Article
Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease.
Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA.
American Journal of Transplantation (impact factor:
6.39).
06/2011;
11(6):1148-57.
DOI:10.1111/j.1600-6143.2011.03558.x
pp.1148-57
Source: PubMed
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Citations (0)
- Cited In (3)
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Article: Novel regulatory therapies for prevention of Graft-versus-host disease.
[show abstract] [hide abstract]
ABSTRACT: Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease.BMC Medicine 05/2012; 10:48. · 6.03 Impact Factor -
Article: Common gamma chain cytokines promote rapid in vitro expansion of allo-specific human CD8+ suppressor T cells.
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ABSTRACT: Human CD8(+) regulatory T cells, particularly the CD8(+)CD28(-) T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8(+) T cells which results in significant expansions of donor-specific CD8(+)CD28(-) T suppressor cells in vitro. The expanded CD8(+)CD28(-) T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4(+) T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8(+)CD28(-) T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation.PLoS ONE 01/2011; 6(12):e28948. · 4.09 Impact Factor -
Article: Are we ready for the use of foxp3(+) regulatory T cells for immunodiagnosis and immunotherapy in kidney transplantation?
[show abstract] [hide abstract]
ABSTRACT: The existence of T-cell subsets naturally committed to perform immunoregulation has led to enthusiastic efforts to investigate their role in the immunopathogenesis of transplantation. Being able to modulate alloresponses, regulatory T cells could be used as an immunodiagnostic tool in clinical kidney transplantation. Thus, the measurement of Foxp3 transcripts, the presence of regulatory T cells in kidney biopsies, and the phenotypic characterisation of the T-cell infiltrate could aid in the diagnosis of rejection and the immune monitoring and prediction of outcomes in kidney transplantation. Interestingly, the adoptive transfer of regulatory T cells in animal models has been proven to downmodulate powerful alloresponses, igniting translational research on their potential use as an immunomodulatory therapy. For busy transplant clinicians, the vast amount of information in the literature on regulatory T cells can be overwhelming. This paper aims to highlight the most applicable research findings on the use of regulatory T cells in the immune diagnosis and potential immunomodulatory therapy of kidney transplant patients. However, can we yet rely on differential regulatory T-cell profiles for the identification of rejection or to tailor patient's immunosuppression? Are we ready to administer regulatory T cells as inductive or adjunctive therapy for kidney transplantation?Journal of Transplantation 01/2012; 2012:397952.
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Keywords
Adoptive transfer
auto-
cells secrete IL-2
graft-versus-host disease
human T cells
induced Treg
inducing Treg function
Ionomycin stimulation
iTreg cellular therapy
levels higher
memory CD4+ T cells
murine CD4+25- T cells
nTreg
potent suppressor function
published methods
Rapa/TGFß induces suppressive function
Rapa/TGFß iTregs
single apheresis unit
TGFß induces Foxp3 expression
thymus-derived natural regulatory T cells
