Dataset Information

Blockade of Host ?2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs.

ABSTRACT: Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that ?2-adrenergic receptor (?2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a ?2AR blocker significantly increases the GVT effect of donor CD8+ T cells by decreasing tumor burden without increasing graft-versus-host disease. ?2AR-deficient host mice have significantly increased effector memory and central memory CD8+ T cells and improved reconstitution of T cells, including CD4+Foxp3+ regulatory T cells. Notably, ?2AR deficiency induces increased CD11c+ DC development. Also, ?2AR-deficient bone marrow-derived DCs induce higher CD8+ T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that ?2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host ?2AR signaling in suppressing T cell reconstitution and GVT activity.

SUBMITTER: Mohammadpour H

PROVIDER: S-EPMC5860988 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs.

Mohammadpour Hemn H O'Neil Rachel R Qiu Jingxin J McCarthy Philip L PL Repasky Elizabeth A EA Cao Xuefang X

Journal of immunology (Baltimore, Md. : 1950) 20180214 7

Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that β2-adrenergic receptor (β2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a β2AR blocker significantly increases the GVT effect of donor CD8<sup>+</sup> T cells by decrea ...[more]

PMID: 29445008

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Project description:Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after HCT for malignant disease. Graft versus tumor (GVT) is a major component of the overall beneficial effects of allogeneic HCT in the treatment of hematological malignancies. Better understanding of GVHD pathogenesis is important to identify new therapeutic targets for GVHD prevention and therapy. Emerging data suggest opposing roles for different T cell subsets, e.g., IFN-γ producing CD4+ and CD8+ T cells (Th1 and Tc1), IL-4 producing T cells (Th2 and Tc2), IL-17 producing T cells (Th17 and Tc17), IL-9 producing T cells (Th9 and Tc9), IL-22 producing T cells (Th22), T follicular helper cells (Tfh), regulatory T-cells (Treg) and tissue resident memory T cells (Trm) in GVHD and GVT etiology. In this review, we first summarize the general description of the cytokine signals that promote the differentiation of T cell subsets and the roles of these T cell subsets in the pathogenesis of GVHD. Next, we extensively explore preclinical findings of T cell subsets in both GVHD/GVT animal models and humans. Finally, we address recent findings about the roles of T-cell subsets in clinical GVHD and current strategies to modulate T-cell differentiation for treating and preventing GVHD in patients. Further exploring and outlining the immune biology of T-cell differentiation in GVHD that will provide more therapeutic options for maintaining success of allo-HCT.

Dataset Information

Blockade of Host ?2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs.

Publications

Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs.

Similar Datasets

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