Impact of Immunosuppressive Drugs on CD4+CD25+FOXP3+ Regulatory T Cells: Does In Vitro Evidence Translate to the Clinical Setting?

2008 ◽  
Vol 85 (6) ◽  
pp. 783-789 ◽  
Author(s):  
Ahmet Demirkiran ◽  
Thijs K. Hendrikx ◽  
Carla C. Baan ◽  
Luc J. W. van der Laan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Clinical Setting ◽  
Immunosuppressive Drugs

scholarly journals In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation

2020 ◽  
Vol 6 (11) ◽  
pp. eaax8429 ◽  
Author(s):  
James D. Fisher ◽  
Wensheng Zhang ◽  
Stephen C. Balmert ◽  
Ali M. Aral ◽  
Abhinav P. Acharya ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Tolerance ◽  
Immunosuppressive Drugs ◽  
Vascularized Composite Allotransplantation ◽  
Local Enrichment ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (Treg) to suppress inflammation. Specifically, a microparticle-based system engineered to release the Treg-recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These “Recruitment-MP” prolonged hindlimb allograft survival indefinitely (>200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched Treg populations in allograft skin and draining lymph nodes and enhanced Treg function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human Treg in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive Treg.

Chronic Cutaneous GVHD Does Not Correlate with Frequency and FoxP3 Gene Expression of Regulatory T Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1819-1819
Author(s):  
Peter Haeusermann ◽  
Laura Tabellini ◽  
Mary E. Flowers ◽  
Paul J. Martin ◽  
Paul A. Carpenter ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Regulatory T Cells ◽  
Whole Blood ◽  
Hematologic Malignancy ◽  
Chronic Gvhd ◽  
Immunosuppressive Drugs ◽  
Comparable Amount ◽  
Preliminary Results

Abstract OBJECTIVE: The pathogenesis of chronic GVHD and particularly of its skin involvement is incompletely understood. Regulatory CD4+CD25+ T-cells have been shown to influence acute and chronic GVHD disease and so far heterogeneous results considering the frequency of these cells in chronic GVHD have been published. Additionally, reports indicate that chronic GVHD is associated with reduced expression of FoxP3 of these specific T-cells potentially related to posttransplant thymic insufficiency. These investigations have so far not been conducted in the particular setting of isolated chronic cutaneous GVHD. Our objective therefore was to investigate number, immunophenotype and gene expression of T-cells and particularly of regulatory T-cells in whole blood, CD4-enriched T-cells and regulatory T-cells in these patients. Moreover, as immunosuppressive drugs (calcineurin inhibitors and Rapamycine) have been shown to influence the frequency of regulatory T-cells in vitro, our focus was to specifically study highly selected patients without immunosuppressive medications including cyclosporine, FK-506, Rapamycine, Glucocorticosteroids and MTX and with or without active chronic cutaneous GVHD. METHODS: Since June 2005, 14 patients more than 365 days posttransplant because of hematologic malignancy and 4 normal controls have been investigated in this still ongoing study clinically and by T-cell immunophenotyping (whole blood, CD4+ T cells and regulatory T-cells) and gene expression (FoxP3, Il–10 and TGF-beta) with real time PCR. RESULTS: Of all patients included so far, preliminary results indicate, that patients without GVHD at all and without immunosuppressive drugs as well as patients with isolated chronic cutaneous GVHD and off immunosuppressive drugs have a comparable amount of regulatory T-cells and level of gene expression for FoxP3. Patients within these two highly selected subgroups do not have clinical and/or laboratory evidence for gastrointestinal or liver affection. CONCLUSION: With respect to our preliminary results, active chronic cutaneous GVHD in posttransplant patients after day 365 is not related to a decreased number of regulatory T-cells as well as to a reduced level of FoxP3 expression.

scholarly journals In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines

2002 ◽  
Vol 195 (5) ◽  
pp. 603-616 ◽  
Author(s):  
Franck J. Barrat ◽  
Daniel J. Cua ◽  
André Boonstra ◽  
David F. Richards ◽  
Chad Crain ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Immunosuppressive Drugs ◽  
T Helper ◽  
Ifn Γ ◽  
Th1 And Th2 ◽  
Helper Type

We show that a combination of the immunosuppressive drugs, vitamin D3 and Dexamethasone, induced human and mouse naive CD4+ T cells to differentiate in vitro into regulatory T cells. In contrast to the previously described in vitro derived CD4+ T cells, these cells produced only interleukin (IL)-10, but no IL-5 and interferon (IFN)-γ, and furthermore retained strong proliferative capacity. The development of these IL-10–producing cells was enhanced by neutralization of the T helper type 1 (Th1)- and Th2–inducing cytokines IL-4, IL-12, and IFN-γ. These immunosuppressive drugs also induced the development of IL-10–producing T cells in the absence of antigen-presenting cells, with IL-10 acting as a positive autocrine factor for these T cells. Furthermore, nuclear factor (NF)-κB and activator protein (AP)-1 activities were inhibited in the IL-10–producing cells described here as well as key transcription factors involved in Th1 and Th2 subset differentiation. The regulatory function of these in vitro generated IL-10–producing T cells was demonstrated by their ability to prevent central nervous system inflammation, when targeted to the site of inflammation, and this function was shown to be IL-10 dependent. Generating homogeneous populations of IL-10–producing T cells in vitro will thus facilitate the use of regulatory T cells in immunotherapy.

scholarly journals MiR-146a regulates regulatory T cells to suppress heart transplant rejection in mice

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jian Lu ◽  
Weiwei Wang ◽  
Peiyuan Li ◽  
Xiaodong Wang ◽  
Chao Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Heart Transplant ◽  
Transplant Rejection ◽  
Mouse Heart ◽  
Allograft Survival ◽  
Treg Function ◽  
Ifn Γ ◽  
Heart Transplant Rejection

AbstractRegulatory T cells (Tregs), which characteristically express forkhead box protein 3 (Foxp3), are essential for the induction of immune tolerance. Here, we investigated microRNA-146a (miR-146a), a miRNA that is widely expressed in Tregs and closely related to their homeostasis and function, with the aim of enhancing the function of Tregs by regulating miR-146a and then suppressing transplant rejection. The effect of the absence of miR-146a on Treg function in the presence or absence of rapamycin was detected in both a mouse heart transplantation model and cell co-cultures in vitro. The absence of miR-146a exerted a mild tissue-protective effect by transiently prolonging allograft survival and reducing the infiltration of CD4+ and CD8+ T cells into the allografts. Meanwhile, the absence of miR-146a increased Treg expansion but impaired the ability of Tregs to restrict T helper cell type 1 (Th1) responses. A miR-146a deficiency combined with interferon (IFN)-γ blockade repaired the impaired Treg function, further prolonged allograft survival, and alleviated rejection. Importantly, miR-146a regulated Tregs mainly through the IFN-γ/signal transducer and activator of transcription (STAT) 1 pathway, which is implicated in Treg function to inhibit Th1 responses. Our data suggest miR-146a controls a specific aspect of Treg function, and modulation of miR-146a may enhance Treg efficacy in alleviating heart transplant rejection in mice.

scholarly journals Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Cristian Doñas ◽  
Macarena Fritz ◽  
Valeria Manríquez ◽  
Gabriela Tejón ◽  
María Rosa Bono ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Trichostatin A ◽  
Gene Promoter ◽  
Treg Cells ◽  
Specific Subset ◽  
Global Increase ◽  
And Function ◽  
H3 Acetylation

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that thefoxp3gene promoter becomes hyperacetylated inin vitrodifferentiated Tregs compared to naïve CD4+T cells. We also show that the histone deacetylase inhibitor TSA stimulated thein vitrodifferentiation of naïve CD4+T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+Treg cells.

scholarly journals Regulatory T Cells Contribute to Resistance against Lyme Arthritis

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Emily M. Siebers ◽  
Elizabeth S. Liedhegner ◽  
Michael W. Lawlor ◽  
Ronald F. Schell ◽  
Dean T. Nardelli
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lyme Disease ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Interleukin 17 ◽  
Content Type

ABSTRACT The symptoms of Lyme disease are caused by inflammation induced by species of the Borrelia burgdorferi sensu lato complex. The various presentations of Lyme disease in the population suggest that differences exist in the intensity and regulation of the host response to the spirochete. Previous work has described correlations between the presence of regulatory T cells and recovery from Lyme arthritis. However, the effects of Foxp3-expressing CD4+ T cells existing prior to, and during, B. burgdorferi infection have not been well characterized. Here, we used C57BL/6 “depletion of regulatory T cell” mice to assess the effects these cells have on the arthritis-resistant phenotype characteristic of this mouse strain. We showed that depletion of regulatory T cells prior to infection with B. burgdorferi resulted in sustained swelling, as well as histopathological changes, of the tibiotarsal joints that were not observed in infected control mice. Additionally, in vitro stimulation of splenocytes from these regulatory T cell-depleted mice resulted in increases in gamma interferon and interleukin-17 production and decreases in interleukin-10 production that were not evident among splenocytes of infected mice in which Treg cells were not depleted. Depletion of regulatory T cells at various times after infection also induced rapid joint swelling. Collectively, these findings provide evidence that regulatory T cells existing at the time of, and possibly after, B. burgdorferi infection may play an important role in limiting the development of arthritis.

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