Low-dose chidamide restores immune tolerance in ITP in mice and humans
| Autor: | Ming Hou, Fangmiao Jing, Yang Liu, Tao Sun, Yajing Zhao, Hong-yu Zhao, Yu Hou, Hai Zhou, Lizhen Li, Ya-hui Ma, Panpan Han, Xinguang Liu, Ping Li, Jun Peng, Daqi Li |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Immunology Aminopyridines chemical and pharmacologic phenomena T-Lymphocytes Regulatory Biochemistry Peripheral blood mononuclear cell Immune tolerance Mice Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo hemic and lymphatic diseases Chidamide Immune Tolerance Animals Humans CTLA-4 Antigen IL-2 receptor Aged Purpura Thrombocytopenic Idiopathic Dose-Response Relationship Drug FOXP3 Acetylation Forkhead Transcription Factors Cell Biology Hematology Middle Aged Prognosis In vitro Mice Inbred C57BL 030104 developmental biology chemistry 030220 oncology & carcinogenesis Benzamides Leukocytes Mononuclear Cancer research Female Histone deacetylase |
| Zdroj: | Blood. 133:730-742 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Increased macrophage phagocytosis of antibody-coated platelets, as well as decreased numbers and/or impaired function of CD4+CD25+Foxp3+ regulatory T (Treg) cells, has been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi’s) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3+ Treg cells, but it is unclear whether they have the potential to promote immune tolerance and platelet release in ITP. In this study, we performed in vitro and in vivo experiments and found that a low-dose HDACi (chidamide) alleviated thrombocytopenia in passive and active murine models of ITP. Further, low-dose HDACi’s attenuated macrophage phagocytosis of antibody-coated platelets, stimulated the production of natural Foxp3+ Treg cells, promoted the peripheral conversion of T cells into Treg cells, and restored Treg cell suppression in vivo and in vitro. Finally, we confirmed that low-dose HDACi’s could regulate CTLA4 expression in peripheral blood mononuclear cells through modulation of histone H3K27 acetylation. Low-dose HDACi treatment in ITP could be offset by blocking the effect of CTLA4. Therefore, we propose that low-dose chidamide administration has potential as a novel treatment for ITP in the clinic. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|