Including Interferon Beta Research Articles

Induction of DNA Damage in Ovarian Cancer Induces Type I Interferon Signaling

ObjectiveEpithelial ovarian cancer patients initially respond to cytotoxic chemotherapy, however the majority develop recurrent disease that is resistant to current treatments and 5‐year survival is less than 50%. Immunotherapies have shown promise in some solid tumors, yet response rates in ovarian cancer are only 10–15%. We therefore sought to identify new approaches to increase ovarian cancer tumor immunogenicity with the goal of improving immunotherapy response rates. We previously found that the DNA damage repair protein DEK is overexpressed in ovarian cancer cell lines and primary tumors, and that decreasing DEK levels induces DNA damage and apoptotic cell death. Cytoplasmic DNA from damaged cells can activate the DNA‐sensing protein STING, resulting in induction of the type I interferon (IFN‐I) signaling pathway that facilitates antigen‐presenting cell (APC) maturation and cross‐priming of T cells. Therefore, our objective was to determine if decreasing DEK levels induces IFN‐I signaling to enhance ovarian cancer immune signaling.MethodsWe developed a new machine learning tool, Fast and Robust Deconvolution of Expression Profiles (FARDEEP) to characterize the landscape of tumor‐infiltrating lymphocytes (TIL) in 299 high grade serous ovarian cancers from the Cancer Genome Atlas (TCGA). We then performed RNA‐Seq analysis on OVCAR8 and OVCAR3 ovarian cancer cell lines with stable expression of shRNA targeting DEK (shDEK) or control shRNA. Gene expression patterns were analyzed by Gene Set Enrichment Analysis and confirmed by RT‐PCR. In addition, IFN‐I signature transcripts were further validated by RT‐PCR after ovarian cancer cell lines were infected with lentivirus expressing shDEK or control. ID8 cells from an immunocompetent ovarian cancer mouse model were analyzed by RT‐PCR for IFN‐I signatures after being transfected with siRNA targeting Dek or control without or with Sting expression plasmid.ResultsFARDEEP analysis demonstrated that elevated levels of IFN‐I signature genes including CXC chemokines CXCL9 and CXCL10 are correlated with TIL subsets essential for anti‐tumor immunity, indicating IFN‐I signaling is important in preventing ovarian cancer immune escape. RNA‐Seq in ovarian cancer cell lines revealed that decreasing DEK levels resulted in an upregulation of interferon response signals. Further evaluation of IFN‐I signaling demonstrated that decreasing DEK levels enhanced transcription of IFN‐I signature genes, including interferon beta 1 (IFNB1), CXCL9 and CXCL10. In addition, Dek‐deficiency in ID8 cells enhanced Sting‐mediated induction of Ifnb1, Cxcl9 and Cxcl10.ConclusionOur TIL deconvolution findings support the hypothesis that IFN‐I signaling is pivotal for the immunogenicity of ovarian cancer. Decreasing DEK expression induces DNA damage and resultant IFN‐I signaling. Further studies are underway with the ID8 ovarian cancer mouse model system. Our results suggest a potential approach to increase immune signaling in the tumor microenvironment and thus improve response rates to immunomodulatory therapies in ovarian cancer.Support or Funding InformationMichigan Ovarian Cancer Alliance Geri Fournier Ovarian Cancer Research AwardsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of teriflunomide on QuantiFERON-TB Gold results.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by damage to myelin and axons, over time leading to progressive neuronal degeneration and microglial activation. There is still no curative treatment, but during the last 20years eight different therapies have become available including interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab, fingolimod, alemtuzumab, mitoxantrone and teriflunomide. Teriflunomide is an immunomodulatory drug that exerts an inhibitory effect on T cell activation in central nervous system of the patients with multiple sclerosis. We determined whether teriflunomide affect the production of interferon-gamma, interleukin-2 and tumor-necrosis-factor-α in the QuantiFERON-TB in-Tube-assay. Blood from 24 adults with latent tuberculosis infection was added to one standard set of QuantiFERON tubes and one further set containing teriflunomide. Teriflunomide resulted in a change in QuantiFERON results from positive to negative in four patients with a marked reduction in interferon-γ. Our data indicated that results from QuantiFERON in patients on teriflunomide therapy should be interpreted with caution.

Impact of Disease-Modifying Therapies on the Survival of Patients with Multiple Sclerosis in Taiwan, 1997–2008

Little is known about the impact of disease-modifying therapies (DMTs) on the survival of patients with multiple sclerosis (MS) throughout the world. We conducted this study to investigate the association between DMTs and the survival of patients with MS in Taiwan. A total of 1,240 individuals who had a primary diagnosis of MS and a seriously disabling disease certificate in Taiwan between 1 January 1997 and 1 December 2008 were followed up until 31 December 2009 to check what medical services were provided to them and whether they had a date of death recorded in the national mortality database. Disease-modifying therapies, including interferon beta 1-a, interferon beta 1-b and glatiramer acetate, were included in the analysis. Follow-up information was available on all individuals; the mean follow-up time was 54.3 months (standard deviation [SD] 38.8 months). A Cox regression model was utilized to reveal the effect of DMTs on MS mortality by controlling for sex, age, residence, insurance amount and geographic region. Eighty-eight of the 1,240 individuals (7.1 %) died. The risk of mortality in the first year showed a 7-fold age- and sex-standardized mortality rate increase over that of the general population in Taiwan. In the fully adjusted model, the final independent risk factors were older age, rural residence, lower economic status and lower adherence to DMTs. The results of this study support the notion that DMTs can improve the survival of patients with MS, and show that individuals with the risk factors of older age, rural residence and lower economic status had a higher MS-related mortality risk in Taiwan.

Treatment Options in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that results in inflammation, demyelination, and axonal and neuronal loss. The typical course of MS is one of symptom exacerbations followed by periods of remission; however, patients will eventually accrue disability from the exacerbations. Several drugs, including interferon beta, glatiramer acetate, natalizumab, and fingolimod, are effective in lowering relapse rates and slowing the progression of MS. For patients with suboptimal response to medication, switching to another first- or second-line medication can be an effective strategy.

Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults

The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]). From 2003 to 2010, 45 patients (ages 8-20 years), including 1 patient with stage II NPC and 44 patients with stage III/IV NPC, were recruited to the study. The patient with stage II disease received radiotherapy (59.4 grays [Gy]). The patients with stage III/IV disease received 3 courses of neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and folinic acid. The cumulative irradiation dose was 54 Gy in 5 patients, who achieved complete remission after neoadjuvant chemotherapy, and 59.4 Gy in the remaining 40 patients. All patients received concomitant cisplatin during the first week and last week of irradiation. After irradiation, all patients received interferon beta for 6 months. Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans. After the completion of treatment, 43 of 45 patients were in complete remission. In 2 patients, only a partial response was achieved, followed by distant metastases (1 patient) or local progression and distant metastases (1 patient), 6 months and 10 months after diagnosis, respectively. Another patient developed a solitary pelvic bone metastasis 21 months after diagnosis. After a median follow-up of 30 months (range, 6-95 months), the event-free survival rate was 92.4%, and the overall survival was 97.1%. Acute toxicity consisted mainly of leucopenia, mucositis, and nausea; and late toxicity consisted of hearing loss and hypothyroidism. Combined therapy with neoadjuvant chemotherapy, radiochemotherapy, and interferon beta was well tolerated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups.

PEGylated Interferon Beta-1a: Meeting an Unmet Medical Need in the Treatment of Relapsing Multiple Sclerosis

Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex®, Rebif®, and Betaseron/Betaferon®), glatiramer acetate (Copaxone®), and an anti-VLA4 monoclonal antibody (Tysabri®). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patient's decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125 microg administered via the subcutaneous route every 2 or 4 weeks.

Diagnostic potential of plasma carboxymethyllysine and carboxyethyllysine in multiple sclerosis

BackgroundThis study compared the level of advanced glycation end products (AGEs), N-(Carboxymethyl)lysine (CML) and N-(Carboxyethyl)lysine (CEL), in patients with multiple sclerosis (MS) and healthy controls (HCs), correlating these markers with clinical indicators of MS disease severity.MethodsCML and CEL plasma levels were analyzed in 99 MS patients and 43 HCs by tandem mass spectrometry (LC/MS/MS). Patients were stratified based on drug modifying therapies (DMTs) including interferon beta, glatiramer acetate and natalizumab.ResultsThe level of plasma CEL, but not CML, was significantly higher in DMT-naïve MS patients when compared to HCs (P < 0.001). Among MS patients, 91% had higher than mean plasma CEL observed in HCs. DMTs reduced CML and CEL plasma levels by approximately 13% and 40% respectively. CML and CEL plasma levels correlated with the rate of MS clinical relapse.ConclusionOur results suggest that AGEs in general and CEL in particular could be useful biomarkers in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma level of AGEs and MS disease pathology. These studies will pave the way for use of AGE inhibitors and AGE-breaking agents as new therapeutic modalities in MS.

Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis

Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis

Sirs: Relapsing neuromyelitis optica (RNMO) is characterised by recurrent longitudinally extensive myelitis (RLEM) and severe optic neuritis [5, 7, 10, 14]. The effects of disease-modifying therapies, including interferon beta (IFNβ), have not been fully established in RNMO or RLEM [15]. The neuromyelitis optica immunoglobulin G (NMO-IgG) auto-antibody (Ab) is a marker for NMO [3], which binds to the aquaporin 4 (AQP4) water channel protein [2]. AntiAQP4 antibody titres may have implications in diagnosing NMO [13]. We report two cases of RNMO or RLEM with anti-AQP4 Ab, in which extensive (tumefactive) brain lesions developed within 2 months after initiation of IFNβ-1b.

Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-β induction

The host innate response to viral infection includes the production of interferons, which is dependent on the coordinated activity of multiple transcription factors. Herpes simplex virus 1 (HSV-1) has been shown to block efficient interferon expression by multiple mechanisms. We and others have demonstrated that HSV-1 can inhibit the transcription of genes promoted by interferon regulatory factor-3 (IRF-3), including interferon beta (IFN-β), and that the immediate–early ICP0 protein is sufficient for this function. However, the exact mechanism by which ICP0 blocks IRF-3 activity has yet to be determined. Unlike some other viral proteins that inhibit IRF-3 activity, ICP0 does not appear to affect phosphorylation and dimerization of IRF-3. Here, we show that a portion of activated IRF-3 co-localizes with nuclear foci containing ICP0 at early times after virus infection. Co-localization to ICP0-containing foci is also seen with the IRF-3-binding partners and transcriptional co-activators, CBP and p300. In addition, using immunoprecipitation of infected cell lysates, we can immunoprecipitate a complex containing ICP0, IRF-3, and CBP. Thus we hypothesize that ICP0 recruits activated IRF-3 and CBP/p300 to nuclear structures, away from the host chromatin. This leads to the inactivation and accelerated degradation of IRF-3, resulting in reduced transcription of IFN-β and an inhibition of the host response. Therefore, ICP0 provides an example of how viruses can block IFN-β induction by sequestration of important transcription factors essential for the host response.

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses

The persistent nature of hepatitis C virus (HCV) infection suggests that HCV encodes proteins that enable it to overcome host antiviral responses. Toll-like receptor 3 (TLR3)-mediated signaling, which recognizes the double-stranded RNA that is produced during viral replication and induces type I interferons, including interferon beta (IFN-beta), is crucial to the host defense against viruses. Recent studies suggest that a TIR domain-containing adaptor protein, TRIF, and two protein kinases, TANK-binding kinase-1 (TBK1) and IkappaB kinase-epsilon (IKKepsilon), play essential roles in TLR3-mediated IFN-beta production through the activation of the transcriptional factor interferon regulatory factor 3 (IRF-3). We report that the HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of IRF-3 activation. In conclusion, these results suggest the mechanisms of the inhibition of the innate immune responses of HCV infection by NS3 protein.

Neutralizing antibodies to disease-modifying agents in the treatment of multiple sclerosis

Protein- and peptide-based disease-modifying agents for multiple sclerosis (MS), including interferon beta (IFNbeta) and glatiramer acetate (GA), have been associated with the formation of antibodies. Neutralizing antibodies (NAbs) block or neutralize the biological effects of the protein or polypeptide, potentially decreasing the therapeutic effects of these agents. Although the clinical relevance of antibodies against GA requires further investigation; both the incidence of NAbs to the three IFNbeta products (IFNbeta1b-Betaseron, IFNbeta1a-Rebif, and IFNbeta1a-Avonex) and the clinical relevance are quite clear. Data from clinical trials of IFNbeta products show that the immunogenicity of Betaseron > Rebif > Avonex and persistent NAbs reduce the clinical efficacy of IFNbeta. Because the initial detection of NAbs in the serum of patients receiving IFNbeta usually occurs between 6 and 15 months and appears to precede any apparent reduction in clinical efficacy by approximately 6 to 12 months, trials with a duration of less than 3 years are problematic when the clinical impact of NAbs is assessed. The potential development of NAbs is an important consideration in selection and monitoring treatment of MS. Long-term prospective studies are needed to further define the clinical effects of NAbs on patients receiving disease-modifying therapies for MS.

In vitro combined effects of a triazene compound and interferon-beta on natural immunity against lymphoblastoid cells: studies at effector and target cell level.

It was shown that Dacarbazine and other triazene compounds render murine leukemias highly immunogenic and susceptible to natural immunity (NI). In addition a pilot clinical study revealed that Dacarbazine can be cytotoxic for bone marrow blasts in patients with acute non-lymphoblastic leukemias through a mechanism that could be, at least in part, of immunological origin. However triazenes depress antigen-dependent responses and NI, whereas interferons, including interferon-beta (IFN), antagonize drug-induced impairment of NI. Therefore the complex interaction between triazenes and IFN on NI effector (i.e. NK) lymphocytes and human target lymphoblastoid cells has been investigated. The results show that: (a) IFN increases NK activity and antagonizes the depressive effects of methyl-triazene-benzoic acid (MTBA, an in vitro active triazene compound) on the NK function; (b) a lymphoblastoid cell line exposed to multiple in vitro treatments with MTBA, shows increased growth rate, augmented chemoresistance to MTBA, and higher susceptibility to NI than parental cells; (c) as expected IFN pretreatment down-regulates the susceptibility of lymphoblastoid cells to NK effectors; (d) however a net "therapeutic gain" was found if the overall influence of MTBA+IFN on target and effector cells is considered.