TGF-β1 gene modified immature dendritic cells exhibit enhanced tolerogenicity but induce allograft fibrosis in vivo

Sun, Wenji; Wang, Quanxing; Zhang, Lihuang; Pan, Jianping; Zhang, Min; Lü, Guohua; Yao, Hang‐Ping; Wang, Jianli; Cao, Xuetao

doi:10.1007/s00109-002-0346-2

Cited by 28 publications

(28 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Culture supernatants of TGF-b1-DCs or LacZ-DCs were harvested 48 h after transfection of Ad-TGF-b1 or Ad-LacZ, 13 respectively; culture supernatants of day-6 DCs were used as a control. The level of TGF-b1 was detected by ELISA.…”

Section: Resultsmentioning

confidence: 99%

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

Cai

Zhang²,

Li³

et al. 2010

Cell Mol Immunol

Self Cite

View full text Add to dashboard Cite

Inflammatory bowel disease (IBD) is caused by an uncontrolled immune response in the intestinal lumen, leading to inflammation in genetically predisposed individuals. Immunotherapy may be a promising approach to the treatment of IBD. Here, we show that transforming growth factor-b1 (TGF-b1) gene-modified immature dendritic cells (imDCs) could enhance the inhibitory function of imDCs and delay the progress of IBD induced by dextran sodium sulfate in mice. The results of fluorescence-activated cell sorter (FACS) demonstrated that this protective effect is mediated partially by inducing CD4 1 Foxp3 1 regulatory T cells (Tregs) in mesentery lymph nodes to control inflammation. In vitro experiments also supported this hypothesis. In conclusion, we provide evidence that TGF-b1-modified bone marrow-derived imDCs may have a therapeutic effect to IBD.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Cai

Zhang²,

Li³

et al. 2010

Cell Mol Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…To provide a comparison between the effects of direct TNF-␣ blockade by secreted sTNFRI and those of DC-sTNFRI in vivo, 2 ϫ 10 6 sTNFRI genemodified L929 cells (L929-sTNFRI, H-2 d ), which secreted comparable levels of sTNFRI to DC-sTNFRI in vitro, were infused into separate recipients. On day 0, fully allogeneic cervical vascularized heart transplantation was performed from C57BL/6 or C3H (as third-party) donors to size-matched BALB/c recipients as described previously (12). Graft survival was assessed by daily palpation of grafted hearts, with rejection defined as total cessation of cardiac contraction.…”

Section: Heterotopic Heart Transplantation and Skin Transplantationmentioning

confidence: 99%

“…Our previous studies showed that the efficacy of Ad-mediated transfection of BM-derived DC was Ͼ95% (12,30). First, the levels of sTNFRI in supernatants of gene-modified DC were determined.…”

Section: Resistance Of Dc-stnfri To Maturation Inductionmentioning

confidence: 99%

Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor

Wang

Liu

Wang

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The ability of dendritic cells (DC) to initiate immune responses or induce immune tolerance is strictly dependent on their maturation state. TNF-α plays a pivotal role in the differentiation and maturation of DC. Blockade of TNF-α action may arrest DC in an immature state, prolonging their window of tolerogenic opportunity. Immature DC (imDC) were transfected with recombinant adenovirus to express soluble TNF-α receptor type I (sTNFRI), a specific inhibitor of TNF-α. The capacity of sTNFRI gene-modified imDC (DC-sTNFRI) to induce immune tolerance was analyzed. sTNFRI expression renders imDC resistant to maturation induction and impairs their capacity to migrate or present Ag. This process leads to induction of allogeneic T cell hyporesponsiveness and the generation of IL-10-producing T regulatory-like cells. In vivo pretreatment of transplant recipients with DC-sTNFRI induces long-term survival of cardiac allografts in 50% of cases, and leads to a substantial increase in the generation of microchimerism and T regulatory cell numbers. Thus, blockade of TNF-α action by sTNFRI genetic modification can inhibit the maturation of DC and potentiate the in vivo capacity of imDC to induce donor-specific immune tolerance and prolong allograft survival.

show abstract

“…Though TGF-b and IL-10 are commonly accepted to be important for the induction of tolerance [28][29][30][31], both are not involved in the inhibitory functions of DCreg. It is well known that NO, PGE2 and IDO can all inhibit T-cell proliferation by acting upon multiple signaling pathways [32].…”

Section: Discussionmentioning

confidence: 99%

Pulmonary stromal cells induce the generation of regulatory DC attenuating T‐cell‐mediated lung inflammation

Guo

et al. 2008

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E 2 (PGE 2 ) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-b is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4 1 CD25 1 Foxp3 1 Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung.Key words: DC . Immune regulation . Lung inflammation . Treg . Stromal cells Introduction DC are the most potent APC in the immune system, with unique capacity to activate naïve T cells and to initiate immune responses [1]. Now, increasing evidence demonstrates that, depending on the maturation state or subsets, DC can induce tolerance or downregulate immune responses [2,3]. Immature DC (imDC) have been shown to be able to induce Treg and promote alloantigen-specific tolerance. Recently, several types of DC with negative regulatory functions, designated as regulatory DC (DCreg), have been reported [3][4][5]. Up to now, regulatory DCreg were generated by culturing imDC in the presence of immunosuppressive cytokines such as IL-10 and TGF-b or immunomodulatory drugs [4][5][6], which does not represent the in vivo physiologic conditions of DCreg in the organ microenvironment. More and more data show that the microenvironment in certain tissues has the ability to induce DC development [7][8][9][10] and also affects the function of DC; for example, DC in brain and kidney display regulatory functions but not T-cell-activating functions [11,12]. Our previous studies demonstrate that endothelial splenic stromal cells, which are used to mimic the in vivo splenic microenvironment, can promote the proliferation of mature DC (maDC) [7] and hematopoietic stem cells [8], driving them to Ã These authors contributed equally to this work. The lung is one of the organs connected with the outside environment of the organism and interfaces a vast quantity of environmental antigens, some of which are dan...

show abstract

TGF-β1 gene modified immature dendritic cells exhibit enhanced tolerogenicity but induce allograft fibrosis in vivo

Cited by 28 publications

References 19 publications

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

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

Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor

Pulmonary stromal cells induce the generation of regulatory DC attenuating T‐cell‐mediated lung inflammation

Contact Info

Product

Resources

About