Overexpression of Jagged‐1 combined with blockade of CD40 pathway prolongs allograft survival

Lin, Yingying; Chen, Weili; Li, Jiali; Yan, Guoliang; Li, Chun; Jin, Ning; Chen, Jie; Gao, Chang; Ma, Ping; Xu, Shuangyue; Qi, Zhongquan

doi:10.1038/icb.2014.84

Cited by 16 publications

(10 citation statements)

References 43 publications

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“…Although Dll1‐overexpressing L cells delayed allograft rejection in a CD8 + T cell–dependent manner, it is unclear whether the effects were the result of direct engagement of Dll1 with Notch receptor in T cells. Similar observations were reported recently on in vivo transfer of a Jag1‐transduced DC line in combination with CD40 blockade . Altogether, these studies suggested that inducing artificially high Notch signals in T cells could generate a state of antigen‐specific tolerance.…”

Section: Early Work On Notch Signaling In T Cell Alloreactivity and Tsupporting

confidence: 87%

Targeting the Notch Pathway to Prevent Rejection

Chung

Riella

Maillard

2016

American Journal of Transplantation

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Immune rejection is mediated by a complex interplay of cellular and humoral mechanisms. Current therapeutic strategies, which rely on global immunosuppression, can result in serious complications and are not completely effective. Notch signaling is a cell-to-cell communication pathway that plays an important role during T cell development and in the regulation of peripheral immune responses. Initial work, performed mainly through gain-of-function approaches, paradoxically identified Notch as an inducer of tolerance; however, recent studies using loss-of-function approaches in mouse models of transplant rejection and graft-versus-host disease have clarified an important role for Notch as a central mediator of T cell alloreactivity. Short-term inhibition of individual Notch ligands in the peritransplant period had long-lasting protective effects. In a vascularized heart allograft model, blockade of Delta-like Notch ligands dampened both cellular and humoral rejection. In this minireview, we summarize current knowledge about the role of Notch signaling during allograft rejection and provide an overarching mechanism through which Notch acts to promote T cell pathogenicity and allograft damage. We propose that targeting elements of the Notch pathway could provide a new therapeutic approach to prevent allograft rejection.

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Section: Early Work On Notch Signaling In T Cell Alloreactivity and Tsupporting

confidence: 87%

Targeting the Notch Pathway to Prevent Rejection

Chung

Riella

Maillard

2016

American Journal of Transplantation

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“…27 Other studies reported that transgenic expression of Jag1 by Epstein-Barr virus-positive lymphoblastoid cell lines induced antigen-specific Treg cells and thereby reduced the alloreactivity of T cells. 26,45 Moreover, Lin et al 46 transduced the Jag1 gene into the DC2.4 cell line by an adenovirus, and they demonstrated that blockade of the CD40 pathway enhanced the immune tolerance by Jag1-overexpressing DC2.4 cells during heart transplantation. Collectively, these results indicate that Jag1 signaling is critical for inducing the generation of Treg cells.…”

Section: Discussionmentioning

confidence: 99%

Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3⁺ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice

et al. 2018

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Summary Dendritic cells (DCs) are professional antigen‐presenting cells that play a key role in directing T‐cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T‐cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow‐derived DCs genetically engineered to express Jag1 (Jag1‐DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1‐DCs to manipulate T helper type 2 (Th2) ‐mediated allergic asthma in mice. We produced Jag1‐DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) ‐stimulated Jag1‐DCs exhibited increased expression of programmed cell death ligand 1 (PD‐L1) and OX40L molecules. Subsequently, co‐culture of these OVA‐pulsed Jag1‐DCs with allogeneic or syngeneic CD4+ T cells promoted the generation of Foxp3+ Treg cells, and blocking PD‐L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA‐pulsed Jag1‐DCs to mice with OVA‐induced asthma reduced allergen‐specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2‐type cytokines (interleukin‐4, interleukin‐5, and interleukin‐13). Notably, an increased number of Foxp3+ Treg cells associated with enhanced levels of transforming growth factor‐β production was observed in Jag1‐DC‐treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3+ Treg cells, which ameliorated Th2‐mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell‐driven deleterious immune diseases.

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“…Differences between both studies may be explained by differences in the generation protocols as well as the detection techniques used. Dex also induced several molecules associated with regulation of immune responses involving Treg and effector T-cell functions (JAG1, TBXAS1, and MERTK) ( 49 , 50 ), DC differentiation and function (IRAK3, GILZ, C1Q, and STAB1) ( 28 , 51 , 52 ) and suppression of inflammatory signaling (MAP3K8/TPL-2, FCGR2B, and VDR). Functional enrichment analysis showed that Dex treatment of moDCs also induced the expression of genes related to the complement system pathway.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

et al. 2017

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There is growing interest in the use of tolerogenic dendritic cells (tolDCs) as a potential target for immunotherapy. However, the molecular bases that drive the differentiation of monocyte-derived DCs (moDCs) toward a tolerogenic state are still poorly understood. Here, we studied the transcriptional profile of moDCs from healthy subjects, modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), referred to as Dex-modulated and MPLA-activated DCs (DM-DCs), as an approach to identify molecular regulators and pathways associated with the induction of tolerogenic properties in tolDCs. We found that DM-DCs exhibit a distinctive transcriptional profile compared to untreated (DCs) and MPLA-matured DCs. Differentially expressed genes downregulated by DM included MMP12, CD1c, IL-1B, and FCER1A involved in DC maturation/inflammation and genes upregulated by DM included JAG1, MERTK, IL-10, and IDO1 involved in tolerance. Genes related to chemotactic responses, cell-to-cell signaling and interaction, fatty acid oxidation, metal homeostasis, and free radical scavenging were strongly enriched, predicting the activation of alternative metabolic processes than those driven by counterpart DCs. Furthermore, we identified a set of genes that were regulated exclusively by the combined action of Dex and MPLA, which are mainly involved in the control of zinc homeostasis and reactive oxygen species production. These data further support the important role of metabolic processes on the control of the DC-driven regulatory immune response. Thus, Dex and MPLA treatments modify gene expression in moDCs by inducing a particular transcriptional profile characterized by the activation of tolerance-associated genes and suppression of the expression of inflammatory genes, conferring the potential to exert regulatory functions and immune response modulation.

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Overexpression of Jagged‐1 combined with blockade of CD40 pathway prolongs allograft survival

Cited by 16 publications

References 43 publications

Targeting the Notch Pathway to Prevent Rejection

Targeting the Notch Pathway to Prevent Rejection

Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3⁺ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

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Overexpression of Jagged‐1 combined with blockade of CD40 pathway prolongs allograft survival

Cited by 16 publications

References 43 publications

Targeting the Notch Pathway to Prevent Rejection

Targeting the Notch Pathway to Prevent Rejection

Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

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Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3⁺ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice