Immunology 1: Adaptive Immunology

Abstract

S | Immunology 1: Adaptive Immunology S72 Journal of Investigative Dermatology (2014), Volume 134 408 A newly developed kappa-opioid receptor agonist ameliorates ongoing inflammation N Sucker, M Soeberdt, C Abels, T Luger and K Loser 1 Dr. August Wolff, Bielefeld, Germany and 2 Univ. of Münster, Münster, Germany Opioids are known as powerful drugs for pain treatment and can induce analgesia by binding to peripheral opioid receptors (OR). Here, we investigated the role of a newly developed kappa-opioid receptor agonist (KORA) on the progression of inflammation. Therefore, human and mouse immune cells were treated with KORA in the presence of LPS and the cytokine expression, cell activation and proliferation was analyzed revealing a potent anti-inflammatory effect of KORA. To investigate the anti-inflammatory properties in vivo mice were treated with the toll-like receptor 7 (TLR7) ligand imiquimod to induce a psoriasis-like skin inflammation and injected with KORA. Compared to PBS-injected controls, recipients of KORA showed a down-regulated expression of IL-23 and decreased levels of Th1 and Th17 cells in lesional skin. Since TLR7 ligation is implicated in the development of itch and signaling via OR modulates itching we quantified the scratching frequencies and the IL31 expression. In contrast to controls, KORA reduced scratching as well as IL-31 indicating an amelioration both, itch and Th1/Th17-mediated inflammation. Of note, this effect was mediated by binding of KORA to KOR since blocking KOR by co-injecting the antagonist nor-BNI abrogated the beneficial effects. To investigate whether KORA ameliorated ongoing inflammation in other organs than the skin colitis was induced by adding dextrane sodium sulfate (DSS) to the drinking water. KORA prevented mice from weight loss and reduced epithelial damage, ulceration and immune cell infiltration into colonic tissue. Moreover, compared to controls recipients of KORA showed reduced numbers of neutrophils and a down-regulated myeloperoxidase activity in the lamina propria and mesenteric lymph nodes. Together, our data demonstrate that KORA, by binding to KOR, ameliorated ongoing inflammation in the skin as well as the gut and down-regulated the activation of pathogenic effector cells. Additionally, in psoriatic mice KORA reduced itching, thus suggesting KORA as a promising novel compound for the treatment of inflammatory/itchy disorders. 409 Alitretinoin, a dual RAR and RXR agonist, modulates leukocyte recruitment pathways and suppresses dendritic cell functions in vitro and in vivo A Kislat, S Meller, R Mota, BA Buhren, PA Gerber, T Ruzicka and B Homey 1 Dermatology, Heinrich Heine Univeristy Hosital, Düsseldorf, Germany and 2 Dermatology, Ludwig-Maximilians-University Munich, Munich, Germany Retinoids are well known for regulating diverse cellular processes including proliferation, differentiation as well as regulation and development of the immune system. Moreover, they have shown clinical efficacy in the treatment of a variety of diseases, including acne vulgaris, pustular psoriasis, ichthyosis. The effects of retinoid acids are mediated by binding to retinoic acid receptors (RAR) and the retinoic X receptors (RXR). Alitretinoin, a retinoid binding to both RAR and RXR, demonstrated significant efficacy in the treatment of chronic hand eczema. To gain inside the mode of action of alitretinoin in vitro and in vivo we analyzed effects of alitretinoin on keratinocytes as well as leukocyte subsets and conducted a clinical study determining the phenotype and activation status of peripheral leukocytes before and under treatment of alitretinoin. Alitretinoin alters chemokine expression of keratinocytes more effectively than acitretin, a RAR-agonist. Further, alitretinoin inhibits the maturation significant higher in comparison to acitretin, leading to a higher impaired T cell activating capability. Patients under therapy show a marked regulation of the “skin-homing” effector T cells. Additionally, alitretinoin treatment significantly decreased the proliferation of leukocytes following allogenic stimulation compared to proliferation before treatment. In conclusion, alitretinoin is significantly more capable to alter the immune responses of the innate and adaptive immune system by suppression of chemokine-induced leukocyte recruitment and inhibition of dendritic cell-mediated T cell activation.