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: 5.68). 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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    • "Thus, identifying safe methodologies to induce donor-specific allograft survival is a top priority. One of the most attractive targets for such therapy is Treg, which have emerged as pivotal immunoregulators in the establishment of allograft tolerance [39]–[41]. While Treg improve graft survival in several experimental models, their low frequency under homeostatic conditions remains a roadblock to their therapeutic use. "
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    ABSTRACT: Adipose tissue-derived mesenchymal stem cells (ADSC) exhibit immunosuppressive capabilities both in vitro and in vivo. Their use for therapy in the transplant field is attractive as they could render the use of immunosuppressive drugs unnecessary. The aim of this study was to investigate the effect of ADSC therapy on prolonging skin allograft survival. Animals that were treated with a single injection of donor allogeneic ADSC one day after transplantation showed an increase in donor skin graft survival by approximately one week. This improvement was associated with preserved histological morphology, an expansion of CD4(+) regulatory T cells (Treg) in draining lymph nodes, as well as heightened IL-10 expression and down-regulated IL-17 expression. In vitro, ADSC inhibit naïve CD4(+) T cell proliferation and constrain Th-1 and Th-17 polarization. In summary, infusion of ADSC one day post-transplantation dramatically increases skin allograft survival by inhibiting the Th-17 pathogenic immune response and enhancing the protective Treg immune response. Finally, these data suggest that ADSC therapy will open new opportunities for promoting drug-free allograft survival in clinical transplantation.
    PLoS ONE 10/2013; 8(10):e76396. DOI:10.1371/journal.pone.0076396 · 3.23 Impact Factor
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    • "The alloimmune response is a complex interplay between pathogenic/inflammatory and regulatory/anti-inflammatory immune mechanisms; the supremacy of either process determines whether the ultimate fate of the allograft is rejection or tolerance, respectively [4]–[6]. Previous studies in renal transplant patients demonstrated that Tregs regulate the alloimmune response and contribute to alloantigen hyporesponsiveness [7], [8]. Various compounds, including Thymoglobulin®, alemtuzumab and sirolimus, are capable of inducing and expanding Tregs in vitro, both in animals and humans [9]–[13]. "
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    ABSTRACT: Despite significant nephrotoxicity, calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression in solid organ transplantation. We, along with others, have reported tolerogenic properties of anti-thymocyte globulin (ATG, Thymoglobulin®), evinced by its ability both to spare Tregs from depletion in vivo and, when administered at low, non-depleting doses, to expand Tregs ex vivo. Clinical trials investigating B7/CD28 blockade (LEA29Y, Belatacept) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations. Rabbit polyclonal anti-murine thymocyte globulin (mATG) was administered as induction and/or prolonged, low-dose therapy, in combination with CTLA4-Ig, in a stringent, fully MHC-mismatched murine skin transplant model to assess graft survival and mechanisms of action. Prolonged, low-dose mATG, combined with CTLA4-Ig, effectively promotes engraftment in a stringent transplant model. Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs, while CTLA4-Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment, and by inhibiting production of anti-rabbit antibodies in the maintenance phase, thereby promoting regulation of alloreactivity. These data provide the rationale for development of novel, CNI-free clinical protocols in human transplant recipients.
    PLoS ONE 01/2013; 8(1):e53797. DOI:10.1371/journal.pone.0053797 · 3.23 Impact Factor
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    • "The role of CD4+CD25+FoxP3+ Treg cells in transplantation is a subject of much current interest [51]. These cells comprise two forms, one generated in the thymus and naturally occurring and the other adaptive. "
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    ABSTRACT: Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance.
    Cancer Immunology and Immunotherapy 05/2010; 59(5):643-51. DOI:10.1007/s00262-009-0809-1 · 3.94 Impact Factor
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