TGF-β1 gene-modified, immature dendritic cells delay the development of inflammatory bowel disease by inducing CD4+Foxp3+ regulatory T cells

Cai, Zhijian; Zhang, Wei; Li, Min; Yue, Yinpu; Yang, Fei; Yu, Lei; Cao, Xuetao; Wang, Jianli

doi:10.1038/cmi.2009.107

Cited by 33 publications

(18 citation statements)

References 23 publications

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“…In this study, imDCs produced IL‐10 themselves in vitro , and IL‐10 gene transduction boosted the production of IL‐10 more than four times. IL‐10 gene‐transduced imDCs had stable low expression of CD80, CD86 and MHC II, and, upon co‐culture with T cells, promoted the secretion of TGF‐β1, which is a Th2 type cytokine that inhibits the activation and proliferation of cytotoxic T lymphocytes . Mixed lymphocyte reactions detected lower levels of TNF‐a in the supernatant of allogenic lymphocytes cocultured with IL‐10/imDCs than that in imDC, which is similar to previous results reporting that IL‐10 inhibited the secretion of Th1 cell cytokines.…”

Section: Discussionsupporting

confidence: 87%

Effects of IL‐10‐ and FasL‐overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model

Zhang

Zhu

et al. 2019

Immunol Cell Biol

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Acute rejection is the major determinant for the long-term survival of donor liver after liver transplantation (LT). The aim of this study was to examine the therapeutic potential of interleukin (IL)-10-FasL-overexpressing immature dendritic cells (imDCs) to induce local immunosuppression in liver grafts. imDCs derived from donors were transduced by lentiviral vectors expressing human IL-10 and/or Fas ligand (FasL) gene(s), and the expression of surface molecules and the ability to induce T-cell proliferation were measured. imDCs were intraperitoneally injected into recipient rats as a model of LT to examine the rejection grade [Banff rejection activity index (RAI)], liver functions [Alanine aminotransferase, Aspartate aminotransferase (AST) and total bilirubin (TBIL)] and post-transplant survival. IL-10 and FasL co-transduction of imDCs induced a greater reduction in CD80, CD86 and major histocompatibility complex class II (MHC II) expression, as well as T-cell proliferation, but increased levels of IL-10 and FasL in culture supernatants compared with mono-transduced or untransduced imDCs (P < 0.05). The infusion of co-transduced imDCs in LT recipients reduced RAI scores, decreased plasma AST and TBIL, and prolonged survival compared with mono-transduced or untransduced imDC-treated liver allografts. These findings demonstrated that the transfusion of IL-10-FasL/imDCs enhanced immune tolerance and prolonged the survival of liver allografts after LT. The immunomodulatory activity of IL-10-and FasL-modified imDCs might be a new therapeutic approach to prevent organ rejection in clinical transplantation.

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Section: Discussionsupporting

confidence: 87%

Effects of IL‐10‐ and FasL‐overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model

Zhang

Zhu

et al. 2019

Immunol Cell Biol

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“…93 In addition, the therapeutic potential of DCs in IBD has also been recognized, with TGF-b1 gene-modified and regulatory probiotic-induced DCs suppressing murine models of intestinal inflammation. 94,95 Work on thymic stromal lymphopoietin (TSLP), a hematopoietic cytokine secreted by the IEC, has shown that dysregulated IEC-intrinsic TSLP expression directly affects the production of DC-derived proinflammatory cytokines. 96 It has also been shown that TSLP and as-yet unidentified IEC-derived factors induce TSLP receptor expression on mucosal DCs, which may skew the normal Th1/Th2 balance, with altered expression in CD patients also described.…”

Section: Antigen Recognitionmentioning

confidence: 99%

Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

Henderson

Limbergen

Schwarze

et al. 2011

Inflammatory Bowel Diseases

108

107

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The intestinal epithelium not only acts as a physical barrier to commensal bacteria and foreign antigens but is also actively involved in antigen processing and immune cell regulation. The inflammatory bowel diseases (IBDs) are characterized by inflammation at this mucosal surface with well-recognized defects in barrier and secretory function. In addition to this, defects in intraepithelial lymphocytes, chemokine receptors, and pattern recognition receptors promote an abnormal immune response, with increased differentiation of proinflammatory cells and a dysregulated relationship with professional antigen-presenting cells. This review focuses on recent developments in the structure of the epithelium, including a detailed account of the apical junctional complex in addition to the role of the enterocyte in antigen recognition, uptake, processing, and presentation. Recently described cytokines such as interleukin-22 and interleukin-31 are highlighted as is the dysregulation of chemokines and secretory IgA in IBD. Finally, the effect of the intestinal epithelial cell on T effector cell proliferation and differentiation are examined in the context of IBD with particular focus on T regulatory cells and the two-way interaction between the intestinal epithelial cell and certain immune cell populations.

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“…TGF-β1 is a negative regulator of pro-inflammatory immune responses. We previously found that systemic administration of TGF-β1 gene-modified immature DCs delayed the development of dextran sulfate sodiuminduced murine inflammatory bowel disease (IBD) [4]. Therefore, * These authors contributed equally to this work.…”

mentioning

confidence: 99%

Exosomes with membrane‐associated TGF‐β1 from gene‐modified dendritic cells inhibit murine EAE independently of MHC restriction

Yang

Jiang

et al. 2013

Eur J Immunol

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We have previously demonstrated that exosomes from dendritic cells (DCs) secreting TGF-β1 (sTGF-β1-EXOs) delay the development of murine inflammatory bowel disease (IBD). In this study, we isolated exosomes from DCs expressing membrane-associated TGF-β1 (mTGF-β1-EXOs) and found mTGF-β1-EXOs had more potent immunosuppressive activity than sTGF-β1-EXOs in vitro. Treatment of mice with mTGF-β1-EXOs inhibited the development and progression of myelin oligodendrocyte glycoprotein (MOG)peptide-induced EAE even after disease onset. Treatment of mice with mTGF-β1-EXOs also impaired Ag-specific Th1 and IL-17 responses, but promoted IL-10 responses ex vivo. Treatment with mTGF-β1-EXOs decreased the frequency of Th17 cells in EAE mice, which might be associated with the down-regulation of the p38, ERK, Stat3, and NF-κB activation and IL-6 expression in DCs. Treatment with mTGF-β1-EXOs maintained the regulatory capacity of Treg cells, and adoptive transfer of CD4 + Foxp3 + Treg cells from mTGF-β1-EXO-treated EAE mice dramatically prevented the development of EAE in the recipients. Moreover, treatment with mTGF-β1-EXOs from C57BL/6 mice effectively prevented and inhibited proteolipid protein (PLP) peptide-induced EAE in BALB/c mice. These results indicate that mTGF-β1-EXOs possess powerful immunosuppressive ability and can effectively inhibit the development and progression of EAE in different strains of mice.Keywords: Autoimmune diseases r Exosomes r TGF-β1 r Th17 r Treg cells IntroductionDCs are unique professional APCs and important for the initiation and regulation of immune response [1,2]. Immature DCs have lower levels of co-stimulatory molecules and usually Correspondence: Dr. Zhijian Cai e-mail: caizj@zju.edu.cn; jlwang@zju.edu.cn induce Ag-specific T-cell anergy [3]. TGF-β1 is a negative regulator of pro-inflammatory immune responses. We previously found that systemic administration of TGF-β1 gene-modified immature DCs delayed the development of dextran sulfate sodiuminduced murine inflammatory bowel disease (IBD) [4]. Therefore, * These authors contributed equally to this work. * * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2462 Lei Yu et al. Eur. J. Immunol. 2013. 43: 2461-2472 TGF-β1 may modify DC development toward a regulatory phenotype, inhibiting inflammation. Exosomes, released by almost all types of cells, are small lipid bilayer vesicles with a size of 50-100 nm. They are formed by membrane budding into the lumen of an endocytic compartment, leading to the formation of multivesicular bodies. Fusion of multivesicular bodies to plasma membrane leads to the extracellular release of exosomes [5,6]. Exosomes from DCs transfected with vIL-10, FasL, or IL-4 gene inhibit delayed-type hypersensitivity and collagen-induced murine arthritis [7,8]. These results indicate that exosomes can be effective vehicles to carry immunoregulatory molecules for the treatment of autoimmune diseases.Ag-specific Th1 and Th17 cells are crucial for the development of...

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TGF-β1 gene-modified, immature dendritic cells delay the development of inflammatory bowel disease by inducing CD4+Foxp3+ regulatory T cells

Cited by 33 publications

References 23 publications

Effects of IL‐10‐ and FasL‐overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model

Effects of IL‐10‐ and FasL‐overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model

Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

Exosomes with membrane‐associated TGF‐β1 from gene‐modified dendritic cells inhibit murine EAE independently of MHC restriction

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