The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses

Moreira, José M.A.; Scheipers, Peter; Sørensen, Poul

doi:10.1186/1471-2407-3-30

Cited by 139 publications

(103 citation statements)

References 66 publications

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“…It is likely that SAHA inhibits the transcription and translation of IL-2 in T cells and subsequently inhibits cytokine secretion by T cells and other cells such as macrophages. It was reported that an HDAC inhibitor (trichostatin A) represses IL-2 gene expression in anti-CD3 activated T cells (22). Low-dose SAHA treatment resulted in increased acetylation of histone H3 and decreased mRNA levels of IFN-␥ and TNF-␣ in activated spleen cells (17).…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

Zhao

Kirschbaum

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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In allogeneic hematopoietic cell transplantation (HCT), donor T cellmediated graft versus host leukemia (GVL) and graft versus autoimmune (GVA) activity play critical roles in treatment of hematological malignancies and refractory autoimmune diseases. However, graft versus host disease (GVHD), which sometimes can be fatal, remains a major obstacle in classical HCT, where recipients are conditioned with total body irradiation or high-dose chemotherapy. We previously reported that anti-CD3 conditioning allows donor CD8 ؉ T cells to facilitate engraftment and mediate GVL without causing GVHD. However, the clinical application of this radiation-free and GVHD preventative conditioning regimen is hindered by the cytokine storm syndrome triggered by anti-CD3 and the high-dose donor bone marrow ( anti-CD3 mAb ͉ graft versus host disease ͉ hematopoietic cell transplantation ͉ systemic lupus erythematosus ͉ suberoylanilide hydroxamic acid

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Section: Discussionmentioning

confidence: 99%

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

Zhao

Kirschbaum

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…22 As such, HDAC inhibitors (HDACis) are now under intensive study for their feasibility as potential anti-rejection agents. 23,24 Suberoylanilide hydroxamic acid (SAHA), an FDAapproved drug for the treatment of cutaneous T-cell lymphoma, 25 is an HDACi composed of hydroxamic acid compound that can be well tolerated by the cancer patients. 26,27 While its role in anti-cancer therapy has been extensively studies, its impact on transplant rejection is yet to be explored.…”

Section: Introductionmentioning

confidence: 99%

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

et al. 2012

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Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA-and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-c but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4 1 T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORct in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.

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“…The antifungal agent TSA is another well-established HDACI also with potent antitumor activity (76)(77)(78). We examined whether the SDL interaction between RPD3 LOF and the overexpression of yTDP1 can be recapitulated using VPA and TSA.…”

Section: Rms Lines Expressingmentioning

confidence: 99%

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

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The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses

Cited by 139 publications

References 66 publications

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

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