Cytokine changes during interferon-beta therapy in multiple sclerosis: Correlations with interferon dose and MRI response

University of Maryland School of Medicine, Department of Neurology, MD, USA.
Journal of Neuroimmunology (Impact Factor: 2.47). 04/2007; 185(1-2):168-74. DOI: 10.1016/j.jneuroim.2007.01.011
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We investigated serum (IL-10 and IL-12p70) and cellular cytokine levels (IL-10, IL-12p40, IL-12p70, IFN-gamma) in stimulated PBMC over 24 weeks in 15 relapsing-remitting multiple sclerosis (MS) patients randomized to receive once-weekly (qw) IFN-beta-1a 30 microg intramuscularly (IM) (n=8) or three-times-weekly (tiw) IFN-beta-1a 44 microg subcutaneously (SC) (n=7). Overall, IFN-beta treatment increased cellular IL-10 (p<0.01) levels and the ratios of cellular IL-10/IL-12p40 (p<0.01) and IL-10/IL-12p70 (p<0.02) while cellular IFN-gamma levels were reduced (p<0.01). Serum IL-10 levels were decreased in non-responders to therapy based on MRI-defined criteria (p<0.01) but did not change in responders over the course of treatment. In addition, non-responders demonstrated a decrease in serum IL-10/IL-12p70 ratio (p=0.031) and a decrease in cellular IL-12p70 (p<0.02). A decrease in cellular IFN-gamma was observed in responders (p=0.013). This is the first study that compares cytokine changes between the two IFN-beta regimes and demonstrates that serum IL-10 levels decrease in those patients who continue to have active MRI lesions while on interferon-beta therapy.

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Available from: Suhayl Dhib-Jalbut, Jul 29, 2015
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    • "Studies have shown that IFNγ and TNF-α levels are increased in MS and that these cytokines act as principal mediators of the inflammatory response and participate in the pathogenesis and progression of MS [5]. Moreover, TNF-α has been correlated with a worse disease prognosis [15] [63]. Ozaki et al. [46] showed that the presence of variant genotype from the TNF-β NcoI polymorphism was associated with 1.5-fold greater transcriptional activity of this gene to express the TNF-β, which contributes to the inflammatory process. "
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    ABSTRACT: To evaluate the association between the tumor necrosis factor beta (TNF-β) NcoI polymorphism and inflammatory and metabolic markers in patients with multiple sclerosis (MS) patients and the association of these markers with disease disability, a 782 base-pair fragment of the TNF-β gene was amplified from genomic DNA and digested with the NcoI restriction enzyme. The serum levels of numerous cytokines (IL-1β, IL-12, IL-6, TNF-α, IFN-γ, IL-4, IL-10, and IL-17) serum lipid levels, plasma insulin levels, and the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) levels were evaluated in 123 female and 43 male patients with MS. Females carrying the TNFB2/B2 genotype presented with decreased IL-4 and IL-10 levels and increased TNF-α, glucose, insulin, and HOMA-IR levels; moreover, there were positive correlations between EDSS and glucose and between EDSS and HOMA-IR in these females. Males carrying the TNFB2/B2 genotype exhibited increased levels of TNF-α, IFN-γ, and IL-17 (p=0.0326) and decreased levels of IL-4, IL-10, insulin, and HOMA-IR; there was a positive correlation between EDSS and TNF-α levels. The TNFB2/B2 genotype of TNF-β NcoI polymorphism was associated with increased inflammatory and metabolic markers and this association was different according to sex of MS patients.
    Journal of the neurological sciences 08/2014; 346(1-2). DOI:10.1016/j.jns.2014.08.016 · 2.47 Impact Factor
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    • "However, despite extensive research it is still not entirely clear how IFNβ exerts its beneficial effects in MS. Treatment with IFNβ in MS has been linked to the inhibition of cell migration [18], down-regulation of cell activation [19], [20], improvement of blood brain barrier (BBB) function [21] and regulation of pro and anti-inflammatory cytokine balance, including IL-1β [22], [23]. "
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    ABSTRACT: Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.
    PLoS ONE 06/2012; 7(6):e39576. DOI:10.1371/journal.pone.0039576 · 3.23 Impact Factor
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    • "IFN-β inhibits the inflammatory response at several ways. It decreases the expression of MHC molecules on APCs (Jiang et al., 1995), inhibits T cell activation (Dhib-Jalbut, 1997), reduces inflammatory cytokines such as IFN-γ and IL-17(Graber et al., 2007; Martin- Saavedra et al., 2008). Also, IFN-β has inhibitory effects on IL-12 production (Wang et al., 2000), deviates the immune response to antiinflammatory position (Dhib-Jalbut, 1997; Yong et al., 1998), by enhancing IL-10 secretion and IL-12 inhibition (Rep et al., 1999 "
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    ABSTRACT: Abstract Interferon-beta (IFN-beta) is an immunomodulatory drug of choice to control relapsing-remitting multiple sclerosis (RR-MS), although its function is still unclear. A reduced suppressive function of CD4(+)CD25(+) regulatory T cells (T(reg)) has been shown in RR-MS patients. In this study, to understand the effect of IFN-ss on CD4(+)CD25(+) regulatory T cells, we analyzed the frequency and function of these cells and Foxp3 gene expression before and after treatment. We evaluated the frequency and function of CD4(+)CD25(+)Foxp3(+) regulatory T cells by flow cytometry and co-culture inhibition test respectively and gene expression of Foxp3 by real-time PCR in a longitudinal follow-up study in 18 relapsing-remitting MS patients. Our data revealed that IFN-beta significantly improved frequency and suppressive function of T(reg) cells (P<0.05) without any significant effect on gene expression of Foxp3 after 6 months. The results of the present study indicate that IFN-beta therapy in some of patients with RR-MS may restore function of regulatory T cells and control the unchecked immune cascade activity. Larger longitudinal studies on more MS patients are required to confirm our findings.
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