Baricitinib prevents GvHD by increasing Tregs via JAK3 and treats established GvHD by promoting intestinal tissue repair via EGFR.
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ABSTRACT:
SUBMITTER: Kim S
PROVIDER: S-EPMC8732299 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Graft-versus-host disease (GvHD) of the skin is a severe allo-immune reaction and complication following allogeneic stem cell transplantation. Over the past years, intensive pre-clinical research has led to an improved understanding of the pathophysiology of acute and to a lesser extend chronic GvHD. This has translated into the approval of several new agents for the treatment of both forms of GvHD. This review summarizes the most recent advances in underlying pathomechanisms, clinical trials and newly approved agents for GvHD, with a special focus on skin involvement.
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Project description:Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (Allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemia (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4(+) or CD8(+) T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4(+) iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8(+) iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4(+) and CD8(+) iTregs could achieve the optimal goal of Allo-HCT. Indeed, the combinational therapy was superior to CD4(+) or CD8(+) iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4(+) and CD8(+) effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8(+) iTregs possess elevated expression of multiple cytolytic molecules compared to CD4(+) iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4(+) and CD8(+) iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.
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Project description:We assessed the impact of the Janus Kinase (JAK) 1 inhibitor itacitinib on xenogeneic graft-versus-host disease (xGVHD). XGVHD was induced by i.v. injection 20 × 106 human peripheral blood mononuclear cells (hPBMC) in NSG mice on day 0. Itacitinib (3 mg, ≈120 mg/kg) or methylcellulose was administered by force-feeding twice a day from day 3 to day 28. Mice were followed for xGVHD score and survival. In addition, human T-cell engraftment and as well as human T-cell subtypes were monitored in blood on days 14, 21, and 28 after transplantation. We observed that itacitinib-treated mice had significantly longer survival than control mice (median 45 versus 33 days; P < 0.001). Further, they also had lower absolute numbers of human CD4+ T cells on days 21 and 28 after transplantation as well as of human CD8+ T cells on days 14, 21, and 28 after transplantation. In addition, itacitinib-treated mice had higher frequencies of human regulatory T cells (Treg) on days 21 and 28 after transplantation. In summary, our data indicate that itacitinib decreases human T-cell engraftment, increases Treg frequencies and attenuates xGVHD in NSG mice transplanted with hPBMC.
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Project description:We find that selective inhibition of one arm of mTORC1 signaling, via deletion of FLCN, promotes activation of the transcription factor TFE3 and profoundly protects against NAFLD and NASH in mice. (1) We performed genome-wide RNA-seq on livers from Control, liver-specific Flcn-null mice (LiFKO), and Flcn/Tfe3 double knock-out (DKO) mice fed either normal chow (NC) or a NAFLD-inducing diet (AMLN). We find TFE3-mediated induction of lysosomal and mitochondrial gene programs, and also suppression of de novo lipogenesis genes. (2) To understand whether TFE3 directly affects gene expression, we performed TFE3 ChIP-seq on livers from Control and LiFKO mice on normal chow. We find TFE3 occupancy on the chromatin at lysosomal genes, Ppargc1a (a driver of mitochondrial genes), and at de novo lipogenesis genes. (3) Finally, we wanted to test whether TFE3 antagonistically competes with the pro-lipogenic transcription factor SREBP-1c on chromatin. We therefore injected HA-tagged constitutively nuclear (active) SREBP-1c (nSREBP-1c), or a control virus, into control and LiFKO mice, treated them with a NAFLD-inducing diet (FPC diet), and collected liver tissue. We consequently performed HA-nSREBP-1c and TFE3 ChIP-seq experiments and observed no evidence of antagonistic competition.
2022-04-15 | GSE160292 | GEO
Project description: Not available
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Project description:Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.
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Project description:SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR-Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely. We further show that this approach extends survival of mice lethally infected with SARS-CoV-2, correlating with decreased lung virus burden, reduced expression of proinflammatory cytokines/chemokines and diminished severity of pulmonary interstitial inflammation. Postinfection treatment by this nanosystem dramatically lowers the lung virus burden and alleviates virus-induced pathological changes. Our results indicate that targeting lung protease mRNA by Cas13d nanosystem represents a unique strategy for controlling SARS-CoV-2 infection and demonstrate that CRISPR can be used as a potential treatment for SARS-CoV-2 infection.
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Project description:Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/- mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.
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Project description:Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T (Tconv) cells (CD45RChi), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RClo/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChi T cells, inhibited CD45RChi B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RChi cells. Our observations highlight the potential role for CD45RChi cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.
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Project description:Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present.
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