Immunomodulatory Effects of Histone Deacetylation Inhibitors in Graft-vs.-Host Disease After Allogeneic Stem Cell Transplantation

Xu, Xiaojun; Li, Xiaoqin; Zhao, Yanmin; Huang, He

doi:10.3389/fimmu.2021.641910

Cited by 9 publications

(9 citation statements)

References 54 publications

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“…Overall, MDS/AML patients receiving HMA maintenance after allo-HSCT had better outcomes as well as a reduced incidence of chronic GvHD, consistent with an updated systematic review and meta-analysis ( 75 ). Panobinostat (PNB, a histone deacetylase inhibitor), due to its immunomodulatory activity ( 76 ) that may enhance leukemia-specific cytotoxicity and mitigate GvHD, was also applied in a transplant setting. The safety and efficacy of PNB was explored in a phase I/II clinical trial ( 53 ) in patients with high-risk MDS/AML, and it was well tolerated, with a relatively low relapse rate and incidence of GvHD.…”

Section: Post-hsctmentioning

confidence: 99%

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

et al. 2022

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for patients with myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse and graft-versus-host disease (GvHD) still affect the survival of patients who receive allo-HSCT, and more appropriate therapeutic strategies should be applied at all stages of transplantation to prevent these adverse events. The use of epigenetics agents, such as hypomethylating agents (HMAs), has been explored to decrease the risk of relapse by epigenetic modulation, which is especially effective among AML patients with poor mutations in epigenetic regulators. Furthermore, epigenetic agents have also been regarded as prophylactic methods for GvHD management without abrogating graft versus leukemia (GvL) effects. Therefore, the combination of epigenetic therapy and HSCT may optimize the transplantation process and prevent treatment failure. Existing studies have investigated the feasibility and effectiveness of using HMAs in the pretransplant, transplant and posttransplant stages among MDS and AML patients. This review examines the application of HMAs as a bridge treatment to reduce the tumor burden and the determine appropriate dose during allo-HSCT. Within this review, we also examine the efficacy and safety of HMAs alone or HMA-based strategies in posttransplant settings for MDS and AML. Finally, we provide an overview of other epigenetic candidates, which have been discussed in the nontransplant setting.

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Section: Post-hsctmentioning

confidence: 99%

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

et al. 2022

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“…Overall, epigenetic modulators like the describes HDACi, were shown to efficiently inhibit GVHD by altering Th polarization via TF modulation. The success of HDACi in preventing GVHD is also displayed by multiple clinical studies validating their beneficial effect often in combinatory therapy in patients [reviewed by Xu et al., ( 217 )].…”

Section: Potential Strategies To Target Transcription Factors Of T Helper Cell Development In Gvhdmentioning

confidence: 99%

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

Campe

Ullrich

2022

Front. Immunol.

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Allogenic hematopoietic stem cell transplantation (allo-HSCT) represents a potent and potentially curative treatment for many hematopoietic malignancies and hematologic disorders in adults and children. The donor-derived immunity, elicited by the stem cell transplant, can prevent disease relapse but is also responsible for the induction of graft-versus-host disease (GVHD). The pathophysiology of acute GVHD is not completely understood yet. In general, acute GVHD is driven by the inflammatory and cytotoxic effect of alloreactive donor T cells. Since several experimental approaches indicate that CD4 T cells play an important role in initiation and progression of acute GVHD, the contribution of the different CD4 T helper (Th) cell subtypes in the pathomechanism and regulation of the disease is a central point of current research. Th lineages derive from naïve CD4 T cell progenitors and lineage commitment is initiated by the surrounding cytokine milieu and subsequent changes in the transcription factor (TF) profile. Each T cell subtype has its own effector characteristics, immunologic function, and lineage specific cytokine profile, leading to the association with different immune responses and diseases. Acute GVHD is thought to be mainly driven by the Th1/Th17 axis, whereas Treg cells are attributed to attenuate GVHD effects. As the differentiation of each Th subset highly depends on the specific composition of activating and repressing TFs, these present a potent target to alter the Th cell landscape towards a GVHD-ameliorating direction, e.g. by inhibiting Th1 and Th17 differentiation. The finding, that targeting of Th1 and Th17 differentiation appears more effective for GVHD-prevention than a strategy to inhibit Th1 and Th17 cytokines supports this concept. In this review, we shed light on the current advances of potent TF inhibitors to alter Th cell differentiation and consecutively attenuate GVHD. We will focus especially on preclinical studies and outcomes of TF inhibition in murine GVHD models. Finally, we will point out the possible impact of a Th cell subset-specific immune modulation in context of GVHD.

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“…Promising activity in subsequent early phase clinical GVHD prophylaxis studies has also been seen ( 56 ). Additional immunomodulatory effects of these agents have recently been reviewed elsewhere ( 57 ).…”

Section: Acute Gvhdmentioning

confidence: 99%

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

Teshima

Hill

2021

Front. Immunol.

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Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.

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Immunomodulatory Effects of Histone Deacetylation Inhibitors in Graft-vs.-Host Disease After Allogeneic Stem Cell Transplantation

Cited by 9 publications

References 54 publications

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

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