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Cold Spring Harbor Perspectives in... Nov 2018Despite that the availability of new therapeutic options has expanded the multiple sclerosis (MS) disease-modifying therapy arsenal, interferon β (IFN-β) remains an... (Review)
Review
Despite that the availability of new therapeutic options has expanded the multiple sclerosis (MS) disease-modifying therapy arsenal, interferon β (IFN-β) remains an important therapy option in the current decision-making process. This review will summarize the present knowledge of IFN-β mechanism of action, the overall safety, and the short- and long-term efficacy of its use in relapsing remitting MS and clinically isolated syndromes. Data on secondary progressive MS is also provided, although no clear benefit was identified.
Topics: Biomarkers; Clinical Trials, Phase III as Topic; Disease Progression; Humans; Interferon-beta; Medication Adherence; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Polyethylene Glycols; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29311124
DOI: 10.1101/cshperspect.a032003 -
Frontiers in Immunology 2020Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive... (Review)
Review
Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive immunity and suppress proliferation of cancer cells. While much has been revealed about IFN-I, it remains a mystery as to why there are 16 different IFN-I gene products, including IFNβ, IFNω, and 12 subtypes of IFNα. Here, we discuss shared and unique aspects of these IFN-I in the context of their evolution, expression patterns, and signaling through their shared heterodimeric receptor. We propose that rather than investigating responses to individual IFN-I, these contexts can serve as an alternative approach toward investigating roles for IFNα subtypes. Finally, we review uses of IFNα and IFNβ as therapeutic agents to suppress chronic viral infections or to treat multiple sclerosis.
Topics: Antiviral Agents; Evolution, Molecular; Host Microbial Interactions; Humans; Immunologic Factors; Interferon Regulatory Factors; Interferon-alpha; Interferon-beta; Multiple Sclerosis; Signal Transduction; Virus Diseases
PubMed: 33542718
DOI: 10.3389/fimmu.2020.605673 -
Journal of Neuroscience Research Feb 2019Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen... (Review)
Review
Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US-FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon-beta (IFN-β), an endogenous cytokine and a key anti-inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN-β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN-β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN-β therapy that may be helpful in improving stroke outcome are also discussed.
Topics: Animals; Brain Ischemia; Humans; Interferon-beta; Stroke
PubMed: 30320448
DOI: 10.1002/jnr.24333 -
International Journal of Molecular... Oct 2022Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and...
Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 ( mice) in MOG-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFNβ-1a in mice resulted in less symptoms primarily in the chronic phase of EAE. mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS.
Topics: Mice; Animals; Interferon beta-1a; Encephalomyelitis, Autoimmune, Experimental; Brain-Derived Neurotrophic Factor; Neurodegenerative Diseases; Interferon-beta; Immunologic Factors; Oligodendroglia; Multiple Sclerosis; Fibroblast Growth Factors
PubMed: 36293040
DOI: 10.3390/ijms232012183 -
Critical Care (London, England) Mar 2023The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN β) for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN β) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN β, and therefore, we aimed at finding the reason behind this.
METHODS
We first sequenced the genes encoding the IFN α/β receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier: NCT02622724 , November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN β-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/β receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling.
RESULTS
We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/β receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN β treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN β and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database.
CONCLUSIONS
The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids.
Topics: Humans; Glucocorticoids; COVID-19; Interferon-beta; Respiratory Distress Syndrome; Interferon-alpha
PubMed: 36927455
DOI: 10.1186/s13054-023-04388-8 -
Trends in Immunology Jun 2011Interferon (IFN)-β is the treatment most often prescribed for relapsing-remitting multiple sclerosis (RRMS). 30-50% of MS patients, however, do not respond to IFN-β.... (Review)
Review
Interferon (IFN)-β is the treatment most often prescribed for relapsing-remitting multiple sclerosis (RRMS). 30-50% of MS patients, however, do not respond to IFN-β. In some cases, IFN-β exacerbates MS, and it consistently worsens neuromyelitis optica (NMO). To eliminate unnecessary treatment for patients who are non-responsive to IFN-β, and to avoid possible harm, researchers are identifying biomarkers that predict treatment outcome before treatment is initiated. These biomarkers reveal insights into the mechanisms of disease. Recent discoveries on human samples from patients with RRMS, NMO, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis, indicate that IFN-β is ineffective and might worsen clinical status in diverse diseases when a Th17 immune response is prominent.
Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Interferon-beta; Models, Immunological; Th17 Cells
PubMed: 21530402
DOI: 10.1016/j.it.2011.03.008 -
Neurotherapeutics : the Journal of the... Jan 2013Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our... (Review)
Review
Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led to their widespread use. We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures. Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis.
Topics: Glatiramer Acetate; Humans; Immunologic Factors; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Peptides
PubMed: 23264098
DOI: 10.1007/s13311-012-0163-4 -
Journal For Immunotherapy of Cancer Mar 2022Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The...
BACKGROUND
Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGFβ with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGFβ participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations.
METHODS
We used the clinically relevant TGFβ receptor 2 (TGFβR2)-neutralizing antibody MT1 and the small molecule TGFβR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer.
RESULTS
We demonstrated that TGFβ pathway inhibition strongly increased the efficacy of RT. TGFβR2 antibody upregulated interferon beta expression in tumor-associated macrophages within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and the increased lymphocyte infiltration observed with the combination of MT1 and RT were dependent on type I interferon signaling.
CONCLUSIONS
These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.
Topics: Animals; Cell Line, Tumor; Humans; Interferon-beta; Mice; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Tumor-Associated Macrophages
PubMed: 35301235
DOI: 10.1136/jitc-2021-003519 -
Cytokine Oct 2022Type I interferons (IFNs) are pleiotropic cytokines and impact various immune cells, including regulatory T cells (Treg cells). The effect of type-I IFNs on the...
Type I interferons (IFNs) are pleiotropic cytokines and impact various immune cells, including regulatory T cells (Treg cells). The effect of type-I IFNs on the development and function of Treg cells is quite controversial. Here we induced Treg cells (iTreg cells) from naïve CD4 T cells in vitro in the presence or absence of IFN-β to elucidate its direct effect on the induction of iTreg cells. We found that IFN-β suppressed the proliferation of iTreg cells but enhanced their expression of anti-apoptotic genes Bcl-2 and Mcl-1 during the development of iTreg cells. We also found that IFN-β promoted suppression of conventional T cell proliferation by iTreg cells. These results suggest that IFN-β promotes the survival and immunomodulatory function of iTreg cells.
Topics: Cell Proliferation; Cytokines; Forkhead Transcription Factors; Interferon-beta; T-Lymphocytes, Regulatory
PubMed: 36049243
DOI: 10.1016/j.cyto.2022.156009 -
JAMA Network Open Sep 2022With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS).
OBJECTIVE
To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS.
DESIGN, SETTING, AND PARTICIPANTS
The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021.
INTERVENTIONS
Patients were randomized to DMF or IFNβ-1a.
MAIN OUTCOMES AND MEASURES
The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group.
RESULTS
Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a.
CONCLUSIONS AND RELEVANCE
This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02283853.
Topics: Adolescent; Child; Dimethyl Fumarate; Female; Humans; Interferon beta-1a; Interferon-beta; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Neoplasm Recurrence, Local
PubMed: 36169959
DOI: 10.1001/jamanetworkopen.2022.30439