Low-dose decitabine modulates T cell homeostasis and restores immune tolerance in immune thrombocytopenia.

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Our previous clinical study demonstrated that low-dose decitabine showed sustained responses in nearly half of refractory immune thrombocytopenia (ITP) patients. The long-term efficacy of decitabine in ITP is not likely due to its simple role in increasing platelet production. Whether decitabine has the potential to restore immune tolerance in ITP is unknown. In this study, we analyzed the effect of decitabine on T cell subpopulations in ITP in vitro and in vivo. We found that low-dose decitabine promoted the generation and differentiation of regulatory T (Treg) cells, and augmented their immunosuppressive function. Splenocytes from CD61 knockout mice immunized with CD61+ platelets were transferred into severe combined immunodeficient (SCID) mouse recipients to induce a murine model of ITP. Low-dose decitabine alleviated thrombocytopenia and restored the balance between Treg and helper T (Th) cells in active ITP mice. Treg deletion and depletion offset the effect of decitabine in restoring CD4+ T cell subpopulations in ITP mice. For patients who received low-dose decitabine, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were suppressed compared with the pretreatment levels. Next-generation RNA sequencing and cytokine analysis showed that low-dose decitabine rebalanced T cell homeostasis, decreased proinflammatory cytokines, and down-regulated phosphorylated STAT3 in ITP patients. STAT3 inhibition analysis suggested that low-dose decitabine might restore Treg cells by inhibiting STAT3 activation. In conclusion, our data indicated that the immunomodulatory effect of decitabine provided one possible mechanistic explanation for the sustained response achieved by low-dose decitabine in ITP.

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Authors: Panpan Han, Yu Hou, Yajing Zhao, Yang Liu, Yunqi Sun, Haoyi Wang, Pengcheng Xu, Guosheng Li, Tao Sun, Xiang Hu, Xinguang Liu, Li-Zhen Li, Jun Peng, Hai Zhou, Ming Hou


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