IDO-Competent-DCs Induced by IFN-γ Attenuate Acute Rejection in rat Liver Transplantation

Sun, Xiaojiang; Zi-tong, Gong; Wang, Zhaowen; Li, Tao; Zhang, Jinyan; Sun, Hongcheng; Liu, Shuang; Huang, Li; Huang, Chen; Peng, Zhihai

doi:10.1007/s10875-012-9681-4

Cited by 28 publications

(37 citation statements)

References 25 publications

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“…By contrast, tumours at their late stage generate much more immunosuppressive factors, which impede the production of IFN-γ by T or NK cells. However, low levels of IFN-γ can stimulate immune cells such as macrophages and DCs to upregulate the expression of IDO1 and PD-L1 to mediate immunosuppression6162.…”

Section: Discussionmentioning

confidence: 99%

Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

et al. 2017

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Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-γ induces tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-γ signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-γ results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-γ-induced dormancy but also results in enhanced repression of tumour growth by IFN-γ-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-γ, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-γ and IDO/AhR inhibitors.

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Section: Discussionmentioning

confidence: 99%

Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

et al. 2017

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“…However, the severe side effects of the current immunosuppressive drugs limits their application for the treatment of graft rejection. Recently, cell-mediated therapies have become more interesting with regard to the process of allograft rejection as well as their effectiveness in the induction and maintenance of immune tolerance [6,7]. …”

Section: Discussionmentioning

confidence: 99%

“…Recently, one promising way to overcome allograft rejection is the induction and maintenance of immune tolerance by cell-based therapies, such as dendritic cells (DCs) and T regulatory cells (Tregs) [6,7]. It is widely accepted that DCs act as the professional antigen-presenting cells to initiate immunity response by activation of native T cell response [8].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

Dong

Wang

Liu

et al. 2015

Int Arch Allergy Immunol

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Background: Obliterative bronchiolitis (OB) ranks as the major obstacle for long-term survival of lung transplantation patients. Rapamycin (Rapa) has recently been confirmed as an immunosuppressant for antirejection due to its suppressive role in T cell activation. Here, we explore the effect of Rapa combined with immature dendritic cells (imDCs) on OB in trachea allograft rats. Methods: The effect of bone marrow-derived imDCs or Rapa-imDCs on lymphocyte cells and CD4⁺ T cells were evaluated by methyl thiazolyl tetrazolium and flow cytometry. Tracheal transplantation was performed from Lewis rats to Wistar recipients. Recipient rats received Rapa+imDCs for 10 consecutive days after implantation. Allograft rejection was assessed by micro-CT image, hematoxylin/eosinHE staining and flow cytometry. The underlying mechanism was also investigated. Results: Rapa-imDCs inhibited lymphocyte and CD4⁺ T cell growth. Furthermore, Rapa-imDC treatment induced T cell hyporesponsiveness by attenuating T cell differentiation into IFN-γ-producing T cells (Th1), but increased CD4⁺CD25⁺Foxp3⁺ T cell (Treg) contents. Importantly, Rapa-imDC administration ameliorated airway obliteration symptoms and CD4⁺ and CD8⁺ T cell infiltration. Furthermore, the proinflammatory factor levels of IL-6, TNF-α, IFN-γ and IL-17 were decreased, concomitant with the upregulation of immunosuppressive cytokines IL-10 and TGF-β1. Further analysis confirmed that Rapa-imDC treatment attenuated the amounts of infiltrated IL-17⁺CD4⁺ T cells (Th17 cells) and Th1 cells, but increased Treg contents in the spleens of recipients. Conclusions: This research may corroborate a protective role of Rapa-imDCs in OB by regulating the balance between effector T cells and Tregs, suggesting a potential applicable strategy to treat OB after lung transplantation.

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“…For example, exogenous IFN-γ prevented GVHD in a murine bone marrow transplantation model through post transplant inhibition of T cell proliferation (19, 20). IFN-γ stimulation of dendritic cells resulted in an upregulation of IDO production which mediated allograft protection in a rat liver transplantation model (21). Most relevant to our findings, a recent study by Garcia et al in a tolerant heart transplant model demonstrated that a monocytic suppressive cell population bearing the phenotype CD11b + Gr1 + CD115 + mediated their suppression via signaling responses to IFN-γ, as Ifngr -/- Gr1 + monocytes could not provide graft protection as wild-type Gr1 + cells did (10).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in transplantation have demonstrated that IFN-γ can be protective via a variety of mechanisms including mediating the suppressive function of MDSCs (10, 19-21). The potential sources of such IFN-γ are thought to be macrophages, T, NK and/or NKT cells, and can also result from phagocytosis of apoptotic cells in the spleen (22).…”

Section: Introductionmentioning

confidence: 99%

Preemptive Donor Apoptotic Cell Infusions Induce IFN-γ–Producing Myeloid-Derived Suppressor Cells for Cardiac Allograft Protection

Bryant

Lerret

Wang

et al. 2014

The Journal of Immunology

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We have previously shown that preemptive infusion of apoptotic donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) induces long-term allograft survival in full MHC-mismatched models of allogeneic islet and cardiac transplantation. The role of myeloid derived suppressor cells (MDSCs) in the graft protection provided by ECDI-SPs is unclear. In this study, we demonstrate that infusions of ECDI-SPs increase two populations of CD11b+ cells in the spleen that phenotypically resemble monocytic-like (CD11b+Ly6CHI) and granulocytic-like (CD11b+Gr1HI) MDSCs. Both populations suppress T cell proliferation in vitro, and traffic to the cardiac allografts in vivo to mediate their protection via inhibition of local CD8 T cell accumulation and potentially also via induction and homing of regulatory T cells. Importantly, repeated treatments with ECDI-SPs induce the CD11b+Gr1HI cells to produce a high level of IFN-γ and to exhibit an enhanced responsiveness to IFN-γ by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-γ completely abolishes the suppressive capacity of this population. We conclude that donor ECDI-SPs induce the expansion of two populations of MDSCs important for allograft protection mediated in part by intrinsic IFN-γ dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction.

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IDO-Competent-DCs Induced by IFN-γ Attenuate Acute Rejection in rat Liver Transplantation

Abstract: Our results suggested that IDO gene expression correlates with the severity of acute rejection and that IFN-γ-induced IDO-positive DCs may attenuate acute rejection and catalyze local tryptophan metabolism via IDO enzyme expression, leading to immune tolerance after liver transplantation.

Cited by 28 publications

References 25 publications

Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

Preemptive Donor Apoptotic Cell Infusions Induce IFN-γ–Producing Myeloid-Derived Suppressor Cells for Cardiac Allograft Protection

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