低剂量西达本胺治疗原发免疫性血小板减少症及其作用机制研究

OBJECTIVE: To explore the effect and mechanism of low-dose chidamide on the treatment of primary immune thrombocytopenia (ITP). METHODS: Passive ITP animal model and active ITP animal model were established by C57BL/6J mice. Different doses of chidamide (0, 0.01, 0.1, 0.5, and 5 mg/kg) were orally administrated twice a week for 120 hours in passive ITP mice. Secondly, low-dose chidamine (0.1 mg/kg) was given intragastrically administrated twice a week in active ITP mice. The platelet counts in the peripheral blood before and after treatment were detected. Four weeks later, mice were executed to prepare splenocyte suspension; natural regulatory T cells (CD4(+)CD25(+)Foxp3(+) nTreg cells) in splenocyte suspension were detected by flow cytometry. Serum IL-6 was measured by ELISA. Peripheral blood mononuclear cells from ITP patients were co-cultured with low-dose chidamide in vitro. After incubation for 72 hours, CD4(+)CD25(+)Foxp3(+) Treg cells of mononuclear cells was detected. CD4(+)CD25(+) Treg cells and CD4(+)CD25(−) effector T cells were separated by immunomagnetic beads. The Treg cells and effector T cells were co cultured in a ratio of 1∶4, and treated with low-dose chidamide. The proliferation of effector T cells was detected. RESULTS: Chidamide with low dose (0.1 mg/kg) significantly improved platelet counts in passive ITP mouse model, as well as in the ITP active mouse model and reduced the mortality related to bleeding. Low-dose chidamide significantly increased the number and proportion of nTreg cells in mouse splenocytes, and decreased serum IL-6 level in active ITP mice. In ITP patients, low-dose chidamide also significantly expanded Treg cells in the PBMC culture system. Besides, the proliferation of effector T cells was suppressed. CONCLUSION: Low-dose chidamide enhances the proliferation of CD4(+)CD25(+)Foxp3(+) regulatory T cells to mediate immunosuppressive function. Serum IL-6 is inhibited for further immune tolerance. In vivo animal study suggestes that low-dose chidamide has a novel therapeutic effect on ITP.