FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

Luessi, Felix; Kraus, Stefan H.P.; Trinschek, Bettina; Lerch, Steffen; Ploen, Robert; Paterka, Magdalena; Roberg, Torsten; Poisa-Beiro, Laura; Klotz, Luisa; Wiendl, Heinz; Bopp, Tobias; Jonuleit, Helmut; Jolivel, Valérie; Zipp, Frauke; Witsch, Esther

doi:10.1177/1352458515574895

Cited by 39 publications

(35 citation statements)

References 35 publications

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“…Functional responses of monocytes and DC may be altered by FTY. Consistent with a previous study 25 we found a reduction in monocyte expression of pro-inflammatory TNFα and an increase in DC expression of CD86. Higher CD86 expression on antigen presenting cells has been associated with induction of tolerogenic Th2 responses 27,28 , and may be relevant to FTY's therapeutic action.…”

Section: Discussionsupporting

confidence: 93%

“…While reductions in total lymphocyte, T-cell and B-cell counts with FTY treatment have been well documented 2,4 , the effects of FTY on monocytes and DCs are less well known. In keeping with prior work 25,26 we observed stable monocyte counts and increased frequencies of monocytes within PBMC due to lymphopenia. We further report that DC numbers were stable, such that DC frequencies similarly increased on-treatment.…”

Section: Discussionsupporting

confidence: 91%

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Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Ghadiri

Rezk

et al. 2020

Sci Rep

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Bar-or 1,3* Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as 'Active' or 'Stable' based on clinical and/ or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre-and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + t cells, CD56 dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Ghadiri

Rezk

et al. 2020

Sci Rep

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“…Our investigation was consistent with previous studies [12] showing that rats treated with fingolimod expressed a lower frequency of TUNEL-positive nuclei after 24 h of reperfusion, supporting the cardioprotective role of fingolimod by activating anti-apoptotic cascade. S1P receptor agonists have important roles in immune suppression [39]. A porcine model of I/R [17] and a spontaneous obstructive coronary atherosclerosis murine model [40] tested for immunosuppression, showed reduction in infarct size and mortality in the fingolimod-treated group.…”

Section: Discussionmentioning

confidence: 99%

Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation

Ahmed

Laghari

Albkhoor

et al. 2019

IJMS

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Background: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation. Methods: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways. Results: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index. Conclusions: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest.

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“…Wpływ fingolimodu na komórki układu odpornościowego widoczny jest już po kilku godzinach od jego podania [24,25]. Długofalowe skutki stosowania fingolimodu obejmują nasilenie działania przeciwzapalnego komórek prezentujących antygen [26] oraz przesunięcie równowagi pomiędzy pro-i przeciwzapalnymi komórkami i cytokinami w stronę fenotypu o mniejszym nasileniu stanu zapalnego [27].…”

Section: Rycinaunclassified

Zastosowanie modulatorów receptorów sfingozyno-1-fosforanu w leczeniu nieswoistych chorób zapalnych jelit

Szymaszkiewicz

Fichna

2020

Postepy Biochem

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Sfingozyno-1-fosforan (S1P) jest przedstawicielem sfingolipidów o wysokiej aktywności biologicznej. Ze względu na swój wpływ na migrację komórek odpornościowych uznawany jest za istotny element w patogenezie wielu chorób, takich jak: toczeń układowy, stwardnienie rozsiane czy nieswoiste choroby zapalne jelit (NChZJ). Nieswoiste choroby zapalne jelit to grupa przewlekłych i postępujących schorzeń układu pokarmowego, które przebiegają z okresami zaostrzeń i remisji. Do najczęstszych zalicza się: chorobę Leśniowskiego-Crohna (ChLC) oraz wrzodziejące zapalenie jelita grubego (WZJG). Obecnie w leczeniu NChZJ stosuje się związki o działaniu przeciwzapalnym i immunomodulującym, których zadaniem jest złagodzenie objawów oraz wprowadzenie pacjenta w stan remisji. W ramach tego artykułu omówiona zostanie rola S1P, receptora dla S1P oraz enzymów biorących udział w jego metabolizmie w warunkach fizjologicznych oraz w przebiegu NChZJ. Ponadto, podsumowane zostaną wyniki badań przedklinicznych i klinicznych nad skutecznością modulatorów receptora dla S1P w przebiegu NChZJ.

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FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

Abstract: Our data indicate that fingolimod - apart from trapping lymphocytes in lymph nodes - exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

Cited by 39 publications

References 35 publications

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation

Zastosowanie modulatorów receptorów sfingozyno-1-fosforanu w leczeniu nieswoistych chorób zapalnych jelit

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