Dataset Information

Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects.

ABSTRACT: The demethylating agent 5-azacytidine (AZA) has proven its efficacy in the treatment of myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Treg). Here, we investigated the impact of AZA on xenogeneic graft-vs.-host disease (xGVHD) and graft-vs.-leukemia effects in a humanized murine model of transplantation (human PBMCs-infused NSG mice), and described the impact of the drug on human T cells in vivo. We observed that AZA improved both survival and xGVHD scores. Further, AZA significantly decreased human T-cell proliferation as well as IFNγ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA significantly increased Treg frequency through hypomethylation of FOXP3i1 as well as increased Treg proliferation. The latter was subsequent to higher STAT5 signaling in Treg from AZA-treated mice, which resulted from higher IL-2 secretion by conventional T cells from AZA-treated mice itself secondary to demethylation of the IL-2 gene promoter by AZA. Importantly, Tregs harvested from AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Finally, graft-vs.-leukemia effects (assessed by growth inhibition of THP-1 cells, transfected to express the luciferase gene) were not abrogated by AZA. In summary, our data demonstrate that AZA prevents xGVHD without abrogating graft-vs.-leukemia effects. These findings could serve as basis for further studies of GVHD prevention by AZA in acute myeloid leukemia patients offered an allogeneic transplantation.

SUBMITTER: Ehx G

PROVIDER: S-EPMC5467988 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Graft-versus-host disease (GVHD) remains the major cause of mortality and morbidity in non-relapse patients after allogeneic hematopoietic cell transplantation (allo-HCT). As the number of patients undergoing allo-HCT increases, it will become imperative to determine safe and effective treatment options for patients with GVHD, especially those who become refractory to systemic steroid therapy. Daratumumab (Dara), a humanized IgG1 (ĸ subclass) monoclonal antibody targeting the CD38 epitope, is used for the treatment of multiple myeloma. CD38 is a multifunctional ectoenzyme that behaves either as an enzyme, a cell adhesion molecule or a cell surface receptor involved in cell signaling. CD38 is also expressed on various immune effector and suppressor cells. However, the role of CD38 in the immune response remains elusive. We questioned whether CD38 is a potential therapeutic target against alloreactive T cells in the GVHD pathological process. Here, we investigated the impact of Dara on xenogeneic GVHD (xeno-GVHD) and graft-versus-leukemia (GVL) effects in a humanized murine model of transplantation, where human peripheral blood mononuclear cells were adoptively transplanted into immunocompromised NOD.SCID.gc-null (NSG) mice. Mice receiving Dara treatment experienced less weight loss, longer survival and lower GVHD scores compared with those in the control group. Histological evaluations, flow cytometry, RNA-sequencing and RT-qPCR analysis revealed that Dara efficaciously mitigated GVHD through multiple mechanisms including inhibition of the proliferation, activation and differentiation of CD8+ cytotoxic T cells, reduced expression of cytotoxic effector molecules, pro-inflammatory cytokines, chemokines and chemoattractant receptors by T cells and promotion of immunosuppressive T cells. More importantly, Dara preserved the GVL effect in a humanized mouse model of leukemia by metabolic reprograming of T cells to promote the induction of Th17, Th1/17and Tc1/17 cells. Our findings indicate that Dara may be an attractive therapeutic option to separate GVHD from GVL effects in patients with hematopoietic malignancies receiving allo-HCT.

Dataset Information

Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets