Prolonged survival effects induced by immature dendritic cells and regulatory T cells in a rat liver transplantation model
Introduction
Liver transplantation is the preferred method of treatment for end-stage liver diseases. Although nonspecific immunosuppressive therapy can greatly prolong graft survival, it can also cause serious complications, including the risk of severe infection and malignancies (Dandel et al., 2010). Finding methods by which to induce and promote donor-specific immune tolerance is crucial for effective clinical transplantation.
Dendritic cells (DCs) are uniquely equipped potent professional antigen-presenting cells that are regarded as pivotal inducers of immunity. They play important roles in directing the immune response towards tolerance or immunity. DCs with tolerogenic properties have been studied extensively in small animal models and human in vitro systems (Suwandi et al., 2015, Saei and Hadjati, 2013, Thome et al., 2012, Morelli and Thomson, 2007). Maturation of DCs is prevented through the modulation of cell surface molecules. Immature DCs express high endocytic and phagocytic capacity, low levels of MHC class II and co-stimulatory molecules (CD40, CD80, and CD86), and low T cell stimulatory ability (Ezzelarab and Thomson, 2011). By contrast, mature DCs that express high levels of MHC class II, CD80, and CD86, have strong T cell stimulatory capacity (Ezzelarab and Thomson, 2011). These differences highlight the fact that the activation and/or maturation status of DCs is critical in determining whether tolerance or immunity is induced.
Regulatory T (Treg) cells are thymic-derived CD4 + CD25 + Foxp3+ T cells that comprise 1–10% thymic and peripheral CD4+ T cells in humans and mice (Sakaguchi, 2000), CD4 + CD25 + Foxp3+ Treg cells are critical in maintaining immune tolerance. Treg cells can also be induced in vivo and play important roles in tolerance to cells and solid organ transplants (Biswas et al., 2015). Furthermore, Treg cells can affect DC development, and modulate DC maturation and function by inducing an atolerogenic phenotype in DCs, including inducing IL-10, as well as immunosuppressive molecules of the B7-H family of DCs. The release of TGF-β1 and IL-10 by Treg cells can keep DCs in an immature state (Kornete and Piccirillo, 2012). Several studies have shown that DCs might be mediated through cell surface molecules or cytokines by down-regulating CD80/CD86 and MHC II expression (Awasthi et al., 2007, Mahnke et al., 2007a, Mahnke et al., 2007b, Li et al., 2008, Houot et al., 2006). Thereby, the interaction between DCs and Treg cells can amplify immunosuppression, and tolerance mechanisms in vivo are supported by the crosstalk between DCs and Treg cells (Mahnke et al., 2007a).
Both Treg cells and DCs are crucial for inducing immune tolerance. However, quantitative studies investigating the suppressive function of infusion of Treg cells and imDCs following solid organ transplantation have not provided conclusive results. The aim of this study was to use a rat liver transplantation model to examine the immune tolerance effects of Treg-imDCs and to compare this with the effects of infusion of imDCs and Treg cells individually. Here, we demonstrate that the expression of IL-10 and TGF-β1 in the Treg-imDCs group was significantly up-regulated, and the expression of IL-12 was significantly down-regulated, especially in the Treg-imDCs group. Moreover, our data suggest that infusion of Treg cells and/or imDCs induces alloantigen tolerance and prolongs liver allograft survival. The infusion of Treg-imDCs together was more effective than imDCs or Treg cells individually.
Section snippets
Animals
Male DA and Lewis rats (8–10 week old and weighing 230 ± 20 g) were purchased from the Laboratory Animal Center of the 2nd Affiliated Hospital of Harbin Medical University (Heilongjiang, China) and Shanghai SLAC Laboratory Animal Co. Ltd. (Shanghai, China). A total of 92 pairs of DA/Lewis rats were divided into four groups: control group (n = 23), imDCs group (n = 23), Treg cells group (n = 23), Treg-imDCs group (n = 23). Five rats in each group were euthanized on days 3, 7, and 10 post-transplantation,
Liver function evaluation
Both TBIL and ALT levels increased significantly 10 days after transplantation in the control group when compared with those measured on days 3 and 7 (P < 0.001). Both TBIL and ALT levels remained stable or even decreased slightly on days 3, 7, and 10 following transplantation in the imDCs, Treg cells and Treg-imDCs groups when compared with those measured in the control group. Both the TBIL and ALT levels in the Treg-imDCs and imDCs groups were significantly lower than those of the control and
Discussions
In this study, we established a heterotopic liver transplantation model to study the immune tolerance effects of infusion of Treg cells and/or imDCs. We demonstrate that infusion of Treg cells and/or imDCs induces alloantigen tolerance and prolongs liver allograft survival. The infusion of Treg-imDCs in combination was more effective than imDCs or Treg cells individually. Moreover, our data showed that the expression of IL-10 and TGF-β1 were significantly up-regulated, and the expression of
Grants
Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation): 2015J01308; the Science and Technology Project of Fuzhou: 2013‐S‐125‐9; Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation): 2016J01435; Training Young Talents in Health System Foundation of Fujian Province: 2014-ZQN-JC-5; Training Young Talents in Health System Foundation of Fujian Province: 2014-ZQN-JC-25.
Disclosures
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions
L.C., L.Z., W.H., L.L., and L.G. performed experiments; W.H. drafted manuscript; L.C. edited and revised manuscript; W.H. and L.C. conception and design of research; L.C. analyzed data; W.H. interpreted results of experiments; L.C. prepared figures. W.H., L.C., L.Z., L.L., and L.G. approved final version of manuscript.
References (36)
- et al.
Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4 + CD25 + FoxP3+ Treg
Blood
(2015) - et al.
IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction–a comparative study of human clinical-applicable DC
Clin. Immunol.
(2012) - et al.
Impact of different long-term maintenance immunosuppressive therapy strategies on patients' outcome after heart transplantation
Transpl. Immunol.
(2010) - et al.
Tolerogenic dendritic cells and their role in transplantation
Semin. Immunol.
(2011) - et al.
Dendritic cells matured in the presence of the lycopodium alkaloid annotine direct T cell responses toward a Th2/Treg phenotype
Phytomedicine
(2015) - et al.
A technique of recipient portal venoplasty and cuff insertion for portal revascularization in orthotopic rat liver transplantation
J. Surg. Res.
(2012) - et al.
A technique of recipient portal venoplasty and cuff insertion for portal revascularization in orthotopic rat liver transplantation
J. Surg. Res.
(2013) - et al.
Tolerogenic dendritic cells and regulatory T cells: a two-way relationship
J. Dermatol. Sci.
(2007) Regulatory T cells: key controllers of immunologic self-tolerance
Cell
(2000)- et al.
Expression of TRAIL, DR4, and DR5 in kidney and serum from patients receiving renal transplantation
Transplant. Proc.
(2004)