Advertisement

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

Anusara Daenthanasanmak, Supinya Iamsawat, Paramita Chakraborty, Hung D. Nguyen, David Bastian, Chen Liu, Shikhar Mehrotra and Xue-Zhong Yu

Key points

  • Deficiency of Sirt-1 reduces T-cell pathogenicity in GVHD by enhancing p53 acetylation in T cells and promoting iTreg stability.

  • Treatment with a Sirt-1 inhibitor reduces Tfh generation, B-cell activation and plasma cell differentiation during cGVHD development.

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 knock-out mice as well as a pharmacological Sirt-1 inhibitor. Using MHC-mismatched and -matched murine BMT models, we found that Sirt-1-/- T cells had a reduced ability to induce acute GVHD via enhanced p53 acetylation. Sirt-1 deficient T cells also promoted iTreg differentiation and inhibited IFN-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 GVL effect. Consistently, Sirt-1-deficient T cells also displayed a remarkably reduced ability to induce chronic GVHD. 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, as well as 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.

  • Submitted July 13, 2018.
  • Accepted November 27, 2018.