Tolerizing Effects of Co-stimulation Blockade Rest on Functional Dominance of CD4+CD25+ Regulatory T Cells

Coenen, Jeroen J.A.; Koenen, Hans J. P. M.; Rijssen, Esther van; Hilbrands, Luuk B.; Joosten, Irma

doi:10.1097/01.tp.0000147460.93587.87

Cited by 24 publications

(20 citation statements)

References 32 publications

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“…This locus contains CpG motifs, which are completely demethylated in regulatory T cells but methylated in naive and effector T cells. 22,[45][46][47][48][49] On the basis of this concept, we evaluated the effect of 5-azaC on T cells. We found that 5-azaC inhibited T-cell activation, proliferation, and secretion of proinflammatory cytokines at 2 to 4 days of culture.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting

Sánchez‐Abarca

Gutierrez-Cosio

Santamaría

et al. 2010

Blood

201

165

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Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleosidebased DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G 0 to G 1 phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-␣ and interferon-␥. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versushost disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease. (Blood.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting

Sánchez‐Abarca

Gutierrez-Cosio

Santamaría

et al. 2010

Blood

201

165

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“…It has recently been demonstrated and frequently observed that naturally occurring T REG cells can inhibit autoimmune diseases (6, 7, 36) and allergic responses (4, 5, 37), as well as induce tolerance (38), affect antitumor immunity (39), and regulate the activation of other peripheral T cells. These types of T REG cells have the phenotype CD4 ϩ CD25 ϩ and constitute ϳ10% of peripheral CD4 ϩ T cells in normal mice.…”

Section: Discussionmentioning

confidence: 99%

Induction of Adaptive T Regulatory Cells That Suppress the Allergic Response by Coimmunization of DNA and Protein Vaccines

Jin

Kang

Zhao

et al. 2008

The Journal of Immunology

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Allergen-induced immediate hypersensitivity (AIH) is a health issue of significant concern. This robust inflammatory reaction is initiated by the allergen-specific T cell responsiveness. Severe lesion reactions on skin are consequential problem requiring medical treatment. Effective Ag-specific treatments or preventions are lacking. Using a rodent model of AIH induced by flea allergens, we first report that coimmunization of DNA and protein vaccines encoding the flea salivary specific Ag-1 ameliorated experimental AIH, including Ag-induced wheal formation, elevated T cell proliferation, and infiltration of lymphocytes and mast cells to the site of allergen challenge. The amelioration of AIH was directly related to the induction of a specific population of flea antigenic specific T cells exhibiting a CD4+CD25−FoxP3+ phenotype, a characteristic of regulatory T (TREG) cells. These TREG cells expressing IL-10, IFN-γ, and the transcriptional factor T-bet after Ag stimulation were driven by a tolerogenic MHC class II+/CD40low dendritic cell population that was induced by the coimmunization of DNA and protein vaccines. The tolerogenic dendritic cell could educate the naive T cells into CD4+CD25−FoxP3+ TREG cells both in vitro and in vivo. The study identified phenomenon to induce an Ag-specific tolerance via a defined Ag vaccinations and lead to the control of AIH. Exploitation of these cellular regulators and understanding their induction provides a basis for the possible development of novel therapies against allergic and related disorders in humans and animals.

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“…13 In addition, agents interfering with costimulatory pathways (eg, anti-CD40L) can prevent allograft rejection and induce tolerance by functional dominance of CD4 ϩ CD25 ϩ Tregs. 21 Thus, Treg activation appears to play an important role in the establishment of antigen-specific immune tolerance.…”

Section: Introductionmentioning

confidence: 99%

CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice

Miao

Harmeling²,

Ziegler³

et al. 2009

Blood

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Tolerizing Effects of Co-stimulation Blockade Rest on Functional Dominance of CD4+CD25+ Regulatory T Cells

Abstract: The authors therefore conclude that co-stimulation blockade contributes to functional dominance of regulatory T cells by preventing expansion of alloreactive effector T cells. Tolerance-inducing protocols should ideally facilitate this phenomenon.

Cited by 24 publications

References 32 publications

Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting

Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting

Induction of Adaptive T Regulatory Cells That Suppress the Allergic Response by Coimmunization of DNA and Protein Vaccines

CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice

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