Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Schutt, Steven; Wu, Yongxia; Tang, Chih-Hang Anthony; Bastian, David; Nguyen, Hung; Sofi, M. Hanief; Zhang, Mengmeng; Liu, Chen; Helke, Kristi L.; Wilson, Carole L.; Schnapp, Lynn M.; Valle, Juan R. Del; Hu, Chih‐Chi Andrew; Yu, Xue-Zhong

doi:10.1182/bloodadvances.2017009068

Cited by 18 publications

(19 citation statements)

References 74 publications

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“…Plasma cell differentiation and autoantibody production have also been demonstrated to contribute to disease pathology. [17][18][19][20] In the current study, we demonstrate that Sirt-1 inhibition, either by genetic ablation or pharmacological blockade, diminished T-cell activation and pathogenicity in GVHD through enhancing p53 acetylation and signaling. Sirt-1 deficiency in T cells not only decreased alloreactivity of donor T cells but also promoted iTreg differentiation after allo-BMT.…”

Section: Introductionsupporting

confidence: 52%

“…GVL models, cGVHD models, T-cell purification, and T-cell depleted bone marrow, antibodies and flow cytometry, in vitro T-cell polarization, in vitro and in vivo mixed lymphocyte reactions, in vitro and in vivo iTreg stability assay, lymphocyte isolation from recipient liver, histological analysis, DNA methylation assay, human Sirt-1 activity assay, and western blotting analysis are described in previously published work [20][21][22][23][24][25][26][27] and are also detailed in the supplemental Methods, available on the Blood Web site.…”

Section: Methodsmentioning

confidence: 99%

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

Daenthanasanmak¹,

Iamsawat²,

Chakraborty

et al. 2019

Blood

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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®

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Section: Introductionsupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

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

Daenthanasanmak¹,

Iamsawat²,

Chakraborty

et al. 2019

Blood

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“…ER stress is important in B cell function and autoimmunity [69]. Recently, conditioned knockdown of XBP1 in B cells was shown to prevent chronic GvHD and to preserve the graft-versus-leukemia in chronic GvHD mouse model [70]. These findings suggest a possibility that the IRE-1a/XBP1 pathway can be a new therapeutic target of chronic GvHD.…”

Section: Graft Versus Host Diseasementioning

confidence: 99%

Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

et al. 2019

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Endoplasmic reticulum (ER) stress is a mechanism that allows to protect normal cellular functions in response to both internal perturbations, such as accumulation of unfolded proteins, and external perturbations, for example redox stress, UVB irradiation, and infection. A hallmark of ER stress is the accumulation of misfolded and unfolded proteins. Physiological levels of ER stress trigger the unfolded protein response (UPR) which is required to restore normal ER functions. However, the UPR can also initiate a cell death program/apoptosis pathway in response to excessive or persistent ER stress. Recently, it has become evident that chronic ER stress occurs in several diseases, including skin diseases like Darier’s disease, rosacea, vitiligo, and melanoma; furthermore, it is suggested that ER stress is directly involved in the pathogenesis of these disorders. Here, we review the role of ER stress in skin function, and discuss its significance in skin diseases.

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“…In support of this possibility is work in autoimmune syndromes showing that blocking ER stress with tauroursodeoxycholic acid ameliorates experimental autoimmune encephalomyelitis and reduces Th17 differentiation (24). In a donor B cell dependent chronic GVHD model, suppressing XBP-1s in donor B cells reduces murine chronic GVHD (25). While these findings in murine chronic GVHD are important, translational questions regarding how the ER stress response influences human acute GVHD pathogenesis were not addressed.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity

et al. 2018

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Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1β, TGFβ, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.

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Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Cited by 18 publications

References 74 publications

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

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

Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity

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