Regulation of Rat and Human T-Cell Immune Response by Pharmacologically Modified Dendritic Cells

Fazekasova, Henrieta; Golshayan, Déla; Read, Joseph; Tsallios, A; Tsang, Julia Y. S.; Dorling, Anthony; George, Andrew J.T.; Lechler, Robert I.; Lombardi, Giovanna; Mirenda, Vincenzo

doi:10.1097/tp.0b013e3181a5504c

Cited by 15 publications

(9 citation statements)

References 40 publications

(54 reference statements)

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“…In contrast, in the presence of TGF-β1, a distinct population of activated T cells also concurrently expressed high levels of Foxp3, albeit only a small percentage (2.7%). Recent reports suggest that DCs alternatively differentiated in pharmacological agents are more conducive for stimulating and expanding nTregs (17,24). We next asked whether preconditioning donor DCs with rapamycin could enhance their ability to induce Foxp3 upon coculture with naïve T cells.…”

Section: Resultsmentioning

confidence: 99%

Rapamycin-Conditioned Donor Dendritic Cells Differentiate CD4+CD25+Foxp3+ T Cells In Vitro with TGF-β1 for Islet Transplantation

Pothoven

Kheradmand

Yang

et al. 2010

American Journal of Transplantation

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Dendritic cells (DCs) conditioned with the mammalian target of rapamycin (mTOR) inhibitor rapamycin have been previously shown to expand naturally existing regulatory T cells (nTregs). This work addresses whether rapamycin-conditioned donor DCs could effectively induce CD4+CD25+Foxp3+ Tregs (iTregs) in cell cultures with alloantigen specificities, and whether such in vitro-differentiated CD4+CD25+Foxp3+ iTregs could effectively control acute rejection in allogeneic islet transplantation. We found that donor BALB/c bone marrow-derived DCs (BMDCs) pharmacologically modified by the mTOR inhibitor rapamycin had significantly enhanced ability to induce CD4+CD25+Foxp3+ iTregs of recipient origin (C57BL/6 (B6)) in vitro under Treg driving conditions compared to unmodified BMDCs. These in vitro-induced CD4+CD25+Foxp3+ iTregs exerted donor-specific suppression in vitro, and prolonged allogeneic islet graft survival in vivo in RAG−/− hosts upon coadoptive transfer with T-effector cells. The CD4+CD25+Foxp3+ iTregs expanded and preferentially maintained Foxp3 expression in the graft draining lymph nodes. Finally, the CD4+CD25+Foxp3+ iTregs were further able to induce endogenous naïve T cells to convert to CD4+CD25+Foxp3+ T cells. We conclude that rapamycin-conditioned donor BMDCs can be exploited for efficient in vitro differentiation of donor antigen-specific CD4+CD25+Foxp3+ iTregs. Such in vitro-generated donor-specific CD4+CD25+Foxp3+ iTregs are able to effectively control allogeneic islet graft rejection.

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Section: Resultsmentioning

confidence: 99%

Rapamycin-Conditioned Donor Dendritic Cells Differentiate CD4+CD25+Foxp3+ T Cells In Vitro with TGF-β1 for Islet Transplantation

Pothoven

Kheradmand

Yang

et al. 2010

American Journal of Transplantation

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“…“Mature” DC express high levels of MHC and co-stimulatory molecules, migrate to secondary lymphoid tissue, and initiate effector T cell responses. By contrast, “immature” or steady-state DC that lack adequate T cell stimulatory capacity and suppress T cell responses via anergy, deletion, or regulatory T cell (Treg) enrichment [9, 21, 22]. Use of immature or “tolerogenic” donor- or recipient-derived DC to down-regulate T cell responses is a potential therapeutic option to inhibit allograft rejection (reviewed in [9]).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8+ T cells in vitro and in vivo

Fischer

Turnquist

Wang

et al. 2011

Transplant Immunology

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Dendritic cells (DC) are “professional” bone marrow-derived antigen (Ag)-presenting cells of interest both as therapeutic targets and potential cellular vaccines due to their ability to regulate innate and adaptive immunity. Harnessing the inherent tolerogenicity of DC is a promising and incompletely explored approach to the prevention of allograft rejection. Previously, we and others have reported the ability of pharmacologically-modified DC that resist maturation to inhibit CD4+ T cell responses and prolong allograft survival. Here we evaluated the ability of murine myeloid DC conditioned with the immunosuppressive pro-drug rapamycin (RAPA) to acquire and directly present alloAg to syngeneic CD8+ T cells. RAPA-conditioned DC (RAPA-DC) pulsed with allogeneic splenocyte lysate acquired and expressed donor MHC class I and enhanced the apoptotic death of directly-reactive donor Ag-specific CD8+ T cells in vitro. Moreover, following their adoptive transfer, they reduced the survival of these T cells in vivo. The ability of RAPA-DC to inhibit the survival of alloAg-specific CD8+ T cells provides a potential mechanism by which host-derived DC may act as negative regulators of T cell alloreactivity and support donor-specific unresponsiveness. Adoptive cell therapy with alloAg-pulsed RAPA-DC may offer an effective approach to suppression of alloimmunity, with reduced dependence on systemic immunosuppression.

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“…Studies have shown [20,21] that dexamethasone-treated DC cells induced the production of regulatory T cells, inhibited the responses of effector T cells, and induced immune tolerance. By using RNA interference to specifically silence the expressions of CD40, CD80, and CD86 in DCs, effector T cell-elicited immune response was effectively suppressed and the development of autoimmune diseases was thus avoided [22,23].…”

Section: Discussionmentioning

confidence: 99%

Experimental study of the mechanism of tolerance induction in dexamethasone-treated dendritic cells

Gong

Huang

Li³

et al. 2011

Med Sci Monit

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SummaryBackgroundThe aim of this study was to investigate the mechanisms underlying tolerance induction of dexamethasone (Dex)-treated dendritic cells (DCs).Material/MethodsWell-grown DC2.4 cells were randomly assigned to receive control, 50 μg/L, 100 μg/L, or 200 μg/L of dexamethasone and then were cultured for 6 days. The expressions of CD80, CD86, galectin-9, and PD-L1 on the surface of DC2.4 cells were analyzed with flow cytometry and the level of IL-12 secreted by DC2.4 cells was determined by ELISA. The stimulating activity of DC2.4 cells on allogeneic T cells was assessed with mixed lymphocyte reaction. Dexamethasone-treated DC2.4 cells were co-cultured with allogeneic splenic lymphocytes and the Foxp3 expression in naive T lymphocytes was determined with flow cytometry.ResultsCompared with the control group, the expressions of CD80, CD86, galectin-9, and PD-L1 on the surface of DC2.4 cells exposed to different doses of dexamethasone showed no significant changes; however, dexamethasone treatment significantly reduced IL-12 secretion and inhibited DC2.4’s stimulation on the proliferation of allogeneic T lymphocytes. Moreover, dexamethasone-treated DC2.4 cells effectively promoted FOXP3 expression in naive T lymphocytes.ConclusionsDC2.4 is a stable cell line with high expressions of CD80, CD86, and PD-L1. Dexamethasone does not significantly change the cell phenotype of DC2.4 cells, but inhibits the secretion of IL-12 cytokine and attenuates DC2.4’s stimulation of the proliferation of allogeneic T cells. Dexamethasone-treated DC2.4 cells also effectively promote FOXP3 expression in naive T lymphocytes.

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Regulation of Rat and Human T-Cell Immune Response by Pharmacologically Modified Dendritic Cells

Abstract: These data suggest that Dex-DC induced tolerance by different mechanisms in the two systems studied. Both rat and human Dex-DC were able to induce and expand regulatory T cells, which occurred in an IL-2 dependent manner in the rat system.

Cited by 15 publications

References 40 publications

Rapamycin-Conditioned Donor Dendritic Cells Differentiate CD4+CD25+Foxp3+ T Cells In Vitro with TGF-β1 for Islet Transplantation

Rapamycin-Conditioned Donor Dendritic Cells Differentiate CD4+CD25+Foxp3+ T Cells In Vitro with TGF-β1 for Islet Transplantation

Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8+ T cells in vitro and in vivo

Experimental study of the mechanism of tolerance induction in dexamethasone-treated dendritic cells

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