AB0196 MESENCHYMAL STEM CELLS TUNE THE DIFFERENTIATION OF MYELOID-DERIVED SUPPRESSOR CELLS IN SJöGREN’S SYNDROME THROUGH INHIBITING IL-12

Abstract

Background The preliminary animal and human studies, including ours, showed that mesenchymal stem cell (MSC) transplantation could reestablish salivary function and reduce lymphocytic infiltration in salivary glands in Sjogren’s syndrome (SS). However, the mechanisms of the encouraging results of MSCs on the SS remain to be elucidated. Myeloid-derived suppressor cells (MDSCs) represent an important class of immunoregulatory cells. MDSCs have multiple phenotypes which inhibit T cell responses by multiple mechanisms, and the environment dictates the development of suppressive properties and activation. Previous studies have demonstrated that MDSCs played important roles in systemic lupus erythematosus and rheumatic arthritis. However, the involvement of MDSCs in the immunopathology of SS is largely unknown. Objectives This study aims to investigate effects of MDSCs in SS progression and the potential association of MDSCs with the therapeutic effects of MSCs in the patients with SS and mice with SS-like symptoms. Methods The frequencies of MDSCs in the blood and bone marrow were detected by flow cytometry analysis in SS mice (NOD mice) and patients with SS. The NOD mice were adoptively transferred with MDSCs or treated with anti-Gr1 antibody to eliminate MDSCs. The salivary flow rate was measured and inflammatory infiltration in salivary glands was assessed. MSCs were infused into NOD mice to investigate the effects of MSCs on SS-like syndrome and changes of MDSCs. The percentages of MDSCs in SS patients before and after MSC transplantation were determined. Results The percentage of MDSCs increased significantly with the development of SS-like syndrome in NOD mice. The SS-like syndrome exacerbated after transfer of MDSCs, whereas deletion of MDSCs alleviated SS-like syndrome in NOD mice. MSC transplantation enhanced salivary flow rates and decreased lymphocyte infiltration in salivary glands in NOD mice. The percentages of MDSCs were down-regulated after MSC transplantation. MSC reduced IL-12 production in dendritic cells in vitro and in vivo. The IL-12 promoted generation of MDSCs in vitro. The numbers of MDSCs were positively correlated with disease activities of SS patients. The percentages of MDSCs were reduced after MSC transplantation in patients with SS. Conclusion 1. MDSC expansion positively correlated with inflammation during the progression of SS. 2. MSC transplantation had beneficial effects in SS mice. 3. IL-12 production by dendritic cells was reduced by MSCs. 4.The MDSCs expansion was induced by inflammatory IL-12 and reversed by MSC transplantation in SS. Thus, we have revealed a previously unrecognized function of MSC-mediated reduction of MDSCs in suppressing SS-like syndrome through inhibition of IL-12 production by DCs, which provided novel therapeutic strategies to treat patients with SS. Acknowledgement This work was supported by the National Natural Science Foundation of China (NSFC) (grant no. 81571583 and 81770061 to GY). Disclosure of Interests None declared