AB0149 ARSENIC TRIOXIDE IMPROVES TREG AND TH17 BALANCE VIA MODULATING STAT3 IN TREATMENT-NAïVE RA PATIENTS. (June 2019)

• Record Type: Journal Article
• Authors: Zhang, Yue; Chunling, LI; Zhang, Zhiyi
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 1532
• Page End: 1532
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.8330
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: We have a long-term interest in novel arsenic trioxide As2 O3 (ATO) medical application since some acute promyelocytic leukemia (APL) patients have been cured by first using ATO and survived for more than 45 years successfully treated by Prof. Zhang Tingtong in our institute. Moreover, our previous studies have shown that ATO significantly suppress angiogenesis and induced fibroblast like synoviocytes (FLS) apoptosis in collagen induced arthritis (CIA) model[1, 2]. However, the extract mechanism by which ATO anti-rheumatic and whether this occurs via modulation of immune system are still unclear. Objectives: To investigated the immunologic mechanism by which ATO may inhibit T helper 17 cells (Th17) differentiation while promote regulatory T cells (Treg) generation via modulating signal transducer and activator transcription 3 (STAT3) in treatment-naïve RA patients. Methods: Naïve CD4 + T cells sorted by fluorescence-activated cell sorting (FACS) from treatment-naïve RA patients and healthy controls were used to investigated the effect of ATO on its polarization process and related cytokines. Knockown or enforced expression of STAT3 transfection experiments were conducted by small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of ATO on Th17/Treg balance in vitro. Collagen-induced arthritis (CIA) model was constructed to detect the clinical score, histopathological change, bone destruction, Th17/Treg proportion and joint tissues immunohistochemistry. Single cell sequencing and other methods have been appplied too. Results: We found that ATO prevented activated naïve CD4 + T-cell differentiate into Th17 cell and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptor (RORγt). Notably, ATO reduced Th17 cells frequency while increased Treg cells frequency under specific polarizing conditions from treatment-naïve RA patients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we have noticed that intervention of ATO in CIA model attenuated joint inflammatory infiltration and bone destruction, significantly improved the imbalanced Treg/Th17 ratio. In-detail single cell sequeining analysis is ongoing. Conclusion: ATO may be a immune modulator candidate for treatment-naïve RA patients via balancing well Treg/Th17 cell ratio through STAT3 regulation. References: [1] Zhang, J., et al., Inhibition of angiogenesis by arsenic trioxide via TSP-1-TGF-beta1-CTGF-VEGF functional module in rheumatoid arthritis. Oncotarget, 2017. 8(43): p.73529-73546. [2] Mei, Y., et al., Arsenic trioxide induces apoptosis of fibroblast-like synoviocytes and represents antiarthritis effect in experimental model of rheumatoid arthritis. J Rheumatol, 2011. 38(1): p.36-43. [3] Vasheghani, F., et al., PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis, 2015. 74(3): p. 569-78. Acknowledgement: National Science Foundation of China (NO. 81273291) and (NO. 81771748, 81771749) Disclosure of Interests: None declared