Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo

Dominguez‐Villar, Margarita; Raddassi, Khadir; Danielsen, Ann Caroline; Guarnaccia, Joseph; Hafler, David A.

doi:10.1016/j.jaut.2018.08.002

Cited by 45 publications

(37 citation statements)

References 72 publications

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“…The analysis of fingolimod effects on T cells during 12 months of treatment also evidenced a modulation of the phenotype of Th cells and Treg cells. Effector Th cells showed a decrease of IL-17 and IFN-γ and an increase of TGF-β and IL-10 production together with the expression of exhaustion markers such as programmed death 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3) [189]. Moreover, the suppressive functions of Treg in fingolimod-treated RRMS patients were also upregulated, thus evidencing an additional role of fingolimod in restoring peripheral tolerance besides the retention of T lymphocytes in lymph nodes [189].…”

Section: T Cell Targeting Therapymentioning

confidence: 99%

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

Kunkl

Frascolla

Amormino

et al. 2020

Cells

175

107

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Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.

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Section: T Cell Targeting Therapymentioning

confidence: 99%

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

Kunkl

Frascolla

Amormino

et al. 2020

Cells

175

107

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“…The reduction in the absolute number of IL-17 + T cells in the peripheral blood might be due to sequestration of cells in the lymph nodes or due to immunomodulatory effects of fingolimod. [36,37,43,44] Reduction of central memory Th17 cells in the peripheral blood after fingolimod treatment have been reported previously although others have shown a subset of patients that had increased Th17 cells. [37,43] Fingolimod may also reduce polarization to Th17 by reducing Th17-polarizing cytokine production by dendritic cells [36] or suppressing IL-17 production by CD4 + T cells.…”

Section: Discussionmentioning

confidence: 62%

“…Fingolimod also has immunomodulatory properties particularly on Th17 and Treg cells. [33][34][35][36] In this study we compared Th17 cell number, and Th17associated cytokines in the peripheral blood of untreated RRMS patients to those treated with fingolimod via flow cytometry-based assays. Previous studies have shown a reduction in IL-17 producing cells in the peripheral blood after Fingolimod treatment.…”

Section: Discussionmentioning

confidence: 99%

“…[37,43] Fingolimod may also reduce polarization to Th17 by reducing Th17-polarizing cytokine production by dendritic cells [36] or suppressing IL-17 production by CD4 + T cells. [44] Lastly, we also compared the serum levels of IL-17A, IL-22, and GM-CSF between the fingolimod-receiving and untreated RRMS patient groups. Interestingly we did not observe a difference between healthy controls, fingolimod treated and untreated RRMS group.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Peripheral Blood Th17 Cells and Associated Cytokines in Fingolimod-Receiving and Untreated Multiple Sclerosis Patients

Eken¹,

Yetkin²,

Okuş³

et al. 2019

Turk J Immunol

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Introduction: Th17 cells are critical mediators of pathology in several autoimmune diseases including multiple sclerosis (MS). The aim of this study was to quantify Th17 cells and-associated cytokines in the peripheral blood of relapsing remitting multiple sclerosis patients (RRMS). We also aimed to compare those levels in fingolimod-treated, and untreated patients. Material and Methods:Fifteen fingolimod administered RRMS, 9 untreated-RRMS patients and 6 healthy controls were evaluated. Their peripheral blood mononuclear cells (PBMCs) were isolated and sera separated. IL-17A + , IL-22 + and GM-CSF + T-cells were quantified via intracellular cytokine staining after stimulation using flouresecein activated cell sorter. Serum cytokine levels from all groups were measured via enzyme-linked immunosorbent assay (ELISA).Results: Fingolimod-treated RRMS patients had reduced number of IL-17A + (p=0.02), IL-22 + (p=0.05), and GM-CSF + (p=0.003) T cells in their peripheral blood compared to those of untreated RRMS patients. This is consistent with sequestration of lymphocytes in the secondary lymphoid organs after fingolimod use. However, the levels of same cytokines in the serum were statistically not different. Conclusions:Fingolimod treatment reduced circulating IL-17A + , IL-22 + or GM-CSF + T cells in RRMS patients. ÖzGiriş: Th17 hücreleri, multipl sklerozun da dahil olduğu birçok otoimmün hastalığın patogenezinde rol alan kritik bir hücre popülasyonudur. Bu çalışmada, fingolimod tedavisi alan ve almayan tekrarlayan-gerileyen multipl sklerozlu (TGMS) hastalarının kanındaki Th17 hücre sayısı ve ilişkili sitokinlerin miktarlarını irdelemeyi amaçladık. Gereç ve Yöntemler:On beş fingolimod tedavisi alan TGMS hastası, ve tedavi almayan 9 TGMS hastası ile 6 sağlıklı kontrol çalışmaya dahil edildi. Kandan izole edilen periferik kan mononükleer hücreleri stimüle edilmiş, intraselüler hücre boyaması ve FACSAriaIII kullanılarak IL-17A, IL-22 ve GM-CSF üreten T hücreleri sayı ve yüzdeleri ölçüldü. Serum sitokin seviyeleri ELISA yöntemi ile saptandı.Bulgular: Fingolimod tedavisi alan RRMS hastalarının kanındaki IL-17A + (p=0,02), IL-22 + (p=0,05), GM-CSF + (p=0,003) T hücrelerinin mutlak sayılarında, fingolimod almayan TSMS hastalarına göre, önemli ölçüde azalma gözlendi. Bu sonuç fingolimod'un lenfositleri sekonder lenfoid organlarda tutma mekanizması ile uyumludur. ELISA ile serumdan ölçülen aynı sitokinlerin seviyerinde anlamlı azalma gözlenmedi.Sonuç: Fingolimod dolaşımdaki IL-17A + , IL-22 + ve GM-CSF + üreten T hücre sayılarını azaltmaktadır.

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“…In the same study it was also shown that in patients undergoing treatment with fingolimod the phenotypic conversion from naïve Treg cells to effector T cells occurs with greater frequency. Fingolimod also affects Treg plasticity by reducing the expression of T-bet and of IFNγ and by enhancing expression of Tim-3, a marker associated with superior suppressor capacity (212). In general, these studies show that Treg function is increased following treatment with fingolimod.…”

Section: Effects Of Immunomodulatory Drugs For Ms On Tregsmentioning

confidence: 73%

One, No One, and One Hundred Thousand: T Regulatory Cells' Multiple Identities in Neuroimmunity

et al. 2019

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As the Nobel laureate Luigi Pirandello wrote in his novels, identities can be evanescent. Although a quarter of a century has passed since regulatory T cells (Treg) were first described, new studies continue to reveal surprising and contradictory features of this lymphocyte subset. Treg cells are the core of the immunological workforce engaged in the restraint of autoimmune or inflammatory reactions, and their characterization has revealed substantial heterogeneity and complexity in the phenotype and gene expression profiles, proving them to be a most versatile and adaptive cell type, as exemplified by their plasticity in fine-tuning immune responses. Defects in Treg function are associated with several autoimmune diseases, including multiple sclerosis, which is caused by an inappropriate immune reaction toward brain components; conversely, the beneficial effects of immunomodulating therapies on disease progression have been shown to partly act upon the biology of these cells. Both in animals and in humans the pool of circulating Treg cells is a mixture of natural (nTregs) and peripherally-induced Treg (pTregs). Particularly in humans, circulating Treg cells can be phenotypically subdivided into different subpopulations, which so far are not well-characterized, particularly in the context of autoimmunity. Recently, Treg cells have been rediscovered as mediators of tissue healing, and have also shown to be involved in organ homeostasis. Moreover, stability of the Treg lineage has recently been addressed by several conflicting reports, and immune-suppressive abilities of these cells have been shown to be dynamically regulated, particularly in inflammatory conditions, adding further levels of complexity to the study of this cell subset. Finally, Treg cells exert their suppressive function through different mechanisms, some of which-such as their ectoenzymatic activityare particularly relevant in CNS autoimmunity. Here, we will review the phenotypically and functionally discernible Treg cell subpopulations in health and in multiple sclerosis, touching also upon the effects on this cell type of immunomodulatory drugs used for the treatment of this disease.

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Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo

Cited by 45 publications

References 72 publications

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

Comparison of Peripheral Blood Th17 Cells and Associated Cytokines in Fingolimod-Receiving and Untreated Multiple Sclerosis Patients

One, No One, and One Hundred Thousand: T Regulatory Cells' Multiple Identities in Neuroimmunity

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