Low‐dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis

Brandt, Claudia; Pavlović, V.; Radbruch, Andreas; Worm, Margitta; Baumgrass, Ria

doi:10.1111/j.1398-9995.2009.02054.x

Cited by 101 publications

(70 citation statements)

References 40 publications

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“…Although in the past decade, further T-cell populations, in particular regulatory T-cells [35,36] were described to be involved in the regulation of allergic inflammation, the protective role of IFN-γ in atopy is still accepted. Data from animal studies clearly demonstrate that the asthma-protective effect induced by microbial exposure depends on IFN-γ [37,38]. In our study, we demonstrate that sleeping on animal fur in the first 3 months of life contributes to persistently higher amounts of IFN-γ-producing peripheral T-cells at least until the age of 3 years in a subgroup of the study population.…”

Section: Discussionsupporting

confidence: 48%

Sleeping on animal fur is related to asthma outcomes in later childhood

et al. 2015

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Animal furs might represent a "proxy" for high and diverse microbial exposures within a critical time window of immune development. We assessed whether sleeping on animal fur shortly after birth is associated with asthma and atopy up to the age of 10 years.LISAplus participants (n=2441) from Munich and Leipzig, Germany, were included in the analysis. Animal fur exposure, cofactors and health outcomes were obtained periodically up to 10 years of age by parental questionnaires. Information on specific IgE to aeroallergens was available at 10 years. Cytokineproducing peripheral T-cells were assessed in a subgroup of children at 2 and 3 years. Confounderadjusted associations were evaluated using logistic regression analyses.Sleeping on animal fur was very common (55%). In adjusted logistic regression analyses, sleeping on animal fur was inversely associated with recurrent early wheezing at 4 years (adjusted OR 0.75, 95% CI 0.61-0.93) and current asthma at 6 years (adjusted OR 0.56, 95% CI 0.31-1.01). Furthermore, sleeping on animal fur during the first 3 months of life was significantly associated with a persistently stimulated interferon-γ response until the age of 3 years.Animal fur could be an effective measure of creating environments associated with higher microbial exposure. @ERSpublications Use of animal fur could be effective for creating environments associated with possibly higher microbial exposure http://ow.ly/IWhTp

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Section: Discussionsupporting

confidence: 48%

Sleeping on animal fur is related to asthma outcomes in later childhood

et al. 2015

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“…Additional studies are needed for the evaluation and establishment of an individualized CsA/FK506 therapy. Individualized immunosuppressive regimes are gaining importance by new concepts of CsA tapering in renal transplant patients (16) and low-dose CsA therapies in atopic dermatitis patients (51).…”

Section: Discussionmentioning

confidence: 99%

Whole blood flow cytometric measurement of NFATc1 and IL‐2 expression to analyze cyclosporine A‐mediated effects in T cells

et al. 2010

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The calcineurin inhibitor Cyclosporine A (CsA) is one of the crucial immunosuppressive drugs given after organ transplantation. The small therapeutic window of CsA generates the dilemma that efficient and toxic drug doses differ only slightly. Moreover, these threshold concentrations differ considerably between individuals; therefore, functional assays are urgently needed. We explored whether the transcription factor NFATc1, a direct as well as indirect target of CsA, can be used as a potential biomarker to determine the individual immunosuppressive activity of CsA. First, in isolated human T cells we showed that flow cytometry is practicable to measure NFATc1, the most abundant NFATc isoform in activated T cells. Second, for whole blood we developed a flow cytometric assay to determine in parallel the inducible transcription factor NFATc1 and the cytokine IL-2 in stimulated T cells. We found that added CsA inhibits both the expression of NFATc1 and IL-2 in T cells of stimulated whole blood samples with IC 50 values of 200 and 150 nM, respectively. The intra-and inter-assay variability was low, and clinical practicability was good. Further experiments have to demonstrate whether the parallel cytometric measurement of NFATc1 and IL-2 in whole blood is a good predictor of individual CsA efficacy and toxicity in CsA-treated patients. '

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“…In addition, it has been shown that the effect of CsA on Treg depends on its concentration. Low CsA concentrations allow Treg expansion, whereas high concentrations lead to a decreased Treg number (17,32,33). This phenomenon can be explained through interleukin-2 (IL-2) action.…”

Section: Application To New Patientsmentioning

confidence: 99%

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

Philippe

Hénin

Bertrand

et al. 2015

AAPS J

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Abstract. Optimal immunosuppressive therapy in acquired severe aplastic anemia (SAA) remains to be refined, especially cyclosporine (CsA) use. Current recommendations state that CsA trough blood concentrations (TBC) should be maintained between 200 and 400 ng/mL despite the lack of supporting data. This study aimed at quantifying relationships between CsA exposure and neutrophil response and determining an effective range for CsA TBC. Twenty-three SAA patients treated with CsA were retrospectively analyzed. Nonlinear mixed effect modeling approaches were used to develop a pharmacokinetic-pharmacodynamic model. The pharmacokinetic model described the relationships between CsA doses and TBC. The pharmacodynamic model allowed to estimate boundaries for optimal CsA effects, neutrophils being used as biomarker of response. A time-to-event model linked effective concentration to time-to-therapeutic success. CsA TBC were adequately described by a twocompartment model with first-order absorption, a lag time, and a linear elimination. The efficient range of CsA TBC was estimated between 87 and 120 ng/mL. Model-based simulations and external validation in three additional patients confirmed these results. This original modeling approach was successful in describing the relationship between CsA TBC and neutrophil response in SAA patients. Although further evaluation of the model is necessary, this work suggests that an optimal CsA TBC target of 100 ng/mL would be associated with a better neutrophil response in children with SAA.

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Low‐dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis

Abstract: Our results indicate that the therapeutic effect of low-dose CsA therapy in AD patients might be not only mediated by the inhibition of T cell hyperactivity but also by an increased population of Treg cells.

Cited by 101 publications

References 40 publications

Sleeping on animal fur is related to asthma outcomes in later childhood

Sleeping on animal fur is related to asthma outcomes in later childhood

Whole blood flow cytometric measurement of NFATc1 and IL‐2 expression to analyze cyclosporine A‐mediated effects in T cells

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

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