SAHA, an HDAC Inhibitor, Attenuates Antibody-Mediated Allograft Rejection

Zhang, Xin; Guo, Meng; Kang, Yindong; Liu, Fang; Zheng, Xueyang; Han, Shu; Fu, Shangxi; Hong, Shanjuan; Ding, Guoyu; Wang, Liming; Wang, Quanxing

doi:10.1097/tp.0b013e31829b7bfc

Cited by 5 publications

(4 citation statements)

References 45 publications

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“…Histone deacetylase inhibitors are being tested in clinical oncology (27). In animal models of transplantation, these agents also promote the development of T regulatory cells and attenuate cellular and antibody-mediated rejection (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Enhanced B Cell Alloantigen Presentation and Its Epigenetic Dysregulation in Liver Transplant Rejection

Ningappa

Ashokkumar

Higgs

et al. 2016

American Journal of Transplantation

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T-cell suppression prevents acute cellular rejection but causes life-threatening infections and malignancies. Previously, liver transplant (LTx) rejection in children was associated with the SNP rs9296068 upstream of the HLA-DOA gene. HLA-DOA inhibits B-cell presentation of antigen, a potentially novel anti-rejection drug target. Using archived samples from 122 Caucasian pediatric LTx (including 77 described previously), we now confirm the association between rs9296068 and LTx rejection (p=0.001, OR=2.55). Next-generation sequencing reveals that the putative transcription-factor-(CTCF)-binding SNP locus rs2395304, in linkage disequilibrium with rs9296068 (D’=0.578, r2=0.4), also associates with LTx rejection (p=0.008, OR=2.34). Further, LTx rejection is associated with enhanced B-cell presentation of donor antigen relative to HLA-non-identical antigen in a novel cell-based assay, and with a downregulated HLA-DOA gene in a subset of these children. In lymphoblastoid B-(Raji) cells, rs2395304 co-immunoprecipitates with CTCF, and CTCF knockdown with morpholino antisense oligonucleotides enhances alloantigen presentation and downregulates the HLA-DOA gene, reproducing observations made with HLA-DOA knockdown and clinical rejection. Alloantigen presentation is suppressed by inhibitors of methylation and histone deacetylation, reproducing observations made during resolution of rejection. Enhanced donor antigen presentation by B-cells and its epigenetic dysregulation via the HLA-DOA gene represent novel opportunities for surveillance and treatment of transplant rejection.

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Section: Discussionmentioning

confidence: 99%

Enhanced B Cell Alloantigen Presentation and Its Epigenetic Dysregulation in Liver Transplant Rejection

Ningappa

Ashokkumar

Higgs

et al. 2016

American Journal of Transplantation

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“…21 A different investigation found that SAHA treatment decreased B-cell proliferation and immunoglobulin production in vitro and reduced immunoglobulin and C4d deposition in the mouse cardiac transplant model, suggesting that SAHA treatment may be effective in preventing antibody-mediated transplant rejection. 22 other therapeutics such as sirolimus are known to expand the numbers and function of FoxP3+ cells while decreasing CD8 effector cell function through inhibition of the mammalian target of rapamycin 23 ; one study found potential synergistic activity between SAHA and sirolimus in enhancement of FoxP3. 24 Although additional investigations are needed, the use of histone deacetylase inhibitors show promise for the prevention and management of allograft rejection alone and as part of a combinatorial strategy to improve the functionality of Tregs.…”

Section: Discussionmentioning

confidence: 99%

Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target

et al. 2016

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Cardiac allograft rejection remains a problem, despite advances with immunosuppressants. Understanding the mechanisms behind rejection is essential for developing targeted therapies. The goal of this investigation is to explore Sirtuin 1 (Sirt1) as a therapeutic target for cardiac allograft rejection. Thirteen endomyocardial biopsy specimens with acute cellular rejection (grade 2R or 3R) were selected. CD3, CD4, CD8, CD20, CD68, T-cell intracytoplasmic antigen (TIA-1), and Sirt1 expressions were determined by immunohistochemical stains. Comparison of Sirt1 expression was made with 10 cases of grade 0R and grade 1R. Quantitative image analysis was performed. There were 2 cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Sirtuin 1 expression was present in the majority of mononuclear cells (median percentage, 73.5; interquartile range, 51.2-100%); staining was also observed in cardiomyocytes. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, coinciding with acute cellular rejection. Sirtuin 1 expression in the nuclei of FoxP3+ cells can lead to deacetylation and inactivation of FoxP3 rendering the T-suppressor cells inactive and promoting acute cellular rejection. The use of a Sirt1 inhibitor may be a therapeutic option in expanding the functionality of the FoxP3+ T-suppressor cells and moderating the severity of such rejection.

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“…The specific inhibition of HDAC8 by ITF2357 (generic givinostat) reduces the gene expression and production of proinflammatory cytokines (IL‐1β, IL‐1α, TNF‐α, and IL‐6) in vitro and in vivo without cell toxicity . SAHA promotes the B cell secretion of interleukin‐10 . In cutaneous T‐cell lymphoma cells, HDAC inhibitors (vorinostat and romidepsin) down‐regulate IL‐10, IL‐2, IL‐4 and up‐regulate IFN‐γ via interfering with STAT3 …”

Section: The Role Of Hdacs In Immune Modulationmentioning

confidence: 99%

“…②suppress antibody‐mediated rejection (AMR), ③ reduce secretion of the proinflammatory cytokines; alleviate intestinal histopathology, clinical severity, and mortality; preserve cytotoxic T cell responses to host antigens; maintain beneficial graft‐vs.‐leukemia (GVL) effects…”

Section: Perspectivesmentioning

confidence: 99%

HDAC Inhibitors: Novel Immunosuppressants for Allo‐ and Xeno‐ Transplantation

et al. 2018

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Immune rejection is the major obstacle to graft survival and quality of life of recipients after organ transplantation. The immunosuppressants applied in clinical face severe safety and efficacy issues. Histone deacetylases (HDACs) are emerging novel drug targets in the treatment of malignancies and immune disorders. HDAC inhibitors show potential as valuable immune regulators after allo-or xeno-organ transplantation. However, studies that evaluate HDAC inhibitors and mechanisms are still limited. In this review, we focused on the immunomodulatory effects of HDAC inhibitors in transplantation. Finally, we discussed the implications and challenges of applying HDAC inhibitors in allo-and xeno-transplantation.

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SAHA, an HDAC Inhibitor, Attenuates Antibody-Mediated Allograft Rejection

Abstract: Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.

Cited by 5 publications

References 45 publications

Enhanced B Cell Alloantigen Presentation and Its Epigenetic Dysregulation in Liver Transplant Rejection

Enhanced B Cell Alloantigen Presentation and Its Epigenetic Dysregulation in Liver Transplant Rejection

Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target

HDAC Inhibitors: Novel Immunosuppressants for Allo‐ and Xeno‐ Transplantation

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