Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice.

Abstract

Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Sirtuin-1 (Sirt-1) plays a crucial role in various biological processes including cellular senescence, metabolism, and inflammatory responses. Sirt-1 deacetylation regulates different transcription factors that are important for modulating immune responses. In the current study, we addressed the role of Sirt-1 in GVHD induction by employing Sirt-1 conditional knockout mice as well as a pharmacological Sirt-1 inhibitor. Using major histocompatibility complex (MHC)-mismatched and MHC-matched murine BMT models, we found that Sirt-1-/- T cells had a reduced ability to induce acute GVHD (aGVHD) via enhanced p53 acetylation. Sirt-1-deficient T cells also promoted induced regulatory T cell (iTreg) differentiation and inhibited interferon-γ production after allo-BMT. Sirt-1 deletion in iTregs increased Foxp3 stability and restrained iTreg conversion into pathogenic T cells. Furthermore, we found that administration with a Sirt-1 inhibitor, Ex-527, significantly improved recipient survival and clinical scores, with no signs of tumor relapse. These results indicate that Sirt-1 inhibition can attenuate GVHD while preserving the graft-versus-leukemia effect. Consistently, Sirt-1-deficient T cells also displayed a remarkably reduced ability to induce chronic GVHD (cGVHD). Mechanistic studies revealed that Sirt-1 deficiency in T cells enhanced splenic B-cell reconstitution and reduced follicular T helper cell development. Sirt-1 deficiency in T cells modulated donor B-cell responses reducing both B-cell activation and plasma cell differentiation. In addition, therapeutic Sirt-1 inhibition could both prevent cGVHD and reduce established cGVHD. In conclusion, Sirt-1 is a promising therapeutic target for the control of aGVHD and cGVHD pathogenesis and possesses high potential for clinical application.

• Authors: Anusara Daenthanasanmak, Supinya Iamsawat, Paramita Chakraborty, Hung D Nguyen, David Bastian, Chen Liu, Shikhar Mehrotra, Xue-Zhong Yu
• Journal: Blood (Blood) Vol. 133 Issue 3 Pg. 266-279 (01 17 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30514750 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
• Carbazoles
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Acetylation
• Animals
• B-Lymphocytes (drug effects, immunology, metabolism)
• Bone Marrow Transplantation
• Carbazoles (pharmacology)
• Cell Differentiation
• Female
• Graft vs Host Disease (drug therapy, immunology, pathology)
• Graft vs Leukemia Effect (drug effects, immunology)
• Lymphocyte Activation (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Sirtuin 1 (antagonists & inhibitors, physiology)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• Transplantation, Homologous
• Tumor Suppressor Protein p53 (metabolism)