Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids

Ramesh, Radha; Kozhaya, Lina; McKevitt, Kelly; Djuretic, Ivana; Carlson, Thaddeus; Quintero, Maria A.; McCauley, Jacob L.; Abreu, María T.; Unutmaz, Derya; Sundrud, Mark S.

doi:10.1084/jem.20130301

Cited by 385 publications

(420 citation statements)

References 56 publications

(125 reference statements)

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“…demonstrated, in CD patients, a MDR1 enrichment within Th1.17 that resist to GC treatment. 61 On the contrary, MDR1 loss of function was identified in a subset of patients with an aggressive form of ileal CD. 78 Therefore, MDR1 role is dual in this pathology.…”

Section: Introductionmentioning

confidence: 99%

“…In healthy subjects, among CD4 + memory T cells, MDR1 delineates a subset of effector T cells (Teff) mainly composed of Th1.17 also called pathogenic Th17. 61 Moreover, our team recently characterized, in human, the CD73 + Teff population that is particularly enriched in Th1.17 and expressed higher MDR1 levels than their CD73 neg counterpart. 62 A recent study also suggests that MDR1 is also selectively expressed by Teff bearing the lectin-like receptor CD161.…”

Section: Introductionmentioning

confidence: 99%

“…The Th1.17 subset expressing high MDR1 level and also secreting pro-inflammatory cytokines, 61,62 appears as an asset in the anti-tumor immune response in contrast to its deleterious impact in autoimmune diseases. In long term chemotherapy treated AML patients, the non-malignant CD4 + CD161 + MDR1 + T cells fraction is increased, and they conserve their anti-viral properties and display self-renewal capacities.…”

Section: Introductionmentioning

confidence: 99%

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MDR1 in immunity: friend or foe?

et al. 2018

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MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MDR1 in immunity: friend or foe?

et al. 2018

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“…Increasing evidence supports the concept of a SR Th17 phenotype, and their adoptive transfer, or the overexpression of their canonical transcription factor retinoid-related orphan receptor (ROR)-γt, has been shown to induce SR disease in a murine model of asthma (12,13). In humans, glucocorticoid-resistant Th17 cells express the multidrug resistance type 1 protein, which is inhibited by cyclosporine A (CsA) (14), and historically CsA was one of the first drugs used to successfully rescue SR diseases (1). We therefore hypothesized that CsA would selectively inhibit human Th17 cells.…”

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confidence: 99%

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Schewitz-Bowers

Lait

Copland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

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“…P-glycoprotein, for example, is under the influence of PXR, FXR, NFκB and AP-1 pathways (Miller, 2010), but examination of co-regulated transcripts using pathway analysis tools may help determine the specific pathway that is active (Krämer et al, 2014). It has been demonstrated that microbial-derived compounds including indole metabolites can function as PXR ligands (Venkatesh et al, 2014) which have functions in other cell types such is the case with P-glycoprotein expressed in phagocytes and T cells (Ramesh et al, 2014;Cory et al, 2016).…”

Section: Alternative Alterations To Absorptionmentioning

confidence: 99%

How to Determine the Role of the Microbiome in Drug Disposition

et al. 2018

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With a paradigm shift occurring in health care towards personalized and precision medicine, understanding the numerous environmental factors that impact drug disposition is of paramount importance. The highly diverse and variant nature of the human microbiome is now recognized as a factor driving inter-individual variation in therapeutic outcomes. The purpose of this review is to provide a practical guide on methodology that can be applied to study the effects of microbes on the absorption, distribution, metabolism, and excretion of drugs. We also highlight recent examples of how these methods have been successfully applied to help build the basis for researching the intersection of microbiome and pharmacology. While in vitro and in vivo preclinical models are highlighted, these methods are also relevant in late-phase drug development or even as a part of routine after-market surveillance. These approaches will aid in filling major knowledge gaps for both current and upcoming therapeutics with the long-term goal of achieving a new type of knowledge-based medicine that integrates data on the host and the microbiome.

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Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids

Abstract: Inflammatory T helper 17 cells in humans are distinguished by selective expression of MDR1 and are enriched in the gut of patients with Crohn’s disease.

Cited by 385 publications

References 56 publications

MDR1 in immunity: friend or foe?

MDR1 in immunity: friend or foe?

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

How to Determine the Role of the Microbiome in Drug Disposition

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