CD4+CD25+ regulatory T cells in transplantation: Progress, challenges and prospects

Transplantation Division, Department of Surgery, University of California, San Francisco, CA, USA.
American Journal of Transplantation (Impact Factor: 6.19). 07/2007; 7(6):1457-63. DOI: 10.1111/j.1600-6143.2007.01829.x
Source: PubMed

ABSTRACT The involvement of CD4(+)CD25(+) regulatory T cells (Treg) in general immune homeostasis and protection from autoimmune syndromes is now well established. Similarly, there has been increasing evidence for Treg involvement in allograft rejection and current immunotherapies. However, despite significant advances in understanding the development, function, and therapeutic efficacy of Treg in certain well-defined rodent models, the relevance of Treg to clinical transplantation remains unclear. In this review, we summarize our current understanding of the role of Treg in immunity and organ transplantation in experimental and clinical settings. In addition, we review advances in using Treg as a form of immune therapy. The goal is to highlight the complexities and opportunities in the field and to provide evidence to support the use of antigen-specific Tregs in the context of transplantation to facilitate a robust and selective state of immune tolerance.

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Available from: Qizhi Tang, Jan 13, 2015
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    • "Several studies have shown that Treg play an important role in maintaining the peripheral immune tolerance [15] [16] [17]. Furthermore, there is increasing evidence that CD4 + CD25 + Treg contribute to the immunological protection against GVHD after bone marrow transplantation (BMT), resulting in tolerization to host alloantigens [18] [19] [20] [21] [22]. It has been demonstrated that the pretreatment of donor mice with alloantigen and anti-CD4 antibodies led to the generation of alloantigen-specific CD4 + CD25 + T cells that could prevent the rejection of skin allografts. "
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    ABSTRACT: Acute graft-versus-host disease following liver transplantation (LTx-aGVHD) poses a major diagnostic and therapeutic challenge, and the mortality rate is as high as 85%. Even the liver contains large numbers of lymphoid cells in the parenchyma and surgical damage of liver transplantation would induce an immunosuppressive, the incidence of LTx-aGVHD is just approximately 1-2%. CD4(+)CD25(+)regulatory T (Treg) cells have recently been shown to suppress proliferative responses of CD4(+)CD25(-)T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD after bone marrow transplantation. To investigate the role of Treg in LTx-aGVHD, we compared the proportional frequency of Treg in syngeneic liver transplantation recipients (sLT group), semiallogeneic liver transplantation recipients (Semi-LT group), LTx-aGVHD induced recipients (LTx-aGVHD group) and healthy controls. Here we show that replacement of (LewisXBN)F1 liver by Lewis liver alone in Semi-LT group was not sufficient to induce aGVHD, and all recipients grew in a normal pattern as the syngeneic LT from Lewis to Lewis rat. However, when 4 x 10(8) of donor splenocytes were transferred simultaneously with LT, the morbidity of lethal aGVHD were 100%. A relative stable percentage of Treg, defined as CD4, CD25 and Foxp3, was detected in peripheral blood mononuclear cells (PBMCs) of sLT group compared with healthy controls. In early time after transplantation, no significantly change of Treg population was observed in these recipients after semiallogeneic liver transplantation in comparison with healthy controls (P>0.05). However, Treg levels showed a relative increase 4 days after transplantation. Especially on 12th and 16th day after transplantation, there was significantly increased proportion of Treg cells compared with healthy controls (P<0.05). The present of Treg decreased progressively in LTx-aGVHD group, which was significantly lower than group 1 and group 2 on the 12th and 16th day after liver transplantation (p<0.05). In conclusion, recipients in semi-LT group harbor an increased percentage of Treg in peripheral blood compared with controls. Treg have an immunoregulatory effect on graft versus host reaction after liver transplantation. Additional donor splenocyte transplanted with the liver provoke the development of aGVHD after liver transplantation, and reversed the change of Treg in PBMCs as in Semi-LT group, which destroy the balance between Treg and conventional effector T cells which determine the outcome of aGVHD after liver transplantation.
    Transplant Immunology 12/2008; 20(4):232-7. DOI:10.1016/j.trim.2008.11.003 · 1.83 Impact Factor
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    • "The establishment of tolerance is prevented by events which are inevitably associated with clinical transplantation, such as I/R injury and brain death of the organ donor. It was for example demonstrated that I/R injury prevents tolerance induction in experimental kidney transplantation (Coulson et al., 2005), and consequently, it was recently highlighted that minimization of I/R injury associated with transplantation will be a key element in future tolerance induction strategies (Kang et al., 2007). "
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    ABSTRACT: Complement is an essential part of the innate immune system and plays a crucial role in organ and islet transplantation. Its activation, triggered for example by ischemia/reperfusion (I/R), significantly influences graft survival, and blocking of complement by inhibitors has been shown to attenuate I/R injury. Another player of innate immunity are the dendritic cells (DC), which form an important link between innate and adaptive immunity. DC are relevant in the induction of an immune response as well as in the maintenance of tolerance. Modulation or inhibition of both components, complement and DC, may be crucial to improve the clinical outcome of solid organ as well as islet transplantation. Low molecular weight dextran sulfate (DXS), a well-known complement inhibitor, has been shown to prevent complement-mediated damage of the donor graft endothelium and is thus acting as an endothelial protectant. In this review we will discuss the evidence for this cytoprotective effect of DXS and also highlight recent data which show that DXS inhibits the maturation of human DC. Taken together the available data suggest that DXS may be a useful reagent to prevent the activation of innate immunity, both in solid organ and islet transplantation.
    Molecular Immunology 09/2008; 45(16):4084-94. DOI:10.1016/j.molimm.2008.07.024 · 3.00 Impact Factor
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