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Y Ye,
S Yan, G Jiang,
L Zhou,
H Xie,
X Xie,
X Yu,
Y Ding,
J Tian,
Y Dai,
S Zheng
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ABSTRACT: Liver allografts are spontaneously accepted across MHC barriers in mice. The mechanisms underlying this phenomenon remain poorly understood. Galectin-1, an endogenous lectin expressed in lymphoid organs, plays a vital role in maintaining central and peripheral tolerance. This study was to investigate the role of galectin-1 in spontaneous tolerance of liver allografts in mice, and to evaluate the therapeutic effects of galectin-1 on liver allograft rejection induced by donor Flt3L pretreatment. Blockade of the galectin-1 pathway via neutralizing antigalectin-1 mAb did not affect survival of the liver allografts from B6 donors into C3H recipients. Administration of rGal-1 significantly prolonged survival of liver allografts from Flt3L-pretreated donors and ameliorated Flt3L-triggered liver allograft rejection. This effect was associated with increased apoptosis of T cells in both allografts and spleens, decreased frequencies of Th1 and Th17 cells, decreased expression of Th1-associated cytokines (IL-12, IL-2 and IFN-γ), Th17-associated cytokines (IL-23 and IL-17) and granzyme B, in parallel with selectively increased IL-10 expression in liver allografts. In vitro, galectin-1 inhibited Flt3L-differentiated DC-mediated proliferation of allo-CD4(+) T cells and production of IFN-γ and IL-17. These data provide new evidence of the potential regulatory effects of galectin-1 in alloimmune responses in a murine model of liver transplantation.
American Journal of Transplantation 01/2013; · 6.39 Impact Factor
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ABSTRACT: Th17, a newly identified CD4+ T-cell subset, has been implicated in transplant rejection. Differentiation of Th17 cells is associated with transforming growth factor-β (TGF-β) and interleukin-6 (IL-6), which are the main products of Küpffer cells.
To determine whether Küpffer cells promote acute liver allograft rejection by inducing Th17 cell differentiation.
A rat model of allogeneic liver transplantation using Dark Agouti (DA) to Brown Norway (BN) rats was established with or without gadolinium chloride (GdCl(3)) pretreatment. Isogeneic liver transplantation (BN to BN) was performed as a control. Concentrations of cytokines secreted by Küpffer cells or Th17-related cytokines detected in the liver and peripheral blood were analyzed using immunohistochemistry assays, flow cytometry, and enzyme-linked immunosorbent assays. Survival differences were compared between treatment groups. In vitro, Küpffer cells from liver grafts were isolated and co-cultured with naïve CD4 T cells.
Both Küpffer cells and Th17 cells infiltrated liver allografts, accompanied by an increase in concentrations of IL-6 and TGF-β. Pretreatment with GdCl(3) attenuated intragraft infiltration of Küpffer cells and Th17 cells, and decreased IL-6 and TGF-β concentrations. Liver function improved after pretreatment, and mean (SD) survival time was prolonged, compared with the control group (16.33 [0.96] days vs 11.50 [0.99] days, respectively; P < .01). In vitro, Küpffer cells from livers with allografts secreted significantly higher concentrations of IL-6 and TGF-β and induced Th17 differentiation more effectively compared with livers with isografts (30.8% vs 8.1%, respectively).
Küpffer cells have the potential to induce Th17 cells by secreting IL-6 and TGF-β, and as a result, promote acute liver allograft rejection.
Transplantation Proceedings 11/2010; 42(9):3784-92. · 1.00 Impact Factor
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ABSTRACT: Chronicity in hepatitis B virus (HBV) infection is maintained by increased type 2 T-helper cell response, possibly because of increased interleukin-10 (IL-10) productions. B7-H1 can negatively regulate T-cell responses via its receptor, programmed death 1. Ligation of B7-H1 to T-cells can result in the preferential secretion of IL-10. In this study, we investigated whether there was an upregulated expression of B7-H1 in peripheral blood mononuclear cells in patients chronically infected by HBV and further explored the correlation between B7-H1 expression and serum interleukin 2, interferon-gamma, IL-10, HBeAg, alanine aminotransferase (ALT) levels and viral load. Fifty-five patients with chronic HBV infection and 20 healthy controls (HCs) were enrolled in the present study. The results showed that in patients with chronic hepatitis B CD14+ monocytes but not CD3+ and CD19+ cells had a significantly increased expression of B7-H1 compared with HCs, which positively correlates with serum IL-10 levels and the presence of HBeAg and negatively correlates with serum ALT levels. In conclusion, chronic HBV patients harbour an increased B7-H1 expression in CD14+ monocytes compared with controls, which may be responsible for the increased serum IL-10 levels. This might be an important way by which HBV evades an adequate immune response, leading to viral persistence and disease chronicity.
Journal of Viral Hepatitis 12/2006; 13(11):725-33. · 4.09 Impact Factor
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ABSTRACT: In addition to its effects on lymphocytes, mycophenolic acid (MPA) may inhibit the allostimulatory capacity of dendritic cells (DC) via unknown mechanisms. B7-H1 and B7-DC surface markers on DC negatively regulate T-cell responses via the receptor PD-1. In this study, we sought to investigate whether B7-H1 and B7-DC are responsible for the inhibitory functions of MPA on DC. Mouse bone marrow-derived DC were cultured with recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 in the presence or absence of MPA (0.01 micromol and 0.1 micromol). The DC phenotype was assessed by flow cytometry, their immunostimulatory capacity measured by mixed lymphocyte reaction (MLR), and cytokine production by ELISA. The results showed that MPA not only inhibited the expression of major histocompatibility complex (MHC) class II and costimulatory molecules CD80 and CD86 but upregulated B7-DC expression on mature DC induced by LPS. These findings were associated with a reduced allostimulatory ability and an altered cytokine secretion pattern of DC. Thus, we suggest that MPA upregulates B7-DC expression during DC maturation induced by LPS in vitro, an effect that may be responsible for MPA-mediated inhibitory effects on the allostimulatory capacity of DC.
Transplantation Proceedings 07/2006; 38(5):1622-4. · 1.00 Impact Factor
