treated mice, as demonstrated by in situ immunofluorescence staining and ELISA. However, the suppressive activity of Treg obtained from IMQ-mice was reduced as indicated by adoptive transfer ex- periments. To study whether the response of Treg to IL-33 is altered in IMQ-mice, Treg from untreated or IMQ-mice were incubated with IL-33 and injected into naı ¨ve mice which were sensitized thereafter. The suppressive capacity of Treg obtained from untreated mice could be further enhanced by IL-33, whereas Treg from IMQ-mice did not respond to IL-33. IL-33 exerts its activity via binding to its receptor ST2. ST2 expression identifies a highly activated, strongly suppressive Treg subset, which is superior to ST2À Treg in suppressing CD4 + T cell proliferation. FACS analysis of Foxp3 + CD4 + CD25 + cells revealed that ST2 expression on IMQ-Treg was down-regulated in comparison to Treg from untreated animals. Decreased expression of the IL-33 receptor could be an explanation for the weaker response of Treg to IL- 33 in IMQ-treated mice and their reduced suppressive activity. Further studies have to elucidate the mechanism by which ST2 expression is down-regulated in the IMQ-model and whether reduced ST2 expression can be also observed in psoriasis. 027 IgA plasma levels, but not IgG, against Streptococcus pyogenes identifies Anti-Streptolysin O negative chronic plaque psoriasis patients with increased specific CLA+ T cells IL17A and IL17F producers C De Jesu ´ s-Gil 1 , L Sans-de San Nicola ´s 1 , M Ferran 2 , A Chiriac 3 , A Celada 4 , R Pujol 2 and LF Santamaria-Babi 1 1 University of Barcelona, Spain, Spain, 2 Department of Dermatology, Hospital del Mar, IMIM, Barcelona, Spain, 3 Department of Dermatophysiology, Apollonia University, Iasi, Romania and 4 Macrophage Biology, University of Barcelona, Barcelona, Spain Streptococcus pyogenes tonsillar infection in early onset psoriasis patients can be associated with severe course and biological therapy. Chronic plaque psoriasis patients (CPPP) have higher incidence of sore throat compared to controls. Plasma from untreated CPPP (n¼27) and healthy controls (HC, n¼21) were analyzed for the presence of IgA and IgG against S. pyogenes extract (SE). Also, circulating CLA+/- T cells from the same patients were cultured with autologous epidermal cells with or without SE stimulation. All CPPP had Anti-Strepto- lysin O titer <200IU. Increased levels of anti-SE IgA were detected in CPPP compared to HC (p<0,001). Of note, CPPP with higher anti-SE IgA levels showed stronger CLA+ T cell- associated IL17F (2433,92pg/ml) and IL17A (298,50pg/ml) response in SE stimulated cultures, when compared to low anti-SE IgA patients and controls. Increased IFNg levels were also observed but it was not restricted to CLA+ T cells. Noteworthy, IgA was IgA alpha 1 and not alpha 2, suggesting upper orogastric and respiratory tracts production after chronic infection. Not such distinction between patients is observed for anti-SE IgG levels, which are more related to an accute tonsillar infection. Patients heterogeneity may shape clinical course and response to treatments. We propose S. pyogenes specific IgA as a potential biomarker to stratify CPPP, and a feasible tool to understand CPPP heterogeneity. 028 The activation status of nuclear factor kB in type 2 conventional dendritic cells before therapy correlates with clinical response to adalimumab R Andres Ejarque and P Di Meglio, o PSORT Consortium King’s College London, London, United Kingdom Biologic therapies have revolutionised the treatment of psoriasis. Nevertheless, clinical response to therapy is unpredictable. Thus, there is a need to identify biomarkers predictive of response to enable patient stratification. Here, we investigate the effects of adalimumab (TNF- inhibitor) on the activation of nuclear factor kB (NF-kB) in the immune cells of psoriasis patients during the early phase of therapy. We hypothesize that monitoring the activation of the transcription factor downstream of the cytokine neutralized by a biologic can guide in the discovery of predictive biomarkers. Whole blood (n¼16) and peripheral blood mononuclear cells (n¼30) samples, obtained from psoriasis patients at baseline and weeks 1, 4 and 12 after commencing treatment, were stimulated with TNF or LPS; NF-kB nuclear translocation was quantified by imaging flow and NF-kB phosphorylation by phospho-flow cytometry. Clinical response was defined as 75% reduction in baseline psoriasis area severity index (PASI75) at week 12. TNF induced NF-kB translocation in T cells, dendritic cells (DCs), monocytes and neutrophils, while LPS, activated monocytes, DCs and neutrophils at baseline. In patients receiving adalimumab, TNF activation was significantly inhibited at each time point in T cells (92% at week 1, p<0.01), and to a lesser extent, in DCs (55% at week 1, p<0.05) compared to baseline but did not change in monocytes or neutrophils. As expected, adalimumab did not affect LPS-induced NF-kB translocation. However, we observed increased LPS-induced NF- kB translocation at baseline in the DC of patients who did not reach PASI75, as compared to patients reaching PASI75 (FDR<0.01). Importantly, this finding was replicated in an extended cohort of patients receiving adalimumab, where we detected increased LPS-induced NF-kB phosphorylation at baseline in type 2 conventional DC (cDC2) of patients not reaching PASI75 (FDR<0.001). Taken together, these data suggest that clinical response to adalimumab may depend on the baseline NF-kB activation status of cDC2. 029 The IL-31-producing circulating T cells subset represents a unique population of CLA + CRTH2 + CCR4 + effector memory T cells A Datsi 1 , K Raba 3 , S Kellermann 1 , A van Lierop 1 , P Olah 1,2 , R Sorg 3 and B Homey 1 1 Department of Dermatology, University of Duesseldorf, Duesseldorf, Germany, 2 Dermatology, University of Pe´cs, Pe´cs, Hungary and 3 Institute of Transplantation Diagnostics and Cell Therapeutics, University of Duesseldorf, Duesseldorf, Germany Recent findings underscore an important role of IL-31/IL-31RA signalling in pruritus. The novel T H 2-derived cytokine interleukin-31 (IL-31) has been implicated in the pathophysiology of atopic dermatitis (AD) and induces pruritus via a synergistic cooperation of dysregulated immune cells and stimulated sensory neurons. In particular, the clinical efficacy of the IL- 31RA-targeting antibody nemolizumab in treating itch in atopic dermatitis patients empha- sized the importance of the IL-31/IL-31RA pathway. Although type 2 memory T cells (T H 2) are considered to be the major source of IL-31 production, the phenotype of IL-31-producing T cells is poorly characterized. In the present study, we established a reliable protocol for intracellular IL-31 staining in re-stimulated T cells and investigated the detailed phenotype of IL-31-producing T cells in AD patients (n¼30) and healthy volunteers. First, we observed that IL-31 is predominantly produced by effector memory T H 2-polarized CRTH2 + T cells co- expressing low levels of IL-4 and IL-13. Intracellular IL-31 is nearly absent in polarized T H 1 or T H 17 cells. Stimulation with the alarmin IL-33 enhances the production of IL-31 in T H 2 cells. In depth examination of the chemokine receptor repertoire indicated that IL-31-producing T cells express in addition to the already reported skin-homing marker CLA, further skin- homing receptors such as CCR4, CCR10, but are negative for CXCR3 or CCR6. Interestingly, the abundance of circulating effector memory IL-31 + T cells as well as the overall IL-31 production by T cells increased in AD patients in comparison to healthy volunteers. Our findings indicate that IL-31 + T cells may represent a unique population of skin-homing type 2 memory T cells that play a role in atopic inflammation. 030 Etrasimod, an oral, selective sphingosine 1-phosphate receptor modulator improves skin inflammation in a contact hypersensitivity dermatitis model CM Crosby, HK Komori and JW Adams Arena Pharmaceuticals, San Diego, CA Etrasimod (APD334) is a selective sphingosine 1-phosphate receptor 1,4,5 (S1P 1,4,5 ) modu- lator in development for atopic dermatitis (AD). S1P 1 modulates trafficking of many immune cells, including those in eczematous skin. This study evaluated the effect of etrasimod on circulating and tissue immune cells and its impact on skin inflammation in a dermatitis mouse model. BALB/c mice were epicutaneously sensitized with fluorescein isothiocyanate (FITC) on the hind flank on Days (D) 0 and 5, then epicutaneously FITC challenged on the ear on D10-12. From D -1, mice were dosed orally once daily with vehicle, dexamethasone (Dex), or etrasimod (1 or 3 mg/kg). Ear thickness was measured with calipers on D0, 5, 10-13. On D2 and 13, draining lymph nodes (dLN) were analyzed by flow cytometry (FACS) for cellu- larity and activation. On D13, we examined blood for immune cell count and cytokines, and ear skin by FACS and histology. Sensitization did not cause skin inflammation, yet on D2 dendritic cells (DC), T cells and B cells expanded in the dLN in all mice. In vehicle mice, challenges amplified skin thickening from D10-13, and terminal analyses revealed worse histologic score and immune cell expansion in dLN and ear skin. Etrasimod dose-dependently lessened ear thickening and histologic score, with the high dose achieving comparable ef- ficacy as Dex on D13. Etrasimod reduced lymphocyte frequency in the blood. In the dLN, etrasimod reduced DC influx, and decreased expansion and activation of T cells. B cells and eosinophils were also reduced in number. In the ear skin, the increase of T cells, B cells, and eosinophils was dose-dependently inhibited. In conclusion, etrasimod effectively reduced ear skin inflammation and dermatitis in FITC-induced hypersensitivity. Etrasimod significantly reduced the activation and expansion of immune cells after challenge in the dLN and ear skin. Notably, the dose-dependent reduction of immune cells in ear skin correlated with improvements in disease. This data encourages further study of etrasimod as a novel therapy for AD. Adaptive Immunity and Autoimmunity | ABSTRACTS www.jidonline.org S219