THU0226 MESENCHYMAL STEM CELL TRANSPLANTATION AMELIORATES EXPERIMENTAL SJÖGREN’S SYNDROME BY DOWNREGUALTING MDSCS VIA COX2/PGE2 PATHWAY

Background: Although mesenchymal stem cells (MSCs) transplantation have been demonstrated to be an effective therapeutic approach to treat experimental Sjögren’s syndrome (ESS) 1 , the specific underlying mechanisms remain to be elucidated. Myeloid-derived suppressor cells (MDSCs) were significantly increased with decreased suppressive capacity during disease development in ESS 2-3 . However, the therapeutic effects and mechanisms by which MSCs regulating MDSCs in SS still remain unknown. Objectives: Here we aim to explore whether regulation of MDSCs was responsible for the beneficial effects of MSC transplantation on SS. Methods: The MSCs were infused intonon-obese diabetic (NOD) mice via the tail vein. The histological features of submandibular glands, lung, saliva flow rate were evaluated. The number and immune-suppressive activity of MDSCs, the subsets of MDSCs, polymorphonuclear MDSCs (PMN-MDSCs) and monocytic-MDSCs (M-MDSCs) in NOD mice were determined. The bone marrow cells under MDSCs differentiation conditions were co-cultured with or without MSCs. The COX2 inhibitor NS-398, anti-TGF-β1, or anti-IFN-β antibodies were added to coculture medium of MSCs and MDSCs induced from bone marrow cells respectively. Results: We found that MDSCs in bone marrow and peripheral blood increased in ESS mice. MSC transplantation ameliorated SS-like syndrome and down-regulated the percentages of MDSCs, PMN-MDSCs and M-MDSCs and promoted their suppressive ability in ESS mice significantly (Figure 1). In vitro, MSCs could down-regulate the differentiation and up-regulate the suppressive ability of MDSCs. Mechanistically, MSCs inhibited the differentiation of MDSCs and PMN-MDSCs via secreting prostaglandin E2, and inhibited the differentiation of M-MDSCs by secreting interferon-β (Figure 2). Figure 1. MSCs ameliorated SS symptoms and decreased MDSCs in NOD mice. Figure 2. MSCs inhibited the differentiation of PMN-MDSCs and M-MDSCs by COX2/PGE2 and IFN-β respectively. Conclusion: Our findings suggested that MSCs alleviated SS-like symptoms by suppressing the aberrant accumulation and improving the suppressive function of MDSCs in ESS mice via COX2/PGE2 pathway. References: [1]Shi B, Qi J, Yao G, et al. Mesenchymal stem cell transplantation ameliorates Sjögren’s syndrome via suppressing IL-12 production by dendritic cells. Stem Cell Res Ther, 2018; 9(1):308. [2]Qi J, Li D, Shi G, et al. Myeloid-derived suppressor cells exacerbates Sjögren’s syndrome by inhibiting Th2 immune responses. Mol Immunol, 2018; 101:251-258. [3]Tian J, Rui K, Hong Y, et al. Increased GITRL impairs the function of myeloid-derived suppressor cells and exacerbates primary Sjögren’s syndrome. J Immunol, 2019; 202(6):1693-1703. Disclosure of Interests: None declared