FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis

Mehling, Matthias; Brinkmann, Volker; Antel, Jack P.; Bar‐Or, Amit; Goebels, Norbert; Vedrine, Corinne; Kristofic, Colette; Kuhle, Jens; Lindberg, Raija L. P.; Kappos, Ludwig

doi:10.1212/01.wnl.0000327609.57688.ea

Cited by 312 publications

(291 citation statements)

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“…Effector memory T cells, which are thought to be important for immune surveillance and memory immune responses in peripheral tissues, are largely spared by fingolimod [48,51]. Within 4-6 h after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases to approximately 75% of baseline in peripheral blood [17].…”

Section: Safety Fingolimodmentioning

confidence: 99%

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon‐β therapy

Freedman

2013

Euro J of Neurology

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Background and purpose: Although the first-line disease-modifying therapies (DMTs) interferon beta and glatiramer acetate have a favourable benefit-to-risk profile, they are only partially effective for treating relapsing-remitting multiple sclerosis (RRMS). The optimization of treatment in patients who do not show a maximum response to first-line therapy is critical for achieving the best long-term outcomes. Treatment strategies for patients with a suboptimal response include switching to another first-line DMT or a second-line DMT. Natalizumab and fingolimod are approved for RRMS with high disease activity in the European Union and Canada. Methods: A comprehensive literature search for articles published between 1990 and April 2012 was undertaken.Results: This review discusses key clinical and safety data for fingolimod and natalizumab, particularly in the patient subgroups for whom these treatments are approved. Benefit-to-risk profiles, including first-dose cardiovascular effects associated with fingolimod and the risk of progressive multifocal encephalopathy with natalizumab, are discussed. Conclusion: A descriptive comparison of fingolimod and natalizumab is provided in the context of the decision-making process of how and when to switch patients who have a suboptimal response to first-line therapy.

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Section: Safety Fingolimodmentioning

confidence: 99%

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon‐β therapy

Freedman

2013

Euro J of Neurology

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“…Fingolimod binds to four of the five subtypes of S1P receptors, causing the internalization and degradation of these receptors, and consequently blocking the egress of CCR7 + lymphocytes from LNs (21,63,64). The main effect of fingolimod is a decrease of CCR7 + cells in peripheral blood, specifically of naïve and central memory T-cells (65)(66)(67)(68). In contrast to T-cells, B-cell subsets have not been extensively studied in patients under fingolimod treatment.…”

Section: Fingolimodmentioning

confidence: 99%

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Teniente‐Serra¹,

Ramo‐Tello

Martı́nez-Cáceres

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Abstract:Advances in the understanding of pathogenic mechanisms of diseases have led to the defining of new biomarkers for diagnosis, prognosis, and therapy response. In this context, flow cytometry has been positioned as one of the most useful technologies for monitoring immune-mediated diseases, such as multiple sclerosis (MS), allowing a detailed analysis of lymphocyte subpopulations in peripheral blood. The autoimmune inflammatory response in MS results in changes in lymphocyte subpopulations that might be useful as surrogate markers for the evaluation of disease activity, progression, and monitoring of therapy response. This chapter discusses the role of T-lymphocyte and B-lymphocyte subpopulations in MS pathogenesis, the effect of MS treatments on these subsets, and their potential usefulness as biomarkers of treatment response.

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“…Disruption of the S1P/S1P1 axis leads to inhibition of this egress and accumulation of T N cells in secondary lymphoid organs. Lymphocytes such as T EM cells are less affected due to their different trafficking routes and NK cells are similarly less affected as they utilize a different S1P receptor to exit lymph nodes [8,[11][12][13]. This specific property of T N cells has been exploited in relapsing-remitting multiple sclerosis with the use of the immunomodulatory agent FTY720 [14].…”

Section: Introductionmentioning

confidence: 99%

“…FTY720 disrupts the S1P/S1P1 axis by inducing internalization and degradation of the S1P1 receptor [14], which leads to rapid sequestration of T N cells, as well as B cells into secondary lymphoid organs and their depletion from peripheral blood (PB) [11]. While the immunomodulatory properties of FTY720 have been studied in various inflammatory conditions as a way of impacting disease, its use in manipulating mobilized stem cell grafts has not previously been examined [11,12,15,16]. Currently, the majority of hematopoietic stem cell transplants are performed using G-CSF-mobilized PB stem cell grafts [17].…”

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confidence: 99%

In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation

et al. 2016

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The immunological attributes of stem cell grafts play an important role in the outcome of allogeneic stem cell transplants. Currently, ex vivo manipulation techniques such as bulk T-cell depletion or positive selection of CD34 + cells are utilized to improve the immunological attributes of grafts and minimize the potential for graft-versus-host disease (GvHD). Here, we demonstrate a novel graft engineering technique, which utilizes the immunomodulatory drug FTY720 for in vivo depletion of naïve T (T N ) cells from donor G-CSF-mobilized grafts without ex vivo manipulation. We show that treatment of donor mice with FTY720 during mobilization depletes grafts of T N cells and prevents lethal GvHD following transplantation in a major mismatch setting. Importantly, both stem cells and NK cells are retained in the FTY720-treated grafts. FTY720 treatment does not negatively affect the engraftment potential of stem cells as demonstrated in our congenic transplants or the functionality of NK cells. In addition, potentially useful memory T cells may be retained in the graft. These findings suggest that FTY720 may be used to optimize the immunological attributes of G-CSF-mobilized grafts by removing potentially deleterious T N cells which can contribute to GvHD, and by retaining useful cells which can promote immunity in the recipient.Keywords: Allogeneic stem cell transplantation r Graft engineering r Graft-versus-host disease r Stem cell mobilization r T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-siteCorrespondence: Dr. Julius G. Juarez e-mail: juliusgjuarez@gmail.com * These authors contributed equally to this work. * * These authors contributed equally to this work as senior co-authors.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1758-1769 Transplantation and tolerance 1759 IntroductionGraft engineering has played a crucial role in improving allogeneic stem cell transplantation (ASCT) and also broadening its potential application [1]. This has been underpinned by our greater understanding of the different cells that constitute the graft and their contribution to alloresponses [2]. Naïve T (T N ) cells from grafts are the major cells responsible for graft-versus-host disease (GvHD), whereas other cells, such as effector memory T (T EM ), central memory T (T CM ), and NK cells, have potential for promoting immunity and antitumor activity, respectively [1,[3][4][5][6]. In order to mitigate alloresponses by donor T N cells, current graftengineering techniques utilize ex vivo bulk T-cell depletion or positive selection of CD34 + cells. These techniques, however, can leave the graft devoid of useful immune cells, potentially making the recipient more susceptible to infection and relapse [1,2].Techniques specifically targeting depletion of T N cells from grafts could potentially help maximize the capacity of grafts for immune reconstitution, antitumor activity as well as prevention of GvHD in recipients [1,[...

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FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis

Cited by 312 publications

References 21 publications

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon‐β therapy

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon‐β therapy

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation

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