Influence of fingolimod on basic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosis patients – preliminary study

Rudnicka, J; Czerwiec, Michał; Grywalska, Ewelina; Siwicka-Gieroba, Dorota; Walankiewicz, Monika; Grafka, Agnieszka; Zgurski, Michał; Surdacka, Agata; Bartosik-Psujek, Halina; Roliński, Jacek

doi:10.5114/ceji.2015.54599

Cited by 22 publications

(14 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We thus examined the direct effects of Fingolimod on T cells populations in vivo, with a focus on cytokine secretion and expression of exhaustion markers. We first confirmed published data demonstrating the decrease in T cell numbers in the circulation of patients under Fingolimod treatment [38,[55][56][57][58][59] and the lack of effects on monocyte and NK cell counts [60].…”

Section: Discussionsupporting

confidence: 85%

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

Dominguez‐Villar

Raddassi

Danielsen

et al. 2019

Journal of Autoimmunity

View full text Add to dashboard Cite

Fingolimod is an approved therapeutic option for patients with relapsing-remitting multiple sclerosis that primarily functions by sequestering T cells in lymph nodes inhibiting their egress to the central nervous system. However, recent data suggests that Fingolimod may also directly affect the immune cell function. Here we examined the in vivo effects of Fingolimod in modulating the phenotype and function of T cell and Foxp3 regulatory T cell populations in patients with multiple sclerosis under Fingolimod treatment. Besides decreasing the cell numbers in peripheral blood and sera levels of pro-inflammatory cytokines, Fingolimod inhibited the expression of Th1 and Th17 cytokines on CD4 T cells and increased the expression of exhaustion markers. Furthermore, treatment increased the frequency of regulatory T cells in blood and inhibited the Th1-like phenotype that is characteristic of patients with multiple sclerosis, augmenting the expression of markers associated with increased suppressive function. Overall, our data suggest that Fingolimod performs other important immunomodulatory functions besides altering T cell migratory capacities, with consequences for other autoimmune pathologies characterized by excessive Th1/Th17 responses and Th1-like regulatory T cell effector phenotypes.

show abstract

Section: Discussionsupporting

confidence: 85%

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

Dominguez‐Villar

Raddassi

Danielsen

et al. 2019

Journal of Autoimmunity

View full text Add to dashboard Cite

show abstract

“…[40][41][42] In this 12M follow-up study, we determined the effect of Fingolimod on the frequency of different cytokine-producing CD4+ and CD8+ T cell subsets. Consistent with other studies, 29,40,43 we also found decreased percentages of both CD4+ and CD8+ T lymphocytes in the peripheral blood of MS patients with a predominant reduction in the CD4+ T cells.…”

Section: Discussionsupporting

confidence: 93%

Characterization of CD4+ and CD8+ T Cell Subsets and Interferon Regulatory Factor 4 (IRF4) in MS Patients Treated with Fingolimod (FTY-720): A Follow-up Study

Laribi

Sahraian

Shekarabi

et al. 2018

IJAAI

View full text Add to dashboard Cite

Fingolimod is a novel immunomodulatory drug used in patients with relapsing multiple sclerosis (MS) which reversibly inhibits egress of lymphocytes from lymph nodes. In this longitudinal study, the frequency of Interferon- gamma (IFN-γ)+, IL4+, IL17+ and IL10+ CD4+ and CD8+ T cell subsets were measured in Fingolimod treated patients before and after 12 months’(12M) therapy using flow cytometry and compared to those of naive, Betaferon treated MS patients and healthy individuals. Additionally, the level of transcription factor IRF4 and IL-6, IL-23, TGF-β1 cytokines, required for differentiation of IL-17+ T cells, were assessed by RT-PCR and ELISA, respectively. In Fingolimod treated MS patients, we observed a significant decrease in the percentage of IFN-γ+/IL17+ CD4+ and CD8+ T cell subsets. In contrast, Fingolimod increased IL10+ CD4+ T cells. We also showed that IFN-γ+IL17+ co-producing CD8+ T cells were reduced in patients under ﬁngolimod therapy. furthermore, Fingolimod could reduce the expression level of IRF4 in patients while IL6 was increased in the supernatant of cultured peripheral blood mononuclear cells. Our data showed that Fingolimod treatment alters CD4+ and CD8+ T cell subsets and reduces expression of IRF-4, which affects the proportion of pathogenic memory T cells in peripheral blood.

show abstract

“…Nevertheless, in the context of a possible clinical trial of the gefitinib-FTY720 combination in breast cancer patients, we investigated whether a FTY720 dose with antitumor efficacy in mice (in combination with gefitinib) would compromise the immune system. FTY720 inhibits T cell mobilization from lymphoid tissues [ 20 ], which in some patients can result in lymphopenia [ 32 , 47 ]. If this depletes tumor-resident lymphocytes it could potentially be deleterious to breast cancer patients undergoing therapy, since a high tumor-associated lymphocyte count is a positive predictor of treatment response [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade

et al. 2017

View full text Add to dashboard Cite

BackgroundNew molecular targets are needed for women with triple-negative breast cancer (TNBC). This pre-clinical study investigated the combination of the EGFR inhibitor gefitinib with the sphingosine kinase (SphK) inhibitor FTY720 (Fingolimod), aiming to block tumorigenic signaling downstream of IGFBP-3, which is abundantly expressed in basal-like TNBC.MethodsIn studies of breast cancer cell growth in culture, proliferation was monitored by IncuCyte live-cell imaging, and protein abundance was determined by western blotting. In vivo studies of mammary tumor growth used two models: orthotopic xenograft tumors derived from three basal-like TNBC cell lines, grown in immune-deficient mice, and syngeneic murine 4T1 tumors grown in immune-competent mice. Protein abundance in tumor tissue was assessed by immunohistochemistry.ResultsQuantitated by live-cell imaging, the inhibitor combination showed synergistic cytostatic activity in basal-like cell lines across several TNBC molecular subtypes, the synergy being decreased by IGFBP-3 downregulation. Suppression of the tumorigenic mediator CD44 by gefitinib was potentiated by FTY720, consistent with CD44 involvement in the targeted pathway. In MDA-MB-468 and HCC1806 orthotopic TNBC xenograft tumors in nude mice, the drug combination inhibited tumor growth and prolonged mouse survival, although this effect was not significant for the gefitinib-resistant cell line HCC70. Combination treatment of murine 4T1 TNBC tumors in syngeneic BALB/c mice was more effective in immune-competent than immune-deficient (nude) mice, and a relative loss of tumor CD3 (T-cell) immunoreactivity caused by FTY720 treatment alone was alleviated by the drug combination, suggesting that, even at an FTY720 dose causing relative lymphopenia, the combination is still effective in an immune-competent setting. Immunohistochemistry of xenograft tumors showed significant enhancement of caspase-3 cleavage and suppression of Ki67 and phospho-EGFR by the drug combination, but SphK1 downregulation occurred only in MDA-MB-468 tumors, so is unlikely to be integral to treatment efficacy.ConclusionsOur data indicate that targeting IGFBP-3-dependent signaling pathways through gefitinib-FTY720 co-therapy may be effective in many basal-like breast cancers, and suggest tissue IGFBP-3 and CD44 measurement as potential biomarkers of treatment efficacy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0882-x) contains supplementary material, which is available to authorized users.

show abstract

Influence of fingolimod on basic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosis patients – preliminary study

Cited by 22 publications

References 34 publications

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

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

Characterization of CD4+ and CD8+ T Cell Subsets and Interferon Regulatory Factor 4 (IRF4) in MS Patients Treated with Fingolimod (FTY-720): A Follow-up Study

Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade

Contact Info

Product

Resources

About