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

Abstract

K E Y P O I N T S l Deficiency of Sirt-1 reduces T-cell pathogenicity in GVHD by enhancing p53 acetylation in T cells and promoting iTreg stability. l Treatment with a Sirt-1 inhibitor reduces Tfh generation, B-cell activation, and plasma cell differentiation during cGVHD development.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 2/2 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-g 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. (Blood. 2019;133 (3):266-279) Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Acute GVHD (aGVHD) is distinguished by uncontrolled activation, migration, and proliferation of allogeneic donor T cells, as well as their production of pro-inflammatory 266 blood®

Quercetin protected against isoniazide‐induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway

“…That is, the SIRT1/ERK pathway was essential for Que protecting against INH‐induced apoptosis. In addition to apoptosis, immune response is another important feature in INH‐induced hepatotoxicity and SIRT1/ERK is also known as a potential regulator of immune process . Hence, SIRT1/ERK‐mediated immune response may be involved in the protective effect of Que on INH hepatotoxicity, which still needs further exploration.…”

Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat)

“…Several articles described effects on cells involved in the immune system, macrophages, and T cells. Beneficial effects on autoimmune diseases and graft rejection problems can be envisioned from these cell assays, for example through reduction of effector T cell proliferation and differentiation 57,69 , and increase in the number and suppressive function of T regulatory cells Tregs (see Chapter undefined for in vivo results) 64 .…”

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

“…The important role played by this enzyme in B- and T cell interaction during the development of GvHD was recently highlighted by Daenthanasanmak et al . ( 165 ). In a murine model, the authors demonstrated that donor T cells lacking sirt1 reduced B cell activation and differentiation but increased Tregs.…”

“…In a murine model, the authors demonstrated that donor T cells lacking sirt1 reduced B cell activation and differentiation but increased Tregs. Moreover, administration of the sirt1 inhibitor selisistat (EX 527) resulted in reduced Tfh responses along with preventing and treating cGvHD by downregulation of IFN-γ, IL-17, and IL-21, which have all been associated with cGvHD pathogenesis ( 165 );…”