Article

Rhesus Macaque Natural CD4 Regulatory T Cells Exhibit Decreased Proliferation But Enhanced Suppression After Pulsing with Sirolimus

The Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
American Journal of Transplantation (Impact Factor: 6.19). 02/2012; 12(6):1441-57. DOI: 10.1111/j.1600-6143.2011.03963.x
Source: PubMed

ABSTRACT Although regulatory T cells (Tregs) suppress allo-immunity, difficulties in their large-scale production and in maintaining their suppressive function after expansion have thus far limited their clinical applicability. Here we have used our nonhuman primate model to demonstrate that significant ex vivo Treg expansion with potent suppressive capacity can be achieved and that Treg suppressive capacity can be further enhanced by their exposure to a short pulse of sirolimus. Both unpulsed and sirolimus-pulsed Tregs (SPTs) are capable of inhibiting proliferation of multiple T cell subpopulations, including CD4(+) and CD8(+) T cells, as well as antigen-experienced CD28(+) CD95(+) memory and CD28(-) CD95(+) effector subpopulations. We further show that Tregs can be combined in vitro with CTLA4-Ig (belatacept) to lead to enhanced inhibition of allo-proliferation. SPTs undergo less proliferation in a mixed lymphocyte reaction (MLR) when compared with unpulsed Tregs, suggesting that Treg-mediated suppression may be inversely related to their proliferative capacity. SPTs also display increased expression of CD25 and CTLA4, implicating signaling through these molecules in their enhanced function. Our results suggest that the creation of SPTs may provide a novel avenue to enhance Treg-based suppression of allo-immunity, in a manner amenable to large-scale ex vivo expansion and combinatorial therapy with novel, costimulation blockade-based immunosuppression strategies.

1 Follower
 · 
97 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Foxp3(+) Tregs are central regulators of immune tolerance. As dysregulated Treg responses contribute to disease pathogenesis, novel approaches to target the immunomodulatory functions of Tregs are currently under investigation. mTORC1 and mTORC2 are therapeutic targets of interest. Recent studies revealed that mTOR signaling impacts conventional T-cell homeostasis, activation and differentiation. Moreover, mTOR controls the differentiation and functions of Tregs, suggesting that its activity could be targeted to modulate Treg responses. Here, we summarize how Tregs suppress immune responses, their roles in disease development and methods used to alter their functions therapeutically. We also discuss the diverse effects exerted by mTOR inhibition on the development, homeostasis, and functions of conventional T cells and Tregs. We conclude with a discussion of how modulation of mTOR activity in Tregs may be therapeutically beneficial or detrimental in different disease settings.
    Immunotherapy 12/2014; 6(12):1295-311. DOI:10.2217/imt.14.84 · 2.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The immunosuppressive drug rapamycin (RAPA) has been used clinically to prevent graft rejection since 1999 because of its suppressive effects on T cell activation and proliferation. Recently, many studies have suggested that RAPA also has the potential to promote tolerance by driving the expansion of naturally occurring regulatory T (Treg) cells, and facilitating the de novo generation of induced Treg cells, which has aroused great interest in its potential ability to promote tolerance after transplantation. However, its effect on Treg cells remains controversial both in vitro and in vivo. Here, we systematically analyzed data on the effects of RAPA from both clinical and basic studies: (1) To compare its clinical effect with calcineurin inhibitors in transplant recipients, and discuss whether its effects on graft survival correlates with its effects on Treg cells. (2) To analyze the effects of RAPA on Treg cells from animal and in vitro studies, and to investigate whether the effects of RAPA on Treg cells was dependent on dosage and timing. (3) To discuss the mechanisms involved and how they might be applied to induce transplant tolerance.
    Immunology Letters 08/2014; 162(1). DOI:10.1016/j.imlet.2014.07.006 · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Experimental studies have shown that rabbit antithymocyte polyclonal globulin (ATG) can expand human CD4+CD25++Foxp3+ cells (Tregs).Methods We investigated the major biological effects of a self-manufactured rabbit polyclonal anti-rat thymoglobulin (rATG) in vitro, as well as its effects on different peripheral T cell subsets. Moreover, we evaluated the allogeneic suppressive capacity of rATG-induced Tregs in an experimental rat renal transplant model. ResultsOur results show that rATG has the capacity to induce apoptosis in CD3+ lymphocytes as a primary mechanism of T-cell depletion. Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T-cell subsets, directly proportional to the rATG dose used, but not of the effector memory T cells, which required significantly higher rATG doses. After rATG administration, we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats, leading to an increase in the Treg/Teffector ratio. Importantly, rATG-induced Tregs displayed a strong donor-specific suppressive capacity when assessed in an antigen-specific allogeneic co-culture. All of these results were associated with better renal graft function in rats that received rATG.Conclusions Our study shows that rATG has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post-transplant homeostatic proliferation.This article is protected by copyright. All rights reserved.
    Transplant International 09/2014; 28(1). DOI:10.1111/tri.12448 · 3.16 Impact Factor

Full-text (2 Sources)

Download
27 Downloads
Available from
Jun 16, 2014

Similar Publications