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Hydroxychloroquine (HCQ) is one of the most commonly prescribed immune-suppressants in treating rheumatoid arthritis (RA). Our previous research showed that HCQ suppressed RA development by inhibiting T follicular helper (Tfh) cells directly. Dendritic cells (DCs) serve as the link between innate and acquired immunity. Whether HCQ suppressed Tfh cell through DCs was not clear. In current study, we found that HCQ efficiently inhibited CD86, chemokine (C-X-C motif) receptor 4 (CXCR4) expression and interferon-α (IFN-α) secretion of healthy donor derived purified DCs stimulated by RA patient serum. To mimic RA, collagen-induced arthritis (CIA) mouse model was used and treated with HCQ daily for fifty-four days prior to sacrifice. We found HCQ inhibited DC maturation and migration to lymph nodes (LNs), manifested as down-regulated expression of CD40, CD80, CD86, MHCII (I-A q ) on LN DCs. In addition, HCQ reduced the level of chemokine receptor 7 (CCR7) and L-selectin on peripheral blood DCs and diminished percentage of LN DCs. Of note, HCQ only inhibited CpG ODN 1826-induced IL-12 secretion by bone marrow DCs (BMDCs) stimulated by various toll like receptor (TLR) agonists. Mechanistically, HCQ down-regulated the expression of TLR9 not only in healthy donor PBMC-derived DCs stimulated by RA patient serum, but also in LN DCs of CIA mice and CpG-activated BMDCs. Furthermore, arthritis scores in TLR9 -/- mice were much lower than that in wild type mice with impaired maturity and migration capability of DCs. Collectively, activation of DCs contributes to the pathogenesis of RA and HCQ shows protective effects on RA by inhibition of DC activation via blocking TLR9., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chidamide is a novel selective histone deacetylase inhibitor (HDACi) with promising activity in hematological malignancies, but its role in chronic myeloid leukemia (CML) was marginally addressed. In this study, we firstly demonstrated that chidamide alone inhibited CML cells proliferation, induced apoptosis and cell cycle arrest. Further, chidamide combined with imatinib (IM) induced synergistic lethality in CML cell line KBM5, as well as IM-resistant CML cells KBM5 T315I , associated with a marked reduction of Bcr-Abl kinase activity and acetyl-histone H3 expression. The combination treatment markedly inhibited constitutive activity of β-catenin signaling in IM-resistant cells and abolished the protective effects of mesenchymal stromal cells (MSCs) to CML cells. In addition, the co-treatment significantly reduced Bcr-Abl and β-catenin transcript levels and induced apoptosis of primary CD34 + stem/progenitor cells derived from blast crisis (BC)-CML patients, but exhibited minimal toxicity to normal CD34 + progenitors. Collectively, our data show that combination of chidamide and imatinib synergistically targets tyrosine kinase inhibitor (TKI) -resistant BC-CML cells via inhibition of Bcr-Abl and β-catenin signaling, suggesting that this combination has the potential for treating TKI-resistant CML and improving clinical outcomes of BC-CML patients., (Copyright © 2020. Published by Elsevier Masson SAS.)

Hydroxychloroquine (HCQ) is an immunosuppressive agent widely used in rheumatoid arthritis (RA). T follicular helper (Tfh) cells play a vital role in the pathogenesis of RA. However, whether HCQ suppresses arthritis development through interfering with Tfh cells have never been reported. To address this issue, we investigated the percent of Tfh cells in newly diagnosed RA patients and found that they were up-regulated in peripheral blood. Importantly, in ex vivo experiments of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, we proved that the percentage of Tfh cells in PBMCs and purified CD4 + T cells were decreased after HCQ treatment. In in vivo experiments of collagen-induced arthritis (CIA) model, we discovered that HCQ suppressed the incidence and score of arthritis, reduced the secretion of proinflammatory cytokines in serum. Similar to ex vivo study, the ratio of Tfh cells in HCQ treated CIA mice declined to the level of vehicle-treated group. Further research demonstrated that HCQ inhibited the generation of Tfh cells stimulated by IL-12 and IL-21. In conclusion, our study indicates a previously unrecognized mechanism of HCQ in RA, that HCQ directly suppresses the generation of Tfh cells by blocking IL-12 and IL-21 signaling pathways probably., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)