CD4 + CD25 + Regulatory T Cells in Transplantation: Progress, Challenges and Prospects

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
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


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.
    Full-text · Article · Oct 2013 · PLoS ONE
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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.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "Canine T reg with a suppressive function were defined as CD4 + CD25 high Foxp3 high T cells. In the setting of allogeneic stem cell transplantation T reg are crucial for the control of alloreactivity, particularly for the prevention of graft versus host disease (GVHD) (Hoffmann et al., 2002;Kang et al., 2007).Ukena et al. (2011)demonstrated that in patients with acute GVHD T reg cell numbers were reduced compared to patients with no clinical signs. In contrast it is well-known that the percentage of T reg is frequently increased in cancer patients (Miller et al., 2006;Bonertz et al., 2009). "
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    ABSTRACT: Denileukin Diftitox (ONTAK(®), DAB(389) IL-2) is a recombinant DNA-derived fusion protein depleting cells that express high-affinity IL-2 receptor. Important cell targets are CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(reg)). Elimination of immunosuppressive T(reg) by Denileukin Diftitox may provide a way to modulate immune tolerance following stem cell transplantation. Here, we combined T(reg) depletion with a vaccination approach to induce donor-specific immune reactions. To investigate this approach we chose the mixed chimerism canine stem cell transplantation model which represents a high state of tolerance between two hematopoietic systems. The aim was therefore to induce a graft versus hematopoiesis effect thereby converting mixed to full donor chimerism. Dog leukocyte antigen identical siblings that had developed a stable mixed chimerism after non-myeloablative stem cell transplantation received a single dose of Denileukin Diftitox (18μg/kg, i.v.) followed by several cell-lysate vaccinations. Host peripheral blood mononuclear cell lysates combined with CpG-ODN, and Montanide(®) ISA 51 were locally applied. In vitro studies demonstrated that canine T(reg) are a target of Denileukin Diftitox. The suppression of T-cell proliferation by T(reg) was abolished by addition of Denileukin Diftitox (10nM). An increase of proliferation of median 300% (range: 200%-425%) was observed. No change in donor chimerism was observed after administration of Denileukin Diftitox and vaccination. This study highlights that application of Denileukin Diftitox resulted in a depletion of T(reg) followed by an increase of immune response in vitro. This effect could not be confirmed in vivo even if the immune system was stimulated by vaccinations.
    Full-text · Article · Nov 2011 · Veterinary Immunology and Immunopathology
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