¹Universitätsmedizin JGU Mainz, I. Medizinische Klinik und Poliklinik, Department of Nephrology and Center of Immunotherapy, Mainz
²Johannes Gutenberg-Universität Mainz, Department of Chemistry, Mainz
³RPTU Kaiserslautern-Landau, Department of Molecular Biotechnology & Systems Biology, Kaiserslautern-Landau
⁴Universitätsmedizin JGU Mainz, Institute of Pharmacology, Mainz

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Introduction: Systemic lupus erythematosus (SLE) is a systemic chronic autoimmune disease characterized by dysregulation of immune system. Increased immune cell activity, impaired phagocytosis as well as formation and deposition of autoantibodies and immune complexes result in damage to various organs. Glucocorticoids, antimalarial drugs and immunosuppressive agents are part of the current treatments, but large numbers of SLE patients do not responds well to these treatments or have severe side effects. This necessitates the development of new therapeutic options.

The macrocyclic lactone Oxacyclododecindione (Oxa) is described as a good therapeutic option in a SLE-model. However, Oxa is difficult to produce, so derivatives could be an alternative. The Oxa-derivative 14-Deoxy-14-methyloxa (14D14m) shows the same anti-inflammatory effects in cell lines, so we tested 14D14m in a SLE-model and primary cells of SLE-patients.

Methods: We tested 14D14m in cells of C57BL/6 and MRL-Faslpr mice as well as PBMCs of SLE-patients and healthy controls under inflammatory conditions. In addition, we treated MRL-Faslpr mice every other day for three weeks after the onset of first visual symptoms (swollen lymph nodes and skin lessens). Effects of 14D14m were validated with histopathological examination, immunostainings and qPCR.

Results: In primary cells of MRL-Faslpr and C57BL/6 mice 14D14m significantly reduce mRNA expression of different inflammatory genes under inflammatory conditions. A similar result we observed in PBMCs of SLE-patients after the treatment with 14D14m. The treatment of MRL-Faslpr mice with 14D14m reduced significant the lymph node swelling and the splenomegaly. We also see an altered immune cell composition with fewer monocytes/macrophages, Th1- and Th2-cells in the lymph nodes and less CD68+-cells in the kidney of treated mice.

Conclusion: Our results show a significant anti-inflammatory effect of 14D14m on murine and human primary cells in vitro as well as a therapeutic effect on the disease development of SLE-mice. Together the results demonstrate a good anti-inflammatory effect of 14D14m and give the first indication of efficacy in human cells. However, further studies needed to evaluate whether 14D14m is a new therapeutic approach of SLE.