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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.

journal_name

Blood

journal_title

Blood

authors

Daenthanasanmak A,Iamsawat S,Chakraborty P,Nguyen HD,Bastian D,Liu C,Mehrotra S,Yu XZ

doi

10.1182/blood-2018-07-863233

subject

Has Abstract

pub_date

2019-01-17 00:00:00

pages

266-279

issue

eissn

0006-4971

issn

1528-0020

pii

blood-2018-07-863233

journal_volume

133

pub_type

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