Low-dose chidamide restores immune tolerance in ITP in mice and humans

Abstract

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.

The histone deacetylase inhibitor chidamide induces intermittent viraemia in HIV‐infected patients on suppressive antiretroviral therapy

“…We also found an increase in the Treg proportion and an upregulation of CD38/HLA-DR co-expression on T cells, which is in line with previous studies involving panobinostat and romidepsin [9,37]. Consistently, a low dose of chidamide stimulates the production of Tregs, promotes the peripheral conversion of T cells into Tregs, and restores Treg suppression in vivo and in vitro [38]. Further, the transcription factor FOXP3 can be acetylated on several lysine residues, and its acetylation increases its stability [39].…”

Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia

“…CD28, constitutively expressed on the surface of T cells, is important for T cell survival, proliferation, and effector function. Alternatively, CTLA4, which is highly expressed after T cell activation, acts as a competitor of CD28 and induces a state of T cell unresponsiveness and anergy ( 26 – 28 ). PD1, a novel co-inhibitory member of the B7/CD28 family, is engaged by PD-L1 to inhibit T cell activation ( 29 – 31 ).…”

Chidamide combined with doxorubicin induced p53-driven cell cycle arrest and cell apoptosis reverse multidrug resistance of breast cancer

“…It is mainly used for various types of lymphocyte or myelogenous leukemia (31).CHI has been used in various clinical and preclinical studies in recent years, In 2019, it was approved in combination with isetam for hormone receptor-positive advanced breast cancer (18).Therefore, the inhibition of HDAC is a new therapeutic approach. The clinical and basic research on the use of CHI in the treatment of breast cancer is ongoing (32)(33)(34). This study was done in vivo and in vitro experiments.…”