Constitutively Active MAVS Inhibits HIV-1 Replication via Type I Interferon Secretion and Induction of HIV-1 Restriction Factors.

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Sachin Gupta

Full Text Available Type I interferon is known to inhibit HIV-1 replication through the induction of interferon stimulated genes (ISG, including a number of HIV-1 restriction factors. To better understand interferon-mediated HIV-1 restriction, we constructed a constitutively active form of the RIG-I adapter protein MAVS. Constitutive MAVS was generated by fusion of full length MAVS to a truncated form of the Epstein Barr virus protein LMP1 (ΔLMP1. Supernatant from ΔLMP1-MAVS-transfected 293T cells contained high levels of type I interferons and inhibited HIV replication in both TZM-bl and primary human CD4+ T cells. Supernatant from ΔLMP1-MAVS-transfected 293T cells also inhibited replication of VSV-G pseudotyped single cycle SIV in TZM-bl cells, suggesting restriction was post-entry and common to both HIV and SIV. Gene array analysis of ΔLMP1-MAVS-transfected 293T cells and trans-activated CD4+ T cells showed significant upregulation of ISG, including previously characterized HIV restriction factors Viperin, Tetherin, MxB, and ISG56. Interferon blockade studies implicated interferon-beta in this response. In addition to direct viral inhibition, ΔLMP1-MAVS markedly enhanced secretion of IFN-β and IL-12p70 by dendritic cells and the activation and maturation of dendritic cells. Based on this immunostimulatory activity, an adenoviral vector (Ad5 expressing ΔLMP1-MAVS was tested as a molecular adjuvant in an HIV vaccine mouse model. Ad5-Gag antigen combined with Ad5-ΔLMP1-MAVS enhanced control of vaccinia-gag replication in a mouse challenge model, with 4/5 animals showing undetectable virus following challenge. Overall, ΔLMP1-MAVS is a promising reagent to inhibit HIV-1 replication in infected tissues and enhance vaccine-mediated immune responses, while avoiding toxicity associated with systemic type I interferon administration.

Interferon-γ Inhibits Ebola Virus Infection.

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Bethany A Rhein

Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

Interferon-γ Inhibits Ebola Virus Infection.

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Rhein, Bethany A; Powers, Linda S; Rogers, Kai; Anantpadma, Manu; Singh, Brajesh K; Sakurai, Yasuteru; Bair, Thomas; Miller-Hunt, Catherine; Sinn, Patrick; Davey, Robert A; Monick, Martha M; Maury, Wendy

2015-01-01

Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

Toscana virus NSs protein inhibits the induction of type I interferon by interacting with RIG-I.

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Gori-Savellini, Gianni; Valentini, Melissa; Cusi, Maria Grazia

2013-06-01

Toscana virus (TOSV) is a phlebovirus, of the Bunyaviridae family, that is responsible for central nervous system (CNS) injury in humans. Previous data have shown that the TOSV NSs protein is a gamma interferon (IFN-β) antagonist when transiently overexpressed in mammalian cells, inhibiting IRF-3 induction (G. Gori Savellini, F. Weber, C. Terrosi, M. Habjan, B. Martorelli, and M. G. Cusi, J. Gen. Virol. 92:71-79, 2011). In this study, we investigated whether an upstream sensor, which has a role in the signaling cascade leading to the production of type I IFN, was involved. We found a significant decrease in RIG-I protein levels in cells overexpressing TOSV NSs, suggesting that the nonstructural protein interacts with RIG-I and targets it for proteasomal degradation. In fact, the MG-132 proteasome inhibitor was able to restore IFN-β promoter activation in cells expressing NSs, demonstrating the existence of an evasion mechanism based on inhibition of the RIG-I sensor. Furthermore, a C-terminal truncated NSs protein (ΔNSs), although able to interact with RIG-I, did not affect the RIG-I-mediated IFN-β promoter activation, suggesting that the NSs domains responsible for RIG-I-mediated signaling and interaction with RIG-I are mapped on different regions. These results contribute to identify a novel mechanism for bunyaviruses by which TOSV NSs counteracts the early IFN response.

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients.

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Helal, Gouda Kamel; Gad, Magdy Abdelmawgoud; Abd-Ellah, Mohamed Fahmy; Eid, Mahmoud Saied

2016-12-01

The therapeutic effect of pegylated interferon (peg-IFN) alfa-2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa-2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa-2a (160 μg) subcutaneous once weekly and oral weight-based ribavirin (1000-1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170-2178, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

Science.gov (United States)

Noh, G; Jang, E H

2014-01-01

Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

Interferon induction in bovine and feline monolayer cultures by four bluetongue virus serotypes.

OpenAIRE

Fulton, R W; Pearson, N J

1982-01-01

The interferon inducing ability of bluetongue viruses was studied in bovine and feline monolayer cultures inoculated with each of four bluetongue virus serotypes. Interferon was assayed by a plaque reduction method in monolayer cultures with vesicular stomatitis virus as challenge virus. Interferon was produced by bovine turbinate, Georgia bovine kidney, and Crandell feline kidney monolayer cultures in response to bluetongue virus serotypes 10, 11, 13 and 17. The antiviral substances produced...

Overlapping positive and negative regulatory domains of the human β-interferon gene

International Nuclear Information System (INIS)

Goodbourn, S.; Maniatis, T.

1988-01-01

Virus of poly(I) x poly(C) induction of human β-interferon gene expression requires a 40-base-pair DNA sequence designated the interferon gene regulatory element (IRE). Previous studies have shown that the IRE contains both positive and negative regulatory DNA sequences. To localize these sequences and study their interactions, the authors have examined the effects of a large number of single-base mutations within the IRE on β-interferon gene regulation. They find that the IRE consists of two genetically separable positive regulatory domains and an overlapping negative control sequence. They propose that the β-interferon gene is switched off in uninduced cells by a repressor that blocks the interaction between one of the two positive regulatory sequences and a specific transcription factor. Induction would then lead to inactivation or displacement of the repressor and binding of transcription factors to both positive regulatory domains

Differential expression of interferon-gamma and interferon-gamma-inducing cytokines in Thai patients with scrub typhus or leptospirosis

NARCIS (Netherlands)

Chierakul, Wirongrong; de Fost, Maaike; Suputtamongkol, Yupin; Limpaiboon, Roongreung; Dondorp, Arjen; White, Nicholas J.; van der Poll, Tom

2004-01-01

Interferon (IFN)-gamma plays an important role in the induction of a type 1 immune response against intracellular pathogens. We compared the plasma levels of IFN-gamma and IFN-gamma-inducing cytokines in adult Thai patients with scrub typhus, caused by the obligate intracellular bacterium Orientia

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Science.gov (United States)

Yoo, S H; Kwon, J H; Nam, S W; Kim, H Y; Kim, C W; You, C R; Choi, S W; Cho, S H; Han, J-Y; Song, D S; Chang, U I; Yang, J M; Lee, H L; Lee, S W; Han, N I; Kim, S-H; Song, M J; Hwang, S; Sung, P S; Jang, J W; Bae, S H; Choi, J Y; Yoon, S K

2018-04-16

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response. © 2018 John Wiley & Sons Ltd.

A Versatile Vector for In Vivo Monitoring of Type I Interferon Induction and Signaling.

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Estanislao Nistal-Villan

Full Text Available Development of reporter systems for in vivo examination of IFN-β induction or signaling of type I interferon (IFN-I pathways is of great interest in order to characterize biological responses to different inducers such as viral infections. Several reporter mice have been developed to monitor the induction of both pathways in response to different agonists. However, alternative strategies that do not require transgenic mice breeding have to date not been reported. In addition, detection of these pathways in vivo in animal species other than mice has not yet been addressed. Herein we describe a simple method based on the use of an adeno-associated viral vector (AAV8-3xIRF-ISRE-Luc containing an IFN-β induction and signaling-sensitive promoter sequence controlling the expression of the reporter gene luciferase. This vector is valid for monitoring IFN-I responses in vivo elicited by diverse stimuli in different organs. Intravenous administration of the vector in C57BL/6 mice and Syrian hamsters was able to detect activation of the IFN pathway in the liver upon systemic treatment with different pro-inflammatory agents and infection with Newcastle disease virus (NDV. In addition, intranasal instillation of AAV8-3xIRF-ISRE-Luc showed a rapid and transient IFN-I response in the respiratory tract of mice infected with the influenza A/PR8/34 virus lacking the NS1 protein. In comparison, this response was delayed and exacerbated in mice infected with influenza A/PR/8 wild type virus. In conclusion, the AAV8-3xIRF-ISRE-Luc vector offers the possibility of detecting IFN-I activation in response to different stimuli and in different animal models with no need for reporter transgenic animals.

Inhibition of interferon production in human fibroblasts by a tumor promoting phorbol ester

International Nuclear Information System (INIS)

Frankfort, H.M.; Vilcek, J.

1982-01-01

The effect of 12-0-tetradecanoylphorbol-13-acetate (TPA) on the induction of interferon in cultures of human fibroblasts was examined. TPA was found to inhibit polyinosinate-polycytidylate [poly(I) X poly(C)]-induced interferon production when added either before or with the inducer. A 3-hour pretreatment of FS-4 cells with TPA produced the greatest ihibitory effect. Partially inhibitory treatments with TPA caused a delay in interferon production. On the other hand, interferon yields were slightly enhanced by TPA added at 1 1/2 or 3 hours postinduction. No gross metabolic perturbations (e.g., inhibition of cellular protein or RNA synthesis) were detected which would explain the phenomenon. The inhibition of interferon production was a stereospecific event: biologically inactive derivatives of TPA (4-0-methyl TPA, 4-α-phorbol-12, 13-didecanoate and phorbol-12, 13-diacetate) had no effect on interferon production. Cellular proteases or nucleases did not appear to be involved in this process. The binding of labeled poly(I) X poly(C) to FS-4 cells was unaltered in TPA-treated cultures. In superinduced cultures (i.e., after enhancement of interferon yields by actinomycin D and cycloheximide), interferon production was generally less inhibited by TPA than after simple induction. Newcastle disease virus (NDV)-induced interferon synthesis in GM-258 cells was also inhibited by the phorbol ester. Both α (leukocyte) and β (fibroblast) interferon production was inhibited to a similar degree in TPA-treated cells inoculated with 0.1 or 1 plaque forming unit (PFU) of NDV per cell. Increasing the multiplicity of infection with NDV to 10 PFU per cell overcame the inhibitory action of TPA. We conclude that the site of TPA action is either the triggering (generation of the hypothetical inducing signal) or transcription of the interferom mRNA. (Author)

Type I interferon induction is detrimental during infection with the Whipple's disease bacterium, Tropheryma whipplei.

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Khatoun Al Moussawi

2010-01-01

Full Text Available Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease, Tropheryma whipplei, we found that T. whipplei induced M2 macrophage polarization which was compatible with bacterial replication. Surprisingly, this M2 polarization of infected macrophages was associated with apoptosis induction and a functional type I interferon (IFN response, through IRF3 activation and STAT1 phosphorylation. Using macrophages from mice deficient for the type I IFN receptor, we found that this type I IFN response was required for T. whipplei-induced macrophage apoptosis in a JNK-dependent manner and was associated with the intracellular replication of T. whipplei independently of JNK. This study underscores the role of macrophage polarization in host responses and highlights the detrimental role of type I IFN during T. whipplei infection.

Predictive value of early viriological response for sustained viriological response in chronic hepatitis c with conventional interferon therapy

International Nuclear Information System (INIS)

Awan, A.; Umar, M.; Khaar, H.T.B.; Kulsoom, A.; Minhas, Z.; Ambreen, S.; Habib, N.; Mumtaz, W.; Habib, F.

2016-01-01

Background: Hepatitis is a major public health problem in Pakistan due to its strong association with liver failure and hepatocellular carcinoma. In Pakistan, conventional interferon therapy along with Ribavirin is favoured especially in Government funded programs for treatment of Hepatitis C, over the more expensive Pegylated Interferon and Ribavirin combination therapy as recommended by Pakistan society of Gastroenterology and GI endoscopy due to its favourable results observed in genotype 3 which is the dominant genotype of this region. Objective of our study was to assess the viriological responses with standard interferon therapy and to determine the predictive values of early viriological response (EVR) for Sustained Viriological Response (SVR) in chronic hepatitis C patients treated with standard interferon therapy. Methods: A cross sectional study was conducted on patients with chronic hepatitis C having received standard interferon and ribavirin therapy for six months. EVR and SVR were noted for analysis. Positive and negative predictive values of EVR on SVR were calculated. Results: Out of the total sample (N=3075), 1946 (63.3 percentage) patients were tested for EVR. 1386 (71.2 percentage) were positive while 560 (28.8 percentage) were negative while 516 (16.8 percentage) were tested for SVR. Two hundred and eighty-five (55.2 percentage) were positive while 231 (44.8 percentage) were negative. EVR and SVR tested were N=117. Positive predictive value of EVR on SVR was 67.1 percentage and negative predictive value was 65.8 percentage. Statistically significant association between EVR and SVR was determined with Chi square statistic of 11.8 (p-value <0.0001). Conclusion: EVR is a good predictor of response of patients to standard interferon and ribavirin therapy. In the absence of an EVR, it seems imperative to stop further treatment. Virilogical responses with conventional interferon therapy are comparable to those of pegylated interferon therapy so

Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4.

Science.gov (United States)

Andrade, Warrison A; Agarwal, Sarika; Mo, Shunyan; Shaffer, Scott A; Dillard, Joseph P; Schmidt, Tobias; Hornung, Veit; Fitzgerald, Katherine A; Kurt-Jones, Evelyn A; Golenbock, Douglas T

2016-06-14

The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS(-/-) and TLR4(-/-) cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection. Copyright © 2016. Published by Elsevier Inc.

Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4

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Warrison A. Andrade

2016-06-01

Full Text Available The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC. Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS, which produces 2′3′-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS−/− and TLR4−/− cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection.

Early bichemical markers of effects: Enzyme induction, oncogene activation and markers of oxidative damage

DEFF Research Database (Denmark)

Poulsen, Henrik E.; Loft, Steffen

1995-01-01

Early bichemical marker, enzyme induction, oncogene activation, oxidative damage, low-density lipoprotein......Early bichemical marker, enzyme induction, oncogene activation, oxidative damage, low-density lipoprotein...

Improving Performance and Operational Stability of Porcine Interferon-α Production by Pichia pastoris with Combinational Induction Strategy of Low Temperature and Methanol/Sorbitol Co-feeding.

Science.gov (United States)

Gao, Min-Jie; Zhan, Xiao-Bei; Gao, Peng; Zhang, Xu; Dong, Shi-Juan; Li, Zhen; Shi, Zhong-Ping; Lin, Chi-Chung

2015-05-01

Various induction strategies were investigated for effective porcine interferon-α (pIFN-α) production by Pichia pastoris in a 10 L fermenter. We found that pIFN-α concentration could be significantly improved with the strategies of low-temperature induction or methanol/sorbitol co-feeding. On this basis, a combinational strategy of induction at lower temperature (20 °C) with methanol/sorbitol co-feeding has been proposed for improvement of pIFN-α production. The results reveal that maximal pIFN-α concentration and antiviral activity reach the highest level of 2.7 g/L and 1.8 × 10(7) IU/mg with the proposed induction strategy, about 1.3-2.1 folds higher than those obtained with other sub-optimal induction strategies. Metabolic analysis and online multi-variable measurement results indicate that energy metabolic enrichment is responsible for the performance enhancement of pIFN-α production, as a large amount of ATP could be simultaneously produced from both formaldehyde oxidation pathway in methanol metabolism and tricarboxylic acid (TCA) cycle in sorbitol metabolism. In addition, the proposed combinational induction strategy enables P. pastoris to be resistant to high methanol concentration (42 g/L), which conceivably occur associating with the error-prone methanol over-feeding. As a result, the proposed combinational induction strategy simultaneously increased the targeted protein concentration and operational stability leading to significant improvement of pIFN-α production.

Our experiences with the induction of opioids for early laryngeal cancer

International Nuclear Information System (INIS)

Sueta, Takayuki; Fukuzaki, Tsutomu; Onishi, Yoshiki; Sugamura, Mayumi; Miyagi, Morimichi; Nakagawa, Takashi; Takase, Hisamitsu

2012-01-01

Radiotherapy and chemo-radiotherapy are generally effective for early laryngeal cancer. However, the local pain due to the mucositis induced by the irradiation often prevents the completion of treatment. Since 2005, we have administrated an opioid to control a pain if necessary. We divided 40 early laryngeal cancer patients into 2 groups of 20 patients, and the influence of treatment with the opioid was investigated in the two groups. One group received the induction of the opioid, and patients were treated from 2008 to 2010. The others were treated before 2004 and did not receive the opioid. Both groups frequently used various painkillers, however, the time after the initiation of treatment when subjects began taking the painkiller was shorter for the after induction group than the before induction group. Ten percent of patients paused radiation treatment in the after induction group, and 70% had to temporarily stop treatment in the before induction group. Thus, the interruption of radiation was significantly less frequent in the after induction group than the before induction group. Our results indicate that the introduction of opioids for radiation patients improved the course of cancer treatment. (author)

Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

Science.gov (United States)

Nakagawa, Shin-ichiro; Hirata, Yuichi; Kameyama, Takeshi; Tokunaga, Yuko; Nishito, Yasumasa; Hirabayashi, Kazuko; Yano, Junichi; Ochiya, Takahiro; Tateno, Chise; Tanaka, Yasuhito; Mizokami, Masashi; Tsukiyama-Kohara, Kyoko; Inoue, Kazuaki; Yoshiba, Makoto; Takaoka, Akinori; Kohara, Michinori

2013-01-01

The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

The structure of classical swine fever virus N(pro: a novel cysteine Autoprotease and zinc-binding protein involved in subversion of type I interferon induction.

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Keerthi Gottipati

Full Text Available Pestiviruses express their genome as a single polypeptide that is subsequently cleaved into individual proteins by host- and virus-encoded proteases. The pestivirus N-terminal protease (N(pro is a cysteine autoprotease that cleaves between its own C-terminus and the N-terminus of the core protein. Due to its unique sequence and catalytic site, it forms its own cysteine protease family C53. After self-cleavage, N(pro is no longer active as a protease. The released N(pro suppresses the induction of the host's type-I interferon-α/β (IFN-α/β response. N(pro binds interferon regulatory factor-3 (IRF3, the key transcriptional activator of IFN-α/β genes, and promotes degradation of IRF3 by the proteasome, thus preventing induction of the IFN-α/β response to pestivirus infection. Here we report the crystal structures of pestivirus N(pro. N(pro is structurally distinct from other known cysteine proteases and has a novel "clam shell" fold consisting of a protease domain and a zinc-binding domain. The unique fold of N(pro allows auto-catalysis at its C-terminus and subsequently conceals the cleavage site in the active site of the protease. Although many viruses interfere with type I IFN induction by targeting the IRF3 pathway, little information is available regarding structure or mechanism of action of viral proteins that interact with IRF3. The distribution of amino acids on the surface of N(pro involved in targeting IRF3 for proteasomal degradation provides insight into the nature of N(pro's interaction with IRF3. The structures thus establish the mechanism of auto-catalysis and subsequent auto-inhibition of trans-activity of N(pro, and its role in subversion of host immune response.

Differential induction of Toll-like receptors & type 1 interferons by Sabin attenuated & wild type 1 polioviruses in human neuronal cells.

Science.gov (United States)

Mohanty, Madhu C; Deshpande, Jagadish M

2013-01-01

Polioviruses are the causative agent of paralytic poliomyelitis. Attenuated polioviruses (Sabin oral poliovirus vaccine strains) do not replicate efficiently in neurons as compared to the wild type polioviruses and therefore do not cause disease. This study was aimed to investigate the differential host immune response to wild type 1 poliovirus (wild PV) and Sabin attenuated type 1 poliovirus (Sabin PV) in cultured human neuronal cells. By using flow cytometry and real time PCR methods we examined host innate immune responses and compared the role of toll like receptors (TLRs) and cytoplasmic RNA helicases in cultured human neuronal cells (SK-N-SH) infected with Sabin PV and wild PV. Human neuronal cells expressed very low levels of TLRs constitutively. Sabin PV infection induced significantly higher expression of TLR3, TLR7 and melanoma differentiation-associated protein-5 (MDA-5) m-RNA in neuronal cells at the beginning of infection (up to 4 h) as compared to wild PV. Further, Sabin PV also induced the expression of interferon α/β at early time point of infection. The induced expression of IFN α/β gene by Sabin PV in neuronal cells could be suppressed by inhibiting TLR7. Neuronal cell innate immune response to Sabin and wild polioviruses differ significantly for TLR3, TLR7, MDA5 and type 1 interferons. Effects of TLR7 activation and interferon production and Sabin virus replication in neuronal cells need to be actively investigated in future studies.

Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

Directory of Open Access Journals (Sweden)

Shin-ichiro Nakagawa

Full Text Available BACKGROUND & AIMS: The interferon (IFN system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV and hepatitis B virus (HBV. METHODS: This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC. Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs in the livers and sera of these humanized chimeric mice. RESULTS: Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1, suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. CONCLUSIONS: These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

Interferon Response and Viral Evasion by Members of the Family Rhabdoviridae

OpenAIRE

Matthias J. Schnell; Elizabeth J. Faul; Douglas S. Lyles

2009-01-01

Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV) and r...

Comparative therapeutic response to pegylated interferon plus ribavirin versus interferon alpha-2b in chronic hepatitis C patients

International Nuclear Information System (INIS)

Ali, S.; Nazir, G.; Khan, S.A.; Fatima, F.; Iram, S.

2010-01-01

Background: Hepatitis C is an epidemic worldwide since discovery in 1989. Conventional interferon alpha-2b plus Ribavirin therapy was started in 1998 but over all sustained viral response (SVR) rates are much below the desired rates to eradicate the diseases and stopping its epidemic. This study was conducted to access the therapeutic and cost-effectiveness of long acting pegylated interferon alpha-2b plus Ribavirin therapy verses conventional interferon alpha-2b plus Ribavirin. Methods: This comparative study was done at PAF Hospital Shorkot Cantt from July 2005 to July 2008. One hundred anti-HCV positive patients were selected randomly for the study according to willingness due to cost afford ability of the patients for conventional interferon. Group-A was labelled as pegylated interferon alpha-2b plus Ribavirin group, and Group-B interferon alpha-2b plus Ribavirin group. Both groups were given treatment for 24 weeks. Early virological response (EVR) was accessed at 12 weeks of the treatment. Sustained virological response (SVR) in both the groups was done at 24 week during the treatment and 6 monthly after treatment for 2 years. Initially non-responders and relapsed patients within 2 years of treatment were re-treated for 24 weeks with the same treatment. In both groups non-responders and relapsed patients were labelled as resistant patients. Both groups were followed with same protocol for 2 years. Results: Out of 100 patients included in the study, 34% were females and 66% were males. Group-A patients over all showed 94% SVR as compare to 80% in Group-B in 2 year follow-up. Group-A showed 6% resistant patients as compare to Group-B (20%). Conventional interferons were better tolerated. Higher incidence of side-effects was seen in Group-A. Conclusion: Pegylated interferon plus Ribavirin showed 94% SVR in 2 years. Pegylated interferon plus Ribavirin is the treatment of choice.

Novel activities by ebolavirus and marburgvirus interferon antagonists revealed using a standardized in vitro reporter system.

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Guito, Jonathan C; Albariño, César G; Chakrabarti, Ayan K; Towner, Jonathan S

2017-01-15

Filoviruses are highly lethal in humans and nonhuman primates, likely due to potent antagonism of host interferon (IFN) responses early in infection. Filoviral protein VP35 is implicated as the major IFN induction antagonist, while Ebola virus (EBOV) VP24 or Marburg virus (MARV) VP40 are known to block downstream IFN signaling. Despite progress elucidating EBOV and MARV antagonist function, those for most other filoviruses, including Reston (RESTV), Sudan (SUDV), Taï Forest (TAFV), Bundibugyo (BDBV) and Ravn (RAVV) viruses, remain largely neglected. Thus, using standardized vectors and reporter assays, we characterized activities by each IFN antagonist from all known ebolavirus and marburgvirus species side-by-side. We uncover noncanonical suppression of IFN induction by ebolavirus VP24, differing potencies by MARV and RAVV proteins, and intriguingly, weaker antagonism by VP24 of RESTV. These underlying molecular explanations for differential virulence in humans could guide future investigations of more-neglected filoviruses as well as treatment and vaccine studies. Published by Elsevier Inc.

Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.

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Sun, Lijun; Wu, Jiaxi; Du, Fenghe; Chen, Xiang; Chen, Zhijian J

2013-02-15

The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.

Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

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Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

2014-06-01

Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

Differential induction of Toll-like receptors & type 1 interferons by Sabin attenuated & wild type 1 polioviruses in human neuronal cells

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Madhu C Mohanty

2013-01-01

Full Text Available Background & objectives: Polioviruses are the causative agent of paralytic poliomyelitis. Attenuated polioviruses (Sabin oral poliovirus vaccine strains do not replicate efficiently in neurons as compared to the wild type polioviruses and therefore do not cause disease. This study was aimed to investigate the differential host immune response to wild type 1 poliovirus (wild PV and Sabin attenuated type 1 poliovirus (Sabin PV in cultured human neuronal cells. Methods: By using flow cytometry and real time PCR methods we examined host innate immune responses and compared the role of toll like receptors (TLRs and cytoplasmic RNA helicases in cultured human neuronal cells (SK-N-SH infected with Sabin PV and wild PV. Results: Human neuronal cells expressed very low levels of TLRs constitutively. Sabin PV infection induced significantly higher expression of TLR3, TLR7 and melanoma differentiation-associated protein-5 (MDA-5 m-RNA in neuronal cells at the beginning of infection (up to 4 h as compared to wild PV. Further, Sabin PV also induced the expression of interferon α/β at early time point of infection. The induced expression of IFN α/β gene by Sabin PV in neuronal cells could be suppressed by inhibiting TLR7. Interpretation & conclusions: Neuronal cell innate immune response to Sabin and wild polioviruses differ significantly for TLR3, TLR7, MDA5 and type 1 interferons. Effects of TLR7 activation and interferon production and Sabin virus replication in neuronal cells need to be actively investigated in future studies.

A Luciferase Reporter Gene Assay to Measure Ebola Virus Viral Protein 35-Associated Inhibition of Double-Stranded RNA-Stimulated, Retinoic Acid-Inducible Gene 1-Mediated Induction of Interferon β.

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Cannas, Valeria; Daino, Gian Luca; Corona, Angela; Esposito, Francesca; Tramontano, Enzo

2015-10-01

During Ebola virus (EBOV) infection, the type I interferon α/β (IFN-α/β) innate immune response is suppressed by EBOV viral protein 35 (VP35), a validated drug target. Identification of EBOV VP35 inhibitors requires a cellular system able to assess the VP35-based inhibitory functions of viral double-stranded RNA (dsRNA) IFN-β induction. We established a miniaturized luciferase gene reporter assay in A549 cells that measures IFN-β induction by viral dsRNA and is dose-dependently inhibited by VP35 expression. When compared to influenza A virus NS1 protein, EBOV VP35 showed improved inhibition of viral dsRNA-based IFN-β induction. This assay can be used to screen for EBOV VP35 inhibitors. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

How Flaviviruses Activate and Suppress the Interferon Response

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Brenda L. Fredericksen

2010-02-01

Full Text Available The flavivirus genus includes viruses with a remarkable ability to produce disease on a large scale. The expansion and increased endemicity of dengue and West Nile viruses in the Americas exemplifies their medical and epidemiological importance. The rapid detection of viral infection and induction of the innate antiviral response are crucial to determining the outcome of infection. The intracellular pathogen receptors RIG-I and MDA5 play a central role in detecting flavivirus infections and initiating a robust antiviral response. Yet, these viruses are still capable of producing acute illness in humans. It is now clear that flaviviruses utilize a variety of mechanisms to modulate the interferon response. The non-structural proteins of the various flaviviruses reduce expression of interferon dependent genes by blocking phosphorylation, enhancing degradation or down-regulating expression of major components of the JAK/STAT pathway. Recent studies indicate that interferon modulation is an important factor in the development of severe flaviviral illness. This suggests that an increased understanding of viral-host interactions will facilitate the development of novel therapeutics to treat these viral infections and improved biological models to study flavivirus pathogenesis.

Deciphering of the Human Interferon-Regulated Proteome by Mass Spectrometry-Based Quantitative Analysis Reveals Extent and Dynamics of Protein Induction and Repression.

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Megger, Dominik A; Philipp, Jos; Le-Trilling, Vu Thuy Khanh; Sitek, Barbara; Trilling, Mirko

2017-01-01

Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transduction). In regard to the signaling and activated promoters, IFNs can be subdivided into two groups. Here, alterations of the cellular proteome of human cells treated with IFNα and IFNγ were elucidated in a time-resolved manner by quantitative proteome analysis. The majority of protein regulations were strongly IFN type and time dependent. In addition to the expected upregulation of IFN-responsive proteins, an astonishing number of proteins became profoundly repressed especially by IFNγ. Thus, our comprehensive analysis revealed important insights into the human IFN-regulated proteome and its dynamics of protein induction and repression. Interestingly, the new class of IFN-repressed genes comprises known host factors for highly relevant pathogens such as HIV, dengue virus, and hepatitis C virus.

Deciphering of the Human Interferon-Regulated Proteome by Mass Spectrometry-Based Quantitative Analysis Reveals Extent and Dynamics of Protein Induction and Repression

Directory of Open Access Journals (Sweden)

Dominik A. Megger

2017-09-01

Full Text Available Interferons (IFNs are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transduction. In regard to the signaling and activated promoters, IFNs can be subdivided into two groups. Here, alterations of the cellular proteome of human cells treated with IFNα and IFNγ were elucidated in a time-resolved manner by quantitative proteome analysis. The majority of protein regulations were strongly IFN type and time dependent. In addition to the expected upregulation of IFN-responsive proteins, an astonishing number of proteins became profoundly repressed especially by IFNγ. Thus, our comprehensive analysis revealed important insights into the human IFN-regulated proteome and its dynamics of protein induction and repression. Interestingly, the new class of IFN-repressed genes comprises known host factors for highly relevant pathogens such as HIV, dengue virus, and hepatitis C virus.

Efficacy of peg-interferon based treatment in patients with hepatitis C refractory to previous conventional interferon-based treatment

International Nuclear Information System (INIS)

Shaikh, S.; Devrajani, B.R.; Kalhoro, M.

2012-01-01

Objective: To determine the efficacy of peg-interferon-based therapy in patients refractory to previous conventional interferon-based treatment and factors predicting sustained viral response (SVR). Study Design: Analytical study. Place and Duration of Study: Medical Unit IV, Liaquat University Hospital, Jamshoro, from July 2009 to June 2011. Methodology: This study included consecutive patients of hepatitis C who were previously treated with conventional interferon-based treatment for 6 months but were either non-responders, relapsed or had virologic breakthrough and stage = 2 with fibrosis on liver biopsy. All eligible patients were provided peg-interferon at the dosage of 180 mu g weekly with ribavirin thrice a day for 6 months. Sustained Viral Response (SVR) was defined as absence of HCV RNA at twenty four week after treatment. All data was processed on SPSS version 16. Results: Out of 450 patients enrolled in the study, 192 were excluded from the study on the basis of minimal fibrosis (stage 0 and 1). Two hundred and fifty eight patients fulfilled the inclusion criteria and 247 completed the course of peg-interferon treatment. One hundred and sixty one (62.4%) were males and 97 (37.6%) were females. The mean age was 39.9 +- 6.1 years, haemoglobin was 11.49 +- 2.45 g/dl, platelet count was 127.2 +- 50.6 10/sup 3/ /mm/sup 3/, ALT was 99 +- 65 IU/L. SVR was achieved in 84 (32.6%). The strong association was found between SVR and the pattern of response (p = 0. 001), degree of fibrosis and early viral response (p = 0.001). Conclusion: Peg-interferon based treatment is an effective and safe treatment option for patients refractory to conventional interferon-based treatment. (author)

Induction of human interferon gene expression is associated with a nuclear factor that interacts with the site of the human immunodeficiency virus-enhancer

International Nuclear Information System (INIS)

Hiscott, J.; Alper, D.; Cohen, L.; Leblanc, J.F.; Sportza, L.; Wong, A.; Xanthoudakis, S.

1989-01-01

The relationship between transcription of alpha and beta interferon (IFN-α and IFN-β) genes and the interaction of IFN promoter-binding transcription factors has been examined in monoblastoid U937 cells following priming with recombinant IFN-α2 (rIFN-α2) and Sendai virus induction. Pretreatment of U937 cells with rIFN-α2 prior to Sendai virus infection increased the mRNA levels of IFN-α1, IFN-α2, and IFN-β as well as the final yield of biologically active IFN. Analysis of nuclear protein-IFN promoter DNA interactions by electrophoretic mobility-shift assays demonstrated increased factor binding to IFN-α1 and IFN-β regulatory domains, although no new induction-specific complexes were identified. On the basis of competition electrophoretic mobility-shift assay results, factors interacting with the IFN-α1 and IFN-β promoters appear to be distinct DNA-binding proteins. Hybrid promoter-chloramphenicol acetyltransferase fusion plasmids, containing either the IFN-β regulatory element or the human immunodeficiency virus enhancer element linked to the simian virus 40 promoter, were analyzed for virus and phorbol ester inducibility in epithelial and lymphoid cells, respectively. These experiments suggest that induction of IFN gene expression may be controlled in part by transcription regulatory proteins binding to an NF-κB-like site within the IFN-β promoter

Early gene expression profiles of patients with chronic hepatitis C treated with pegylated interferon-alfa and ribavirin.

Science.gov (United States)

Younossi, Zobair M; Baranova, Ancha; Afendy, Arian; Collantes, Rochelle; Stepanova, Maria; Manyam, Ganiraju; Bakshi, Anita; Sigua, Christopher L; Chan, Joanne P; Iverson, Ayuko A; Santini, Christopher D; Chang, Sheng-Yung P

2009-03-01

Responsiveness to hepatitis C virus (HCV) therapy depends on viral and host factors. Our aim was to assess sustained virologic response (SVR)-associated early gene expression in patients with HCV receiving pegylated interferon-alpha2a (PEG-IFN-alpha2a) or PEG-IFN-alpha2b and ribavirin with the duration based on genotypes. Blood samples were collected into PAXgene tubes prior to treatment as well as 1, 7, 28, and 56 days after treatment. From the peripheral blood cells, total RNA was extracted, quantified, and used for one-step reverse transcription polymerase chain reaction to profile 154 messenger RNAs. Expression levels of messenger RNAs were normalized with six "housekeeping" genes and a reference RNA. Multiple regression and stepwise selection were performed to assess differences in gene expression at different time points, and predictive performance was evaluated for each model. A total of 68 patients were enrolled in the study and treated with combination therapy. The results of gene expression showed that SVR could be predicted by the gene expression of signal transducer and activator of transcription-6 (STAT-6) and suppressor of cytokine signaling-1 in the pretreatment samples. After 24 hours, SVR was predicted by the expression of interferon-dependent genes, and this dependence continued to be prominent throughout the treatment. Early gene expression during anti-HCV therapy may elucidate important molecular pathways that may be influencing the probability of achieving virologic response.

Interferon-τ increases BoLA-I for implantation during early pregnancy in dairy cows.

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Zhu, Zhe; Li, Binbin; Wu, Yue; Wang, Xiao; Deng, GanZhen

2017-11-10

Interferon-τ (IFN-τ) signals pregnancy recognition in ruminants. We investigated the effects of IFN-τ produced by embryo trophoblastic cells (ETCs) on expression of bovine leukocyte antigen-I (BoLA-I), a bovine analogue of human MHC-I, in endometrial luminal epithelial cells (EECs) during early pregnancy in dairy cows. Expression of IFN-τ and BoLA-I was increased in endometrial tissues during early pregnancy. Expression of the anti-inflammatory cytokine IL-10 was increased in endometrial tissues, while expression of the pro-inflammatory cytokine IL-6 was decreased, indicating immunosuppression. Progesterone increased IFN-τ expression in EECs. IFN-τ increased p-STAT1 and p-STAT3 levels in EECs, but reduced TRAF3 levels. In addition, IFN-τ increased expression of BoLA-I and IL-10, but decreased expression of IL-6 in EECs. These results indicate that IFN-τ enables stable implantation in dairy cows by increasing expression of BoLA-I, and by immunosuppression mediated by increased IL-10 and decreased IL-6 expression.

Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

DEFF Research Database (Denmark)

Kappos, Ludwig; Freedman, Mark S; Polman, Chris H

2009-01-01

with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon...... index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. FINDINGS: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment...

The innovative development in interferon beta treatments of relapsing-remitting multiple sclerosis

DEFF Research Database (Denmark)

Madsen, Claus

2017-01-01

The introduction of interferon beta therapies more than 20 years ago marked a milestone in the treatment of relapsing-remitting multiple sclerosis (RRMS) with a significant impact on the approach to modern multiple sclerosis (MS) care. Key learnings and perspectives from the early days of disease...... modifying therapies in MS have improved the knowledge base of MS, need for treatment, and patient care. The continuous development of interferons over the past two decades outlines a journey with increased understanding of the pharmacodynamics and pharmacokinetic mechanisms of interferons, leading...

Type I Interferon Reaction to Viral Infection in Interferon-Competent, Immortalized Cell Lines from the African Fruit Bat Eidolon helvum

Science.gov (United States)

Biesold, Susanne E.; Ritz, Daniel; Gloza-Rausch, Florian; Wollny, Robert; Drexler, Jan Felix; Corman, Victor M.; Kalko, Elisabeth K. V.; Oppong, Samuel; Drosten, Christian; Müller, Marcel A.

2011-01-01

Bats harbor several highly pathogenic zoonotic viruses including Rabies, Marburg, and henipaviruses, without overt clinical symptoms in the animals. It has been suspected that bats might have evolved particularly effective mechanisms to suppress viral replication. Here, we investigated interferon (IFN) response, -induction, -secretion and -signaling in epithelial-like cells of the relevant and abundant African fruit bat species, Eidolon helvum (E. helvum). Immortalized cell lines were generated; their potential to induce and react on IFN was confirmed, and biological assays were adapted to application in bat cell cultures, enabling comparison of landmark IFN properties with that of common mammalian cell lines. E. helvum cells were fully capable of reacting to viral and artificial IFN stimuli. E. helvum cells showed highest IFN mRNA induction, highly productive IFN protein secretion, and evidence of efficient IFN stimulated gene induction. In an Alphavirus infection model, O'nyong-nyong virus exhibited strong IFN induction but evaded the IFN response by translational rather than transcriptional shutoff, similar to other Alphavirus infections. These novel IFN-competent cell lines will allow comparative research on zoonotic, bat-borne viruses in order to model mechanisms of viral maintenance and emergence in bat reservoirs. PMID:22140523

Antitumoral action of interferons and interleukins in combination with radiotherapy. Pt. I. Immunologic basis

International Nuclear Information System (INIS)

Herskind, C.; Fleckenstein, K.; Wenz, F.; Lohr, F.; Lohr, J.; Li Chuan-Yuan

2004-01-01

Method: the cellular immune response toward tumor cells is reviewed. The role of cytokines in antigen presentation and activation of effector cells and their interactions with radiation are described. Preclinical strategies of the antitumor action of cytokines are presented and discussed based on the induction of IFN-γ by IL-12. Results: recent advances in immunology have demonstrated the importance of local interactions between antigen-presenting cells (APC) and effector cells such as natural killer (NK) cells and T-lymphocytes for an effective immune reaction against tumors. Interferons stimulate such interactions, while IL-2 plays a central role in the activation of NK cells and T-lymphocytes. The interactions between APC and effector cells are suppressed by many tumors but can be stimulated by irradiation. Since systemic application of interferons is quite toxic, present strategies aim at local expression, e.g., the induction of IFN-γ expression in Th1 cells by IL-12. (orig.) [de

Interferon-induced transcription of a gene encoding a 15-kDA protein depends on an upstream enhancer element

International Nuclear Information System (INIS)

Reich, N.; Evans, B.; Levy, D.; Fahey, D.; Knight, E. Jr.; Darnell, J.E. Jr.

1987-01-01

A human gene encoding an interferon-induced 15-kDa protein has been isolated from a genomic library. The gene appears to be single-copy and is composed of two exons, the first of which contains the ATG translation initiation codon. In vitro nuclear run-on assays showed that the transcription rate of the gene is stimulated after interferon treatment. To analyze transcriptional regulatory sequences, the authors constructed recombinant plasmids for use in transient transfection assays of HeLa cells. Constructs containing 115 nucleotides 5' to the transcription initiation site were found to be fully inducible by interferon. Assays of deletion mutants identified a critical element for interferon induction located between -115 and -96, just upstream of the CCAAT box. Moreover, a DNA fragment including this region can confer interferon inducibility on a heterologous promoter (thymidine kinase) when cloned in either orientation upstream of the gene or downstream of the gene. These are properties characteristic of an enhancer element that is active only after treatment with interferon. This regulatory sequence may be shared by a group of interferon-induced genes, since a very similar sequence is present within the functional region near the RNA start site of another interferon-induced gene

Interferon alpha for treatment of chronic myeloid leukemia

DEFF Research Database (Denmark)

Simonsson, Bengt; Hjorth-Hansen, Henrik; Bjerrum, Ole Weis

2011-01-01

Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-a) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-a compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions...

IFNB1/interferon-ß-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function

DEFF Research Database (Denmark)

Ambjørn, Malene; Ejlerskov, Patrick; Liu, Yawei

2013-01-01

IFNB1/interferon (IFN)-ß belongs to the type I IFNs and exerts potent antiproliferative, proapoptotic, antiangiogenic and immunemodulatory functions. Despite the beneficial effects of IFNB1 in experimental breast cancers, clinical translation has been disappointing, possibly due to induction of s...

Role of interferon in resistance and immunity to protozoa

Science.gov (United States)

Sonnenfeld, G.; Degee, A. L. W.; Mansfield, J. M.; Newsome, A. L.; Arnold, R. R.

1985-01-01

Production of interferon (I) in response to protozoan infection, and the interferon-mediated inhibition of parasite replication were studied in order to determine if these effects may be related to immunologic-mediated resistance of the hosts. Two extracellular parasites-Trypanosoma brucei rhodesiense and Naegleria fowlei were used. Upon infection with the trypanosome, only resistant strains of mice produced I. An early peak of alpha/beta I is followed by appearance of gamma I, which coincided with antibody production and a drop in parasitemia. In case of the amoeba, pretreatment of its suspension with alpha/beta I inhibits its replication in vitro, and appears to protect mice from the infection and the disease. It is proposed that production of interferon, with its regulatory effect on the immune responses, may play a major role in regulating the processes of protozoan-caused diseases.

Induction of interferon-stimulated genes by IRF3 promotes replication of Toxoplasma gondii.

Science.gov (United States)

Majumdar, Tanmay; Chattopadhyay, Saurabh; Ozhegov, Evgeny; Dhar, Jayeeta; Goswami, Ramansu; Sen, Ganes C; Barik, Sailen

2015-03-01

Innate immunity is the first line of defense against microbial insult. The transcription factor, IRF3, is needed by mammalian cells to mount innate immune responses against many microbes, especially viruses. IRF3 remains inactive in the cytoplasm of uninfected cells; upon virus infection, it gets phosphorylated and then translocates to the nucleus, where it binds to the promoters of antiviral genes and induces their expression. Such genes include type I interferons (IFNs) as well as Interferon Stimulated Genes (ISGs). IRF3-/- cells support enhanced replication of many viruses and therefore, the corresponding mice are highly susceptible to viral pathogenesis. Here, we provide evidence for an unexpected pro-microbial role of IRF3: the replication of the protozoan parasite, Toxoplasma gondii, was significantly impaired in IRF3-/- cells. In exploring whether the transcriptional activity of IRF3 was important for its pro-parasitic function, we found that ISGs induced by parasite-activated IRF3 were indeed essential, whereas type I interferons were not important. To delineate the signaling pathway that activates IRF3 in response to parasite infection, we used genetically modified human and mouse cells. The pro-parasitic signaling pathway, which we termed PISA (Parasite-IRF3 Signaling Activation), activated IRF3 without any involvement of the Toll-like receptor or RIG-I-like receptor pathways, thereby ruling out a role of parasite-derived RNA species in activating PISA. Instead, PISA needed the presence of cGAS, STING, TBK1 and IRF3, indicating the necessity of DNA-triggered signaling. To evaluate the physiological significance of our in vitro findings, IRF3-/- mice were challenged with parasite infection and their morbidity and mortality were measured. Unlike WT mice, the IRF3-/- mice did not support replication of the parasite and were resistant to pathogenesis caused by it. Our results revealed a new paradigm in which the antiviral host factor, IRF3, plays a cell

Early stage and long term treatment of multiple sclerosis with interferon-β

Directory of Open Access Journals (Sweden)

Angela Applebee

2009-05-01

Full Text Available Angela Applebee, Hillel PanitchDepartment of Neurology, University of Vermont College of Medicine, and Neurology Service, Fletcher Allen Health Care, Burlington, VT, USAAbstract: Multiple sclerosis (MS affects young adults during the most productive years of their lives, and until recently many neurologists were limited to treating symptoms and attacks without any ability to alter the disease course. The 1990s ushered in an era of possibility with the approval of three interferon-beta (IFNβ therapies for the treatment of MS. Though the mechanism of action of these agents is not completely understood, it is clear they reduce magnetic resonance imaging (MRI activity as well as improve clinical outcomes. The principal randomized, blinded, multicenter trials of IFNβ all point to the need for early treatment soon after the diagnosis of MS is made. Efficacy has also been shown in patients treated after a first demyelinating event. Data on IFNβ in the treatment of secondary progressive MS (SPMS is not impressive, although it shows some benefit in SPMS patients who continue to experience MRI activity and clinical relapses, signifying a continued inflammatory component to their disease. There has been no proven efficacy of IFNβ in the treatment of primary progressive MS (PPMS. The IFNβ therapies are generally well tolerated with a favorable side effect profile. Despite benefits in MRI and clinical measures such as relapse rates and Expanded Disability Status Scale progression, patients continue to exhibit clinical progression and radiological atrophy, pointing to confounding factors and perhaps multiple etiologies of a disease that is not yet fully understood. In addition, the subject of neutralizing antibodies has recently assumed importance. The significance of these on treatment efficacy is uncertain, and until a universally accepted reliable assay is adopted, the decision to change treatment continues to rely on the clinical interpretation of

Interferons, properties and applications

NARCIS (Netherlands)

H. Schellekens (Huub); W. Weimar (Willem)

1980-01-01

textabstractThe main theme of this thesis is the clinical evaluation of interferon. From the biology of the interferon system and animal experiments it can be expected that exogenous interferon will exert its optimum effect when used to prevent acute infections or to modulate chronic

The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes.

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de Jong, Tamarah D; Lübbers, Joyce; Turk, Samina; Vosslamber, Saskia; Mantel, Elise; Bontkes, Hetty J; van der Laken, Conny J; Bijlsma, Johannes W; van Schaardenburg, Dirkjan; Verweij, Cornelis L

2016-07-13

The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature's functional consequences. The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis. Blood was collected from 26 patients with early arthritis and lysed directly or separated into peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs). PBMCs were sorted into CD4(+) T cells, CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes by flow cytometry. Messenger RNA expression of three interferon response genes (IRGs RSAD2, IFI44L, and MX1) and type I interferon receptors (IFNAR1 and IFNAR2) was determined in whole blood and blood cell subsets by quantitative polymerase chain reaction. IRG expression was averaged to calculate an IFN score for each sample. Patients were designated "IFN(high)" (n = 8) or "IFN(low)" (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects. The difference in IFN score between IFN(high) and IFN(low) patients was remarkably large for the PMN fraction (mean 25-fold) compared with the other subsets (mean 6- to 9-fold), indicating that PMNs are the main inducers of IRGs. Moreover, the relative contribution of the PMN fraction to the whole-blood IFN score was threefold higher than expected from its abundance in blood (p = 0.008), whereas it was three- to sixfold lower for the other subsets (p ≤ 0.063), implying that the PMNs are most sensitive to IFN signaling. Concordantly, IFNAR1 and IFNAR2 were upregulated compared with healthy controls selectively in patient PMNs (p ≤ 0.0077) but not in PBMCs. PMNs are the main contributors to the whole-blood type I IFN signature in patients with early arthritis, which seems due to

Radiation induction of developmental effects during the very early stages of pregnancy

International Nuclear Information System (INIS)

Jacquet, P.

2009-01-01

Various studies have shown that early embryos of several mouse strains are sensitive to radiation-induction of congenital anomalies. The presence of mutations in particular genes seems to increase the sensitivity of embryos to such effects, but studies in that field are extremely limited. The aim of these studies is to determine (1) whether the sensitivity to radiation-induction of congenital anomalies during very early stages of gestation is transmitted to the following generation; (2) how mutations in genes involved in important cellular processes, like DNA repair, cell cycle regulation and apoptosis (cell suicide of a damaged cell), can influence the radiation sensitivity of the mammalian embryo during sensitive stages of early pregnancy. Emphasis is put on heterozygous mutations (in which only one of the two copies of the gene is mutated), which are relatively numerous in the human population and do not affect the viability and the fertility of individuals carrying them. The studies under way in that field are supported by contracts with the European Union and the Federal Agency for Nuclear Control (FANC-AFCN)

Interferon-inducible protein 10 (IP-10) is associated with viremia of early HIV-1 infection in Korean patients.

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Lee, SoYong; Chung, Yoon-Seok; Yoon, Cheol-Hee; Shin, YoungHyun; Kim, SeungHyun; Choi, Byeong-Sun; Kim, Sung Soon

2015-05-01

Cytokines/chemokines play key roles in modulating disease progression in human immunodeficiency virus (HIV) infection. Although it is known that early HIV-1 infection is associated with increased production of proinflammatory cytokines, the relationship between cytokine levels and HIV-1 pathogenesis is not clear. The concentrations of 18 cytokines/chemokines in 30 HIV-1 negative and 208 HIV-1 positive plasma samples from Korean patients were measured by the Luminex system. Early HIV-1 infection was classified according to the Fiebig stage (FS) based on the characteristics of the patients infected with HIV-1. Concentrations of interleukin-12 (IL-12), interferon-inducible protein-10 (IP-10), macrophage inflammatory protein-1α (MIP-1α) and regulated upon activation, normal T cells expressed and secreted (RANTES) were increased significantly during the early stage of HIV-1 infection (FS II-IV) compared with the HIV-1-negative group. Of these cytokines, an elevated level of IP-10 was the only factor to be correlated positively with a higher viral load during the early stages of HIV-1 infection (FS II-IV) in Koreans (R = 0.52, P IP-10 may be an indicator for HIV-1 viremia and associated closely with viral replication in patients with early HIV-1 infection. © 2015 Wiley Periodicals, Inc.

Interferon-γ-induced protein 10 in Lyme disease.

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Fallahi, P; Elia, G; Bonatti, A

2017-01-01

Lyme disease is an infectious disease caused by bacteria of the Borrelia type, that affects about 300,000 people a year in the USA and 65,000 people a year in Europe. Borrelia infection, and Lyme disease, following occupational exposure has been frequently reported in USA, Europe and Asia. The manifestations of Lyme disease include erythema migrans (EM), arthritis, neuroborrelliosis (NB), and others. Cytokines and chemokines primarily orchestrate leukocyte recruitment to the areas of Borrelia infection, and they are critical mediators of immune and inflammatory responses, in particular of the induction of interferon (IFN)-γ and IFN-γ dependent chemokines. In EM high levels of T helper (Th) 1 cells chemoattranctants [monokine induced by IFN-γ (MIG), IFN-γ-induced protein 10 (IP- 10), and IFN-inducible T cell alpha chemoattractant (I-TAC)] have been shown. Synovial tissues and fluids of patients with Lyme Arthritis (LA) (overall with antibiotic-refractory LA) contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly MIG and IFN-γ. In NB concentrations of IP-10 and I-TAC in the cerebrospinal fluid (CSF) were significantly higher, suggesting that IP-10 and I-TAC create a chemokine gradient between the CSF and serum and recruite C-X-C chemokine receptor 3-expressing memory CD4+ T-cells into the CSF of these patients. A positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction has also been shown. These results suggest that IFN-γ dependent chemokines are important biomarkers to monitor the progression and diffusion of the disease in patients with Borrelia infection; further larger studies are needed.

Interferon production and signaling pathways are antagonized during henipavirus infection of fruit bat cell lines.

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Elena R Virtue

Full Text Available Bats are natural reservoirs for a spectrum of infectious zoonotic diseases including the recently emerged henipaviruses (Hendra and Nipah viruses. Henipaviruses have been observed both naturally and experimentally to cause serious and often fatal disease in many different mammal species, including humans. Interestingly, infection of the flying fox with henipaviruses occurs in the absence of clinical disease. The extreme variation in the disease pattern between humans and bats has led to an investigation into the effects of henipavirus infection on the innate immune response in bat cell lines. We report that henipavirus infection does not result in the induction of interferon expression, and the viruses also inhibit interferon signaling. We also confirm that the interferon production and signaling block in bat cells is not due to differing viral protein expression levels between human and bat hosts. This information, in addition to the known lack of clinical signs in bats following henipavirus infection, suggests that bats control henipavirus infection by an as yet unidentified mechanism, not via the interferon response. This is the first report of henipavirus infection in bat cells specifically investigating aspects of the innate immune system.

The Peculiar Characteristics of Fish Type I Interferons

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Pierre Boudinot

2016-11-01

Full Text Available Antiviral type I interferons (IFNs have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. Mammalian type I IFN genes are intronless while type III have introns; in fish, all have introns, but structurally, both subgroups belong to type I. Type I IFNs likely appeared early in vertebrates as intron containing genes, and evolved in parallel in tetrapods and fishes. The diversity of their repertoires in fish and mammals is likely a convergent feature, selected as a response to the variety of viral strategies. Several alternative nomenclatures have been established for different taxonomic fish groups, calling for a unified system. The specific functions of each type I gene remains poorly understood, as well as their interactions in antiviral responses. However, distinct induction pathways, kinetics of response, and tissue specificity indicate that fish type I likely are highly specialized, especially in groups where they are numerous such as salmonids or cyprinids. Unravelling their functional integration constitutes the next challenge to understand how these cytokines evolved to orchestrate antiviral innate immunity in vertebrates.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants.

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Wang, Jennifer P; Zhang, Lei; Madera, Rachel F; Woda, Marcia; Libraty, Daniel H

2012-07-06

Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. Androgen-mediated regulation of pDC TLR7-driven innate immune responses may contribute to the observed sex differences in response to infections during early infancy.

Ribavirin plus interferon versus interferon for chronic hepatitis C

DEFF Research Database (Denmark)

Brok, Jesper; Gluud, Lise Lotte; Gluud, Christian

2010-01-01

Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial.......Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial....

Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression.

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Eva-K Pauli

2008-11-01

Full Text Available The type I interferon (IFN system is a first line of defense against viral infections. Viruses have developed various mechanisms to counteract this response. So far, the interferon antagonistic activity of influenza A viruses was mainly observed on the level of IFNbeta gene induction via action of the viral non-structural protein 1 (NS1. Here we present data indicating that influenza A viruses not only suppress IFNbeta gene induction but also inhibit type I IFN signaling through a mechanism involving induction of the suppressor of cytokine signaling-3 (SOCS-3 protein. Our study was based on the observation that in cells that were infected with influenza A virus and subsequently stimulated with IFNalpha/beta, phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1 was strongly reduced. This impaired STAT1 activation was not due to the action of viral proteins but rather appeared to be induced by accumulation of viral 5' triphosphate RNA in the cell. SOCS proteins are potent endogenous inhibitors of Janus kinase (JAK/STAT signaling. Closer examination revealed that SOCS-3 but not SOCS-1 mRNA levels increase in an RNA- and nuclear factor kappa B (NF-kappaB-dependent but type I IFN-independent manner early in the viral replication cycle. This direct viral induction of SOCS-3 mRNA and protein expression appears to be relevant for suppression of the antiviral response since in SOCS-3 deficient cells a sustained phosphorylation of STAT1 correlated with elevated expression of type I IFN-dependent genes. As a consequence, progeny virus titers were reduced in SOCS-3 deficient cells or in cells were SOCS-3 expression was knocked-down by siRNA. These data provide the first evidence that influenza A viruses suppress type I IFN signaling on the level of JAK/STAT activation. The inhibitory effect is at least in part due to the induction of SOCS-3 gene expression, which results in an impaired antiviral response.

Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma

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Arai Hajime

2007-08-01

Full Text Available Abstract Background Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ, has demonstrated promising activity against recurrent glioma, the effects last only a few months and drug resistance develops thereafter in most cases. Induction of O6-methylguanine-DNA methyltransferase (MGMT in tumors is considered to be responsible for resistance to TMZ. Interferon-beta has been reported to suppress MGMT in an experimental glioma model. Here we report a patient with TMZ-refractory anaplastic astrocytoma (AA who was treated successfully with a combination of interferon-beta and TMZ. Case presentation A patient with recurrent AA after radiation-chemotherapy and stereotactic radiotherapy was treated with TMZ. After 6 cycles, the tumor became refractory to TMZ, and the patient was treated with interferon-beta at 3 × 106 international units/body, followed by 5 consecutive days of 200 mg/m2 TMZ in cycles of 28 days. After the second cycle the tumor decreased in size by 50% (PR. The tumor showed further shrinkage after 8 months and the patient's KPS improved from 70% to 100%. The immunohistochemical study of the initial tumor specimen confirmed positive MGMT protein expression. Conclusion It is considered that interferon-beta pre-administration increased the TMZ sensitivity of the glioma, which had been refractory to TMZ monotherapy.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants

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Wang Jennifer P

2012-07-01

Full Text Available Abstract Background Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR-mediated responses by plasmacytoid dendritic cells (pDCs. Results In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. Conclusions Androgen-mediated regulation of pDC TLR7-driven innate immune responses may contribute to the observed sex differences in response to infections during early infancy.

Is pegylated interferon superior to interferon, with ribavarin, in chronic hepatitis C genotypes 2/3?

Institute of Scientific and Technical Information of China (English)

Ijaz S Jamall; Shafaq Yusuf; Maimoona Azhar; Selene Jamall

2008-01-01

Over the past decade,significant improvements have been made in the treatment of chronic hepatitis C(CHC),especially with the introduction of combined therapy using both interferon and ribavarin.The optimal dose and duration of treatment is still a matter of debate and,importantly,the efficacy of this combined treatment varies with the viral genotype responsible for infection.In general,patients infected with viral genotypes 2 or 3 more readily achieve a sustained viral response than those infected with viral genotype 1.The introduction of a pegylated version of interferon in the past decade has produced better clinical outcomes in patients infected with viral genotype 1.However,the published literature shows no improvement in clinical outcomes in patients infected with viral genotypes 2 or 3 when they are treated with pegylated interferon as opposed to nonpegylated interferon,both given in combination with ribavarin.This is significant because the cost of a 24-wk treatment with pegylated interferon in lessdeveloped countries is between six and 30 times greater than that of treatment with interferon.Thus,clinicians need to carefully consider the cost-versusbenefit of using pegylated interferon to treat CHC,particularly when there is no evidence for clinically measurable benefits in patients with genotypes 2 and 3 infections.

Independent, parallel pathways to CXCL10 induction in HCV-infected hepatocytes.

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Brownell, Jessica; Wagoner, Jessica; Lovelace, Erica S; Thirstrup, Derek; Mohar, Isaac; Smith, Wesley; Giugliano, Silvia; Li, Kui; Crispe, I Nicholas; Rosen, Hugo R; Polyak, Stephen J

2013-10-01

The pro-inflammatory chemokine CXCL10 is induced by HCV infection in vitro and in vivo, and is associated with outcome of IFN (interferon)-based therapy. We studied how hepatocyte sensing of early HCV infection via TLR3 (Toll-like receptor 3) and RIG-I (retinoic acid inducible gene I) led to expression of CXCL10. CXCL10, type I IFN, and type III IFN mRNAs and proteins were measured in PHH (primary human hepatocytes) and hepatocyte lines harboring functional or non-functional TLR3 and RIG-I pathways following HCV infection or exposure to receptor-specific stimuli. HuH7 human hepatoma cells expressing both TLR3 and RIG-I produced maximal CXCL10 during early HCV infection. Neutralization of type I and type III IFNs had no impact on virus-induced CXCL10 expression in TLR3+/RIG-I+ HuH7 cells, but reduced CXCL10 expression in PHH. PHH cultures were positive for monocyte, macrophage, and dendritic cell mRNAs. Immunodepletion of non-parenchymal cells (NPCs) eliminated marker expression in PHH cultures, which then showed no IFN requirement for CXCL10 induction during HCV infection. Immunofluorescence studies also revealed a positive correlation between intracellular HCV Core and CXCL10 protein expression (r(2) = 0.88, p ≤ 0.001). While CXCL10 induction in hepatocytes during the initial phase of HCV infection is independent of hepatocyte-derived type I and type III IFNs, NPC-derived IFNs contribute to CXCL10 induction during HCV infection in PHH cultures. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Studies on Brucella interferon: Chromatographic behaviour and purification

International Nuclear Information System (INIS)

Bousquet-Ucla, C.; Wietzerbin, J.; Falcoff, E.

1980-01-01

Interferon was induced by infecting mice with Brucella suis. Serum containing interferon activity was analyzed by chromatography on Concanavalin A-Sepharose and Phenyl-Sepharose CL-4B columns. Antiviral activity was completely retained by the lectin column indicating that all the interferon molecules are glycosylated. The chromatographic behaviour of Brucella interferon on Phenyl-Sepharose CL-4B show that, like other interferons, Brucella interferon displays hydrophobic properties. However, the hydrophobicity of the interferon molecule was masked in the crude preparation and was only detectable when purified Brucella interferon was used for chromatography. The antigenic properties of Brucella interferon provided the means for developing an affinity chromatographic method resulting in about 60.000 fold purification. As in the case of viral interferon, treatment of L cells with Brucella interferon induced specific enhanced in vitro phosphorylation of a 67.000 molecular weight protein after incubation of cell extracts with doublestranded RNA and [γ- 32 p]ATP. (auth.)

Radioprotective effect of interferon

Energy Technology Data Exchange (ETDEWEB)

Zasukhina, G.

1984-12-18

A cycle of experiments performed jointly with associations of the Moscow Engineering Physics Institute reportedly demonstrated that interferons protect human cells cultivated in a test tube against the action of fast neutrons and gamma radiation. Cells treated in advance with interferon not only survived irradiation but were almost totally protected against harmful effects of fast neutrons on the structure of chromosomes, according to the author. She mentions that the laboratory has also been studying effects produced on cells by compounds of heavy metals and other chemical compounds, including ones which cause breaks in the DNA molecule. Interferon's ability to protect cells against effects of chemical compounds has been studied in this connection. Another direction of the laboratory's work is research on interferon's effects on blood cells of persons suffering from certain hereditary diseases in which restorative processes of cells are impaired. The purpose of this is to develop courses of treatment which will not cause irreversible damages to chromosomes, the author explains. Interferon has been found to stimulate the reparation systems of cells in cases of Marfan's syndrome, for example.

T-cell homeostasis in chronic HCV-infected patients treated with interferon and ribavirin or an interferon-free regimen

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Hartling, Hans Jakob; Birch, Carsten; Gaardbo, Julie C

2015-01-01

Direct-acting antiviral has replaced pegylated interferon-α and ribavirin-based treatment in the treatment of chronic hepatitis C virus (HCV) infection. While interferon-α is immune modulating and causes lymphopenia, interferon-free regimens seem to be well-tolerated. This study aimed to compare T......-cell homeostasis before, during, and after HCV treatment with or without interferon-α in patients with chronic HCV infection. A total of 20 patients with chronic HCV infection were treated with pegylated interferon-α and ribavirin, and six patients were treated with an interferon-free regimen. All patients were...... compared to prior treatment values. Finally, a proportion of CD8+ effector memory was lower while proportion of apoptotic T cells was higher after sustained virologic response compared to prior treatment. Despite lymphopenia during interferon, alterations in T-cell homeostasis during treatment were...

Improvement of specific growth rate of Pichia pastoris for effective porcine interferon-α production with an on-line model-based glycerol feeding strategy.

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Gao, Min-Jie; Zheng, Zhi-Yong; Wu, Jian-Rong; Dong, Shi-Juan; Li, Zhen; Jin, Hu; Zhan, Xiao-Bei; Lin, Chi-Chung

2012-02-01

Effective expression of porcine interferon-α (pIFN-α) with recombinant Pichia pastoris was conducted in a bench-scale fermentor. The influence of the glycerol feeding strategy on the specific growth rate and protein production was investigated. The traditional DO-stat feeding strategy led to very low cell growth rate resulting in low dry cell weight (DCW) of about 90 g/L during the subsequent induction phase. The previously reported Artificial Neural Network Pattern Recognition (ANNPR) model-based glycerol feeding strategy improved the cell density to 120 g DCW/L, while the specific growth rate decreased from 0.15 to 0.18 to 0.03-0.08 h(-1) during the last 10 h of the glycerol feeding stage leading to a variation of the porcine interferon-α production, as the glycerol feeding scheme had a significant effect on the induction phase. This problem was resolved by an improved ANNPR model-based feeding strategy to maintain the specific growth rate above 0.11 h(-1). With this feeding strategy, the pIFN-α concentration reached a level of 1.43 g/L, more than 1.5-fold higher than that obtained with the previously adopted feeding strategy. Our results showed that increasing the specific growth rate favored the target protein production and the glycerol feeding methods directly influenced the induction stage. Consequently, higher cell density and specific growth rate as well as effective porcine interferon-α production have been achieved by our novel glycerol feeding strategy.

Interferon Response and Viral Evasion by Members of the Family Rhabdoviridae

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Matthias J. Schnell

2009-11-01

Full Text Available Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV and rabies virus (RABV. Despite their structural similarities, VSV and RABV have completely different mechanisms by which they avert the host immune response. VSV relies on the matrix protein to interfere with host gene transcription and nuclear export of anti-viral mRNAs. Alternatively, RABV uses its phosphoprotein to interfere with IRF-3 phosphorylation and STAT1 signaling. Understanding the virus-cell interactions and viral proteins necessary to evade the immune response is important in developing effective vaccines and therapeutics for this viral family.

Interferon antagonist NSs of La Crosse virus triggers a DNA damage response-like degradation of transcribing RNA polymerase II.

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Verbruggen, Paul; Ruf, Marius; Blakqori, Gjon; Överby, Anna K; Heidemann, Martin; Eick, Dirk; Weber, Friedemann

2011-02-04

La Crosse encephalitis virus (LACV) is a mosquito-borne member of the negative-strand RNA virus family Bunyaviridae. We have previously shown that the virulence factor NSs of LACV is an efficient inhibitor of the antiviral type I interferon system. A recombinant virus unable to express NSs (rLACVdelNSs) strongly induced interferon transcription, whereas the corresponding wt virus (rLACV) suppressed it. Here, we show that interferon induction by rLACVdelNSs mainly occurs through the signaling pathway leading from the pattern recognition receptor RIG-I to the transcription factor IRF-3. NSs expressed by rLACV, however, acts downstream of IRF-3 by specifically blocking RNA polymerase II-dependent transcription. Further investigations revealed that NSs induces proteasomal degradation of the mammalian RNA polymerase II subunit RPB1. NSs thereby selectively targets RPB1 molecules of elongating RNA polymerase II complexes, the so-called IIo form. This phenotype has similarities to the cellular DNA damage response, and NSs was indeed found to transactivate the DNA damage response gene pak6. Moreover, NSs expressed by rLACV boosted serine 139 phosphorylation of histone H2A.X, one of the earliest cellular reactions to damaged DNA. However, other DNA damage response markers such as up-regulation and serine 15 phosphorylation of p53 or serine 1524 phosphorylation of BRCA1 were not triggered by LACV infection. Collectively, our data indicate that the strong suppression of interferon induction by LACV NSs is based on a shutdown of RNA polymerase II transcription and that NSs achieves this by exploiting parts of the cellular DNA damage response pathway to degrade IIo-borne RPB1 subunits.

A prospective randomized study of Chop versus Chop plus alpha-2B interferon in patients with intermediate and high grade non-Hodgkin's lymphoma: the International Oncology Study Group NHL1 Study .

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Giles, F J; Shan, J; Advani, S H; Akan, H; Aydogdu, I; Aziz, Z; Azim, H A; Bapsy, P P; Buyukkececi, F; Chaimongkol, B; Chen, P M; Cheong, S K; Ferhanoglu, B; Hamza, R; Khalid, H M; Intragumtornchai, T; Kim, S W; Kim, S Y; Koc, H; Kumar, L; Kumar, R; Lei, K I; Lekhakula, A; Muthalib, A; Patel, M; Poovalingam, V P; Prayoonwiwat, W; Rana, F; Reksodiputro, A H; Ruff, P; Sagar, T G; Schwarer, A P; Song, H S; Suh, C W; Suharti, C; Supindiman, I; Tee, G Y; Thamprasit, T; Villalon, A H; Wickham, N R; Wong, J E; Yalcin, A; Jootar, S

2000-12-01

The addition of a brief alpha interferon regimen to each CHOP induction cycle, plus one year of alpha interferon thrice weekly maintenance therapy, has no early effect on response rates or survival in patients with Intermediate or High grade cell NHL. The CHOP (Cyclophosphamide, Adriamycin. Vincristine, Prednisone) regimen is the most widely used first-line therapy for patients with Intermediate or High Grade (IG/HG) non-Hodgkin's lymphoma (NHL). Alpha 2b interferon (INF) enhances response rates and improves survival in low-grade NHL. The International Oncology Study Group (IOSG) conducted a prospective randomized study comparing CHOP alone or combined with INF in patients with IG/HG-NHL. The primary study aim was to compare the objective response rates in these patient cohorts. Patients with a confirmed diagnosis of measurable NHL of International Working Formulation (IWF) groups D to H histology were randomized to receive CHOP alone or CHOP with 5Mu INF s.c. for 5 days on days 22 to 26 of each 28 day cycle with INF 5 million units (Mu) given three times per week subcutaneously for 52 weeks in those patients who responded to CHOP plus INF. The overall response rates were equivalent in both groups: CHOP alone (214 patients) 81% (complete 55%, partial 26%); CHOP plus INF (221 patients) 80% (complete 54%, partial 26%). At 36 months, the actuarial survival rate was equivalent in both groups. There is no apparent early advantage in terms of response or survival conferred by adding the study INF regimen to CHOP therapy for patients with IG/HG-NHL.

Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation

DEFF Research Database (Denmark)

Sellebjerg, F.; Krakauer, M.; Hesse, D.

2009-01-01

Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)-beta. NAbs impair the effect of treatment. The biological effect of IFN-beta can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other...

Enzyme-linked immunospot: an alternative method for the detection of interferon gamma in Johne's disease

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Begg, Douglas J.; de Silva, Kumudika; Bosward, Katrina

2009-01-01

To date, the sensitivity of the interferon gamma (IFN-) enzyme-linked immunosorbent assay (ELISA) to detect Johne's disease (JD) has been poor, especially in the early stages of disease. To improve the sensitivity of IFN- detection in the early stages of infection, an alternate assay needs to be ...

Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.

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Eveline Kindler

2017-02-01

Full Text Available Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I. This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU activity is key to prevent early induction of double-stranded RNA (dsRNA host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.

No Love Lost Between Viruses and Interferons.

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Fensterl, Volker; Chattopadhyay, Saurabh; Sen, Ganes C

2015-11-01

The interferon system protects mammals against virus infections. There are several types of interferons, which are characterized by their ability to inhibit virus replication and resultant pathogenesis by triggering both innate and cell-mediated immune responses. Virus infection is sensed by a variety of cellular pattern-recognition receptors and triggers the synthesis of interferons, which are secreted by the infected cells. In uninfected cells, cell surface receptors recognize the secreted interferons and activate intracellular signaling pathways that induce the expression of interferon-stimulated genes; the proteins encoded by these genes inhibit different stages of virus replication. To avoid extinction, almost all viruses have evolved mechanisms to defend themselves against the interferon system. Consequently, a dynamic equilibrium of survival is established between the virus and its host, an equilibrium that can be shifted to the host's favor by the use of exogenous interferon as a therapeutic antiviral agent.

Induction of early differentiation as a means of cell sterilization

International Nuclear Information System (INIS)

Wangenheim, K.-H. v.

1979-01-01

Investigations in plants suggest that cytoplasmic growth during mitotic delay induces an early attainment of terminal differentiation and cessation of mitotic activity. In mammals a direct demonstration of these processes is difficult. Plants and mammals show, however, a common phenomenon: Polyploidy does not usually reduce radiosensitivity as drastically as predicted by genetical considerations and certain experimental results. In root meristems of barley it is shown that cytoplasmic growth during mitotic delay increases the amount of cytoplasma per nuclear genome to approximately the same levels in tetraploid as in diploid cells. This results in the same loss, for both ploidy levels, of meristematic cells due to early differentiation. Apparently, under usual conditions, polyploidy is unable to significantly reduce radiosensitivity because the induction of differentiation processes is more important to radiation damage than the direct effect of genetic damage. Since the same basic principles also occur in mammals, it is suggested that early differentiation, and thereby cell sterilization, are induced in mammalian cells by the same mechanism as in plants. (Auth.)

PA from an H5N1 highly pathogenic avian influenza virus activates viral transcription and replication and induces apoptosis and interferon expression at an early stage of infection

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Wang Qiang

2012-06-01

Full Text Available Abstract Background Although gene exchange is not likely to occur freely, reassortment between the H5N1 highly pathogenic avian influenza virus (HPAIV and currently circulating human viruses is a serious concern. The PA polymerase subunit of H5N1 HPAIV was recently reported to activate the influenza replicon activity. Methods The replicon activities of PR8 and WSN strains (H1N1 of influenza containing PA from HPAIV A/Cambodia/P0322095/2005 (H5N1 and the activity of the chimeric RNA polymerase were analyzed. A reassortant WSN virus containing the H5N1 Cambodia PA (C-PA was then reconstituted and its growth in cells and pathogenicity in mice examined. The interferon promoter, TUNEL, and caspase 3, 8, and 9 activities of C-PA-infected cells were compared with those of WSN-infected cells. Results The activity of the chimeric RNA polymerase was slightly higher than that of WSN, and C-PA replicated better than WSN in cells. However, the multi-step growth of C-PA and its pathogenicity in mice were lower than those of WSN. The interferon promoter, TUNEL, and caspase 3, 8, and 9 activities were strongly induced in early infection in C-PA-infected cells but not in WSN-infected cells. Conclusions Apoptosis and interferon were strongly induced early in C-PA infection, which protected the uninfected cells from expansion of viral infection. In this case, these classical host-virus interactions contributed to the attenuation of this strongly replicating virus.

Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques.

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Anna de Lang

2007-08-01

Full Text Available The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. Using functional genomics, we analyzed early host responses to SARS-CoV infection in the lungs of adolescent cynomolgus macaques (Macaca fascicularis that show lung pathology similar to that observed in human adults with SARS. Analysis of gene signatures revealed induction of a strong innate immune response characterized by the stimulation of various cytokine and chemokine genes, including interleukin (IL-6, IL-8, and IP-10, which corresponds to the host response seen in acute respiratory distress syndrome. As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques. Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells. Our studies emphasize that the induction of early IFN signaling may be critical to confer protection against SARS-CoV infection and highlight the strength of combining functional genomics with immunohistochemistry to further unravel the pathogenesis of SARS.

Some biological properties of the human amniotic membrane interferon

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P. C. P. Ferreira

1992-03-01

Full Text Available Human amniotic interferon was investigated to define the species specificity of its antiviral action and compare its anti-cellular and NK cell stimulating activities with those of other human interferons. The antiviral effect was titrated in bovine (RV-IAL and monkey (VERO cells. Amniotic interferon exhibited, in bovine cells, 5% of the activity seen in monkey cells, while alpha interferon displayed 200%. No effect was detected with either beta or gamma interferon in bovine cells. Daudi cells were exposed to different concentrations of various interferons and the cell numbers were determined. The anticellular effect of the amniotic interferon reached its peak on the third day of incubation. Results suggested a higher activity for alpha and gamma interferons and a lower activity for beta when compared to amniotic interferon. Using total mononuclear cells as effector cells and K 562 as target cell in a 51Cr release assay, it was demonstrated that low concentrations of amniotic interferon consistently stimulated NK cell activity in cells derived from several donors, the results indicating a higher level of activity with this interferon than with alpha and beta interferons.

Interferon induced IFIT family genes in host antiviral defense.

Science.gov (United States)

Zhou, Xiang; Michal, Jennifer J; Zhang, Lifan; Ding, Bo; Lunney, Joan K; Liu, Bang; Jiang, Zhihua

2013-01-01

Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IFN-stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5; however, bird, marsupial, frog and fish have only IFIT5. Regardless of species, IFIT5 is always adjacent to SLC16A12. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. However, some viruses can escape the antiviral functions of the IFIT family by suppressing IFIT family genes expression or methylation of 5' cap of viral molecules. In addition, the variants of IFIT family genes could significantly influence the outcome of hepatitis C virus (HCV) therapy. We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.

Teacher induction

NARCIS (Netherlands)

Beijaard, D.; Buitink, J.; Kessels, C.; Peterson, P.; Baker, E.; McGraw, B.

2010-01-01

Teacher induction programs are intended to support the professional development of beginning teachers and thereby contribute to the reduction of teacher attrition during the early teaching years. Teacher induction programs are often based upon a deficit model with a focus on the better organization

Interferon Gamma-1b Injection

Science.gov (United States)

Interferon gamma-1b injection is used to reduce the frequency and severity of serious infections in people with chronic ... severe, malignant osteopetrosis (an inherited bone disease). Interferon gamma-1b is in a class of medications called ...

Similarities of cellular receptors for interferon and cortisol

International Nuclear Information System (INIS)

Filipic, B.; Schauer, P.; Likar, M.

1977-01-01

Cellular receptors are molecules located on the cell membrane. Their function is to bind different molecules to the cell surface. These molecules can penetrate into the cytoplasm and trigger cellular changes. One kind of such bound molecules are interferons and corticosteroids. Until very recently very little was known about interferon's receptors on the cell surface, mechanisms of interferon's binding to them or about kinetics of such binding. On the basis of results published elsewhere and on the basis of experimental results, the authors suggest: receptors for interferon and cortisol are glycoproteins located on the cell surface, in analogy with PHA receptors they are chemically sialoglycoproteins, binding kinetics of cortisol and interferon is similar, interferon and cortisol compete for cellular receptors, binding of cortisol or interferon is dependent on allosteric configuration of receptor molecules. (author)

cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.

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Jennifer Paijo

2016-04-01

Full Text Available Human cytomegalovirus (HCMV infections of healthy individuals are mostly unnoticed and result in viral latency. However, HCMV can also cause devastating disease, e.g., upon reactivation in immunocompromised patients. Yet, little is known about human immune cell sensing of DNA-encoded HCMV. Recent studies indicated that during viral infection the cyclic GMP/AMP synthase (cGAS senses cytosolic DNA and catalyzes formation of the cyclic di-nucleotide cGAMP, which triggers stimulator of interferon genes (STING and thus induces antiviral type I interferon (IFN-I responses. We found that plasmacytoid dendritic cells (pDC as well as monocyte-derived DC and macrophages constitutively expressed cGAS and STING. HCMV infection further induced cGAS, whereas STING expression was only moderately affected. Although pDC expressed particularly high levels of cGAS, and the cGAS/STING axis was functional down-stream of STING, as indicated by IFN-I induction upon synthetic cGAMP treatment, pDC were not susceptible to HCMV infection and mounted IFN-I responses in a TLR9-dependent manner. Conversely, HCMV infected monocyte-derived cells synthesized abundant cGAMP levels that preceded IFN-I production and that correlated with the extent of infection. CRISPR/Cas9- or siRNA-mediated cGAS ablation in monocytic THP-1 cells and primary monocyte-derived cells, respectively, impeded induction of IFN-I responses following HCMV infection. Thus, cGAS is a key sensor of HCMV for IFN-I induction in primary human monocyte-derived DC and macrophages.

Toscana virus induces interferon although its NSs protein reveals antagonistic activity.

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Gori Savellini, Gianni; Weber, Friedemann; Terrosi, Chiara; Habjan, Matthias; Martorelli, Barbara; Cusi, Maria Grazia

2011-01-01

Toscana virus (TOSV) is a phlebotomus-transmitted virus that belongs to the family Bunyaviridae and causes widespread infections in humans; about 30 % of these cases result in aseptic meningitis. In the present study, it was shown that TOSV is an inducer of beta interferon (IFN-β), although its non-structural protein (NSs) could inhibit the induction of IFN-β if expressed in a heterologous context. A recombinant Rift Valley fever virus expressing the TOSV NSs could suppress IFN-β expression in infected cells. Moreover, in cells expressing NSs protein from a cDNA plasmid, IFN-β transcripts were not inducible by poly(I : C). Unlike other members of the family Bunyaviridae, TOSV appears to express an NSs protein that is a weak antagonist of IFN induction. Characterization of the interaction of TOSV with the IFN system will help our understanding of virus-host cell interactions and may explain why the pathogenesis of this disease is mostly mild in humans.

Long-term impact of interferon beta-1b in patients with CIS

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Edan, G; Kappos, L; Montalbán, X

2014-01-01

OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). METHODS: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg...

Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE

DEFF Research Database (Denmark)

Renno, T; Taupin, V; Bourbonnière, L

1998-01-01

The cytokine interferon-gamma (IFNgamma) is implicated in the induction of acute CNS inflammation, but it is less clear what role if any IFNgamma plays in progression to chronic demyelination and neurological deficit. To address this issue, we have expressed IFNgamma in myelinating oligodendrocytes....... In contrast to control mice, which remit from EAE with resolution of glial reactivity and leukocytic infiltration, transgenics showed chronic neurological deficits. While activated microglia/macrophages persisted in demyelinating lesions for over 100 days, CD4(+) T lymphocytes were no longer present in CNS...

Interferon Induced Focal Segmental Glomerulosclerosis

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Yusuf Kayar

2016-01-01

Full Text Available Behçet’s disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet’s disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon.

Induction of the early-late Ddc gene during Drosophila metamorphosis by the ecdysone receptor.

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Chen, Li; Reece, Christian; O'Keefe, Sandra L; Hawryluk, Gregory W L; Engstrom, Monica M; Hodgetts, Ross B

2002-06-01

During Drosophila metamorphosis, the 'early-late' genes constitute a unique class regulated by the steroid hormone 20-hydroxyecdysone. Their induction is comprised of both a primary and a secondary response to ecdysone. Previous work has suggested that the epidermal expression of the dopa decarboxylase gene (Ddc) is likely that of a typical early-late gene. Accumulation of the Ddc transcript is rapidly initiated in the absence of protein synthesis, which implies that the ecdysone receptor plays a direct role in induction. However, full Ddc expression requires the participation of one of the transcription factors encoded by the Broad-Complex. In this paper, we characterize an ecdysone response element (EcRE) that contributes to the primary response. Using gel mobility shift assays and transgenic assays, we identified a single functional EcRE, located at position -97 to -83 bp relative to the transcription initiation site. This is the first report of an EcRE associated with an early-late gene in Drosophila. Competition experiments indicated that the affinity of the Ddc EcRE for the ecdysone receptor complex was at least four-fold less than that of the canonical EcRE of the hsp27 gene. Using in vitro mutagenesis, we determined that the reduced affinity of the EcRE resided at two positions where the nucleotides differed from those found in the canonical sequence. The ecdysone receptor, acting through this EcRE, releases Ddc from a silencing mechanism, whose cis-acting domain we have mapped to the 5'-upstream region between -2067 and -1427 bp. Deletion of this repressive element resulted in precocious expression of Ddc in both epidermis and imaginal discs. Thus, epidermal Ddc induction at pupariation is under the control of an extended genomic region that contains both positive and negative regulatory elements. Copyright 2002 Elsevier Science Ireland Ltd.

Variability of hepatitis C virus hypervariable region 1 (HVR-1) during the early phase of pegylated interferon and ribavirin therapy.

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Caraballo Cortés, K; Laskus, T; Bukowska-Ośko, I; Pawełczyk, A; Berak, H; Horban, A; Fic, M; Radkowski, M

2012-01-01

Genetic variability of hepatitis C virus (HCV) is considered to be an important factor defining viral pathogenesis, persistence and resistance to treatment. The aim of the present study was to characterize HCV genetic heterogeneity within a hypervariable region 1 (HVR-1) before and during the early period of pegylated interferon alfa (PEG-IFN-α) and ribavirin treatment in correlation with treatment outcome. The study involved 24 patients treated with PEG-IFN-α and ribavirin whose sera were collected before (baseline) and at 7, 14, 21 28 and 56 day of treatment. HCV HVR-1 region was amplified by nested RT- PCR and subjected to SSCP (single strand conformational polymorphism) analysis. SSCP changes of HCV HVR-1 over time in each patient were compared to treatment outcome results. In 2/11 (18%) SVR+ and 8/13 (62%) SVR- treated patients, HVR-1 genetic changes manifested by new SSCP bands (new genetic variants) and were significantly more frequent in nonresponders (P HVR-1 variability during the early phase of PEG-IFN-α and ribavirin therapy may be predictive of treatment outcome.

Characteristics of the interferon regulatory factor 5 (IRF5) and its expression in response to LCDV and poly I:C challenges in Japanese flounder, Paralichthys olivaceus.

Science.gov (United States)

Hu, Guo-Bin; Lou, Hui-Min; Dong, Xian-Zhi; Liu, Qiu-Ming; Zhang, Shi-Cui

2012-10-01

Interferon regulatory factor 5 (IRF5) has been identified as a key transcriptional mediator regulating expression of both type I interferons (IFNs) and proinflammatory cytokines. In this study, the cDNA and genomic sequences of IRF5 were isolated from Japanese flounder, Paralichthys olivaceus. The gene of Japanese flounder (Jf)IRF5 is 7326 bp long, contains 9 exons and 8 introns and encodes a putative protein of 472 amino acids. The predicted protein sequence shares 61.1-81.9% identity to fish IRF5 and possesses a DNA-binding domain (DBD), a middle region (MR), an IRF association domain (IAD), a virus activated domain (VAD) and two nuclear localization signals (NLSs) conserved in all known IRF5s. Phylogenetic analysis clustered it into the teleost IRF5 subgroup within vertebrate IRF5 group. JfIRF5 mRNA was constitutively expressed in all tissues examined, with higher levels observed in the gills and head kidney. Gene expression of JfIRF5 was analyzed over a 7-day time course in the gills, head kidney, spleen and muscle of Japanese flounders challenged with lymphocystis disease virus (LCDV) and polyinosinic:polycytidylic acid (poly I:C). The data showed that JfIRF5 expression was slightly up-regulated by LCDV, but its induction time was clearly moved up; in contrast, the induction upon poly I:C challenge started not earlier than day 2 post-injection and was stronger and more persistent with a later peak time in all four organs. The late and long-lasting inductive expression of JfIRF5 following poly I:C challenge suggests that it might be an interferon stimulated gene (ISG), the induction of which is driven by poly I:C-induced type I IFNs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Use of the johnin PPD interferon-gamma assay in control of bovine paratuberculosis

DEFF Research Database (Denmark)

Jungersen, Gregers; Mikkelsen, Heidi; Grell, Susanne N.

2012-01-01

Although the interferon-gamma (IFN-γ) assay for measurements of cell-mediated immune (CMI) responses to paratuberculosis PPD (johnin) has been available for close to 20 years, the assay has not yet emerged as the long desired test to identify infected animals at an early time point. Among other...

Interferon-tau and oxytocin receptor in bovien placentomes through out pregnancy

DEFF Research Database (Denmark)

Dantzer, Vibeke; Ivell, R.; Balvers, M.

Objective: Interferon-tau (IFNT) secreted by the conceptus is an important factor in the maintenance of luteal function in cows during early pregnancy until day 36. In this multiplex, synepitheliochorial placenta the expression of oxytocin receptor (OXTR) is resumed in the intercaruncular but not....../or OXTR expression until parturition. Supported by a grant from the Deutsche Forschungsgemeinschaft to R.I....

Early Maternal Employment and Children's Vocabulary and Inductive Reasoning Ability: A Dynamic Approach

Science.gov (United States)

Kühhirt, Michael; Klein, Markus

2018-01-01

This study investigates the relationship between early maternal employment history and children's vocabulary and inductive reasoning ability at age 5, drawing on longitudinal information on 2,200 children from the Growing Up in Scotland data. Prior research rarely addresses dynamics in maternal employment and the methodological ramifications of…

Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway

Science.gov (United States)

Sun, Lijun; Wu, Jiaxi; Du, Fenghe; Chen, Xiang; Chen, Zhijian J.

2013-01-01

The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers the host immune responses such as the production of type-I interferons (IFN). Cytosolic DNA induces IFN through the production of cyclic-GMP-AMP (cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced IFNβ in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and IFNβ induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP. PMID:23258413

Interferon α subtypes in HIV infection.

Science.gov (United States)

Sutter, Kathrin; Dickow, Julia; Dittmer, Ulf

2018-02-13

Type I interferons (IFN), which are immediately induced after most virus infections, are central for direct antiviral immunity and link innate and adaptive immune responses. However, several viruses have evolved strategies to evade the IFN response by preventing IFN induction or blocking IFN signaling pathways. Thus, therapeutic application of exogenous type I IFN or agonists inducing type I IFN responses are a considerable option for future immunotherapies against chronic viral infections. An important part of the type I IFN family are 12 IFNα subtypes, which all bind the same receptor, but significantly differ in their biological activities. Up to date only one IFNα subtype (IFNα2) is being used in clinical treatment against chronic virus infections, however its therapeutic success rate is rather limited, especially during Human Immunodeficiency Virus (HIV) infection. Recent studies addressed the important question if other IFNα subtypes would be more potent against retroviral infections in in vitro and in vivo experiments. Indeed, very potent IFNα subtypes were defined and their antiviral and immunomodulatory properties were characterized. In this review we summarize the recent findings on the role of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus infection. This includes their induction during HIV/SIV infection, their antiretroviral activity and the regulation of immune response against HIV by different IFNα subtypes. The findings might facilitate novel strategies for HIV cure or functional cure studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

JC virus induces altered patterns of cellular gene expression: Interferon-inducible genes as major transcriptional targets

International Nuclear Information System (INIS)

Verma, Saguna; Ziegler, Katja; Ananthula, Praveen; Co, Juliene K.G.; Frisque, Richard J.; Yanagihara, Richard; Nerurkar, Vivek R.

2006-01-01

Human polyomavirus JC (JCV) infects 80% of the population worldwide. Primary infection, typically occurring during childhood, is asymptomatic in immunocompetent individuals and results in lifelong latency and persistent infection. However, among the severely immunocompromised, JCV may cause a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Virus-host interactions influencing persistence and pathogenicity are not well understood, although significant regulation of JCV activity is thought to occur at the level of transcription. Regulation of the JCV early and late promoters during the lytic cycle is a complex event that requires participation of both viral and cellular factors. We have used cDNA microarray technology to analyze global alterations in gene expression in JCV-permissive primary human fetal glial cells (PHFG). Expression of more than 400 cellular genes was altered, including many that influence cell proliferation, cell communication and interferon (IFN)-mediated host defense responses. Genes in the latter category included signal transducer and activator of transcription 1 (STAT1), interferon stimulating gene 56 (ISG56), myxovirus resistance 1 (MxA), 2'5'-oligoadenylate synthetase (OAS), and cig5. The expression of these genes was further confirmed in JCV-infected PHFG cells and the human glioblastoma cell line U87MG to ensure the specificity of JCV in inducing this strong antiviral response. Results obtained by real-time RT-PCR and Western blot analyses supported the microarray data and provide temporal information related to virus-induced changes in the IFN response pathway. Our data indicate that the induction of an antiviral response may be one of the cellular factors regulating/controlling JCV replication in immunocompetent hosts and therefore constraining the development of PML

Interferon-induced central retinal vein thrombosis

International Nuclear Information System (INIS)

Nazir, L.; Husain, A.; Haroon, W.; Shaikh, M.I.; Mirza, S.A.; Khan, Z.

2012-01-01

A middle-aged lady presented with sudden onset of unilateral central retinal vein thrombosis after completing 6 months course of interferon and ribavirin for chronic hepatitis C infection. She had no risk factors and all her thrombophilia workup was normal, however, she was found to be dyslipidemic which may have contributed to atherosclerosis and predispose to thrombosis. Despite anticoagulation, her visual acuity deteriorated. This case illustrates the possibility of unpredictable visual complication of interferon. Frequent eye examination should be undertaken in patients having underlying risk factors like diabetes, hypertension or dyslipidemia undergoing interferon therapy. (author)

Interferon-induced central retinal vein thrombosis

Energy Technology Data Exchange (ETDEWEB)

Nazir, L; Husain, A; Haroon, W; Shaikh, M I; Mirza, S A; Khan, Z

2012-11-15

A middle-aged lady presented with sudden onset of unilateral central retinal vein thrombosis after completing 6 months course of interferon and ribavirin for chronic hepatitis C infection. She had no risk factors and all her thrombophilia workup was normal, however, she was found to be dyslipidemic which may have contributed to atherosclerosis and predispose to thrombosis. Despite anticoagulation, her visual acuity deteriorated. This case illustrates the possibility of unpredictable visual complication of interferon. Frequent eye examination should be undertaken in patients having underlying risk factors like diabetes, hypertension or dyslipidemia undergoing interferon therapy. (author)

Interferon-α treatment in systemic mastocytosis

DEFF Research Database (Denmark)

Bjerrum, Ole Weis

2011-01-01

classification need treatment. This review on interferon treatment in systemic mastocytosis documents an effect of this biological agent in some patients with mastocytosis. However, the place of interferon-a, as mono- or combination therapy, in the treatment algorithm may only be definitely established...

Early cytokine modulation after the rapid induction phase of sublingual immunotherapy with mite monomeric allergoids.

Science.gov (United States)

Di Gioacchino, M; Perrone, A; Petrarca, C; Di Claudio, F; Mistrello, G; Falagiani, P; Dadorante, V; Verna, N; Braga, M; Ballone, E; Cavallucci, E

2008-01-01

The influence of different treatment schedules of sublingual immunotherapy (SLIT) in activating IL-10-producing T-cells, crucial in inducing allergen-specific tolerance, is not completely understood. The present work was designed to evaluate allergen driven interleukin release by mononuclear cells in the early phase of SLIT, after application of different induction schemes. Twenty mite-allergic patients were enrolled, 10 (group A) treated with a traditional 98 day induction scheme and 10 (group B) with a 16 day scheme with monomeric allergoid vaccine. At the end of the induction phase, the cumulative doses taken by group A and group B patients were equivalent to 50.5 and 50.3 microg of mite group 1 allergens, respectively. The release of Th1-, Th2- and Treg-related interleukins was assessed in culture supernatants of 5 microg/ml Der-p1-stimulated mononuclear cells, isolated before and after the induction phases. No relevant treatment-related side effects were observed. Interleukin release was similar in the two groups at the enrolment. Non-stimulated and Der p 1 stimulated release of studied cytokines was similar in the two groups at enrolment. Der p 1 stimulation significantly increased IL-10 release (pallergoids are utilized.

Heartland virus NSs protein disrupts host defenses by blocking the TBK1 kinase-IRF3 transcription factor interaction and signaling required for interferon induction.

Science.gov (United States)

Ning, Yun-Jia; Feng, Kuan; Min, Yuan-Qin; Deng, Fei; Hu, Zhihong; Wang, Hualin

2017-10-06

Heartland virus (HRTV) is a pathogenic phlebovirus related to the severe fever with thrombocytopenia syndrome virus (SFTSV), another phlebovirus causing life-threatening disease in humans. Previous findings have suggested that SFTSV can antagonize the host interferon (IFN) system via viral nonstructural protein (NSs)-mediated sequestration of antiviral signaling proteins into NSs-induced inclusion bodies. However, whether and how HRTV counteracts the host innate immunity is unknown. Here, we report that HRTV NSs (HNSs) also antagonizes IFN and cytokine induction and bolsters viral replication, although no noticeable inclusion body formation was observed in HNSs-expressing cells. Furthermore, HNSs inhibited the virus-triggered activation of IFN-β promoter by specifically targeting the IFN-stimulated response element but not the NF-κB response element. Consistently, HNSs blocked the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3, an IFN-stimulated response element-activating transcription factor). Reporter gene assays next showed that HNSs blockades the antiviral signaling mediated by RIG-I-like receptors likely at the level of TANK-binding kinase 1 (TBK1). Indeed, HNSs strongly interacts with TBK1 as indicated by confocal microscopy and pulldown analyses, and we also noted that the scaffold dimerization domain of TBK1 is required for the TBK1-HNSs interaction. Finally, pulldown assays demonstrated that HNSs expression dose-dependently diminishes a TBK1-IRF3 interaction, further explaining the mechanism for HNSs function. Collectively, these data suggest that HNSs, an antagonist of host innate immunity, interacts with TBK1 and thereby hinders the association of TBK1 with its substrate IRF3, thus blocking IRF3 activation and transcriptional induction of the cellular antiviral responses. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Autocrine secretion of tumor necrosis factor under the influence of interferon-γ amplifies HLA-DR gene induction in human monocytes

International Nuclear Information System (INIS)

Arenzana-Seisdedos, F.; Mogensen, S.C.; Vuillier, F.; Fiers, W.; Virelizier, J.L.

1988-01-01

Recombinant interferon-γ (IFN-γ) induced HLA-DR gene expression in both U937 and THP-1 human monocytic cell lines, although the former was only very weakly inducible. Combination of recombinant tumor necrosis factor (TNF) and IFN-γ resulted in a synergistic enhancement of DR mRNA and protein induction in both cell lines. TNF alone increased the constitutive expression of the DR gene in THP-1 cells. In the HLA class II-negative U937 cells, TNF used alone was not able to induce DR gene expression. Such a negative result was not due to a lack of TNF receptor expression in U937 cells, since TNF clearly induced HLA class I and TNF gene expression in this cell line. THP-1, but not U937, cells secreted TNF under the influence of IFN-γ. Neutralization of TNF by a specific antibody decreased IFN-γ-induced DR antigen expression in THP-1 cultures. These observations indicate that TNF is not able to directly induce DR gene expression, but rather amplifies ongoing expression of this gene, whether constitutive or induced by IFN-γ. In the two cell lines tested, the level of DR inducibility under the influence of IFN-γ used alone depended on a different inducibility of TNF secretion by IFN-γ. Altogether, the observations indicate that TNF, whether exogenous or endogenously produced under the influence of IFN-γ, amplifies DR gene expression in monocytes, a phenomenon that may provide to such antigen-presenting cells a selective sensitivity to the DR-inducing effects of IFN-γ

Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier.

Science.gov (United States)

Nazli, Aisha; Dizzell, Sara; Zahoor, Muhammad Atif; Ferreira, Victor H; Kafka, Jessica; Woods, Matthew William; Ouellet, Michel; Ashkar, Ali A; Tremblay, Michel J; Bowdish, Dawn Me; Kaushic, Charu

2018-03-19

More than 40% of HIV infections occur via female reproductive tract (FRT) through heterosexual transmission. Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens. These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses. Previously, we have shown that in response to HIV-1 gp120, the genital epithelial cells (GECs) from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection. In this study, we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-β (IFNβ) antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier. The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNβ production. Interferon-β was induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface. The induction of IFNβ was dependent upon activation of transcription factor IRF3 (interferon regulatory factor 3). The IFNβ was biologically active, had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells. This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways. This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.Cellular and Molecular Immunology advance online publication, 19 March 2018; doi:10.1038/cmi.2017.168.

Cyclic changes in gene expression induced by Peg-interferon alfa-2b plus ribavirin in peripheral blood monocytes (PBMC of hepatitis C patients during the first 10 weeks of treatment

Directory of Open Access Journals (Sweden)

Edenberg Howard J

2008-11-01

Full Text Available Abstract Background and Aims This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron™ and ribavirin (administered by weight in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys™ and ribavirin were administered. Methods RNA was isolated from peripheral blood monocytes (PBMC from twenty treatment-naïve patients just before treatment (day 1 and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. Results The expression of many genes differed significantly (p ≤ 0.001 and changed at least 1.5-fold at days 3 (290 probes and 10 (255 probes, but the number dropped at days 6 (165 and 13 (142. Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1, TRAIL, IL1Rα and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1 was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. Conclusion The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our

Effects of Interferon Therapy on Heart

International Nuclear Information System (INIS)

Faisal, A. W. K.; Ali, S. A.; Nisar, S.; Ahmad, F.

2016-01-01

Background: Hepatitis C virus (HCV) infection is a major health problem worldwide. Around 185 million people are suffering from HCV infection all over the world, out of which 10 million people are residing in Pakistan. 4.7 percent (2-14 percent by different studies) of Pakistanis are suffering from this deadly disease. Interferon+Ribavarin IFN/RIB is the mainstay of treatment for this infection. Various cardiovascular adverse reactions have been reported of this therapy. We conducted this study at Punjab Institute of cardiology to look for the cardiac safety of interferon therapy in our population. Methods: We studied HCV infected patients planned for interferon therapy between 21st of November 2012 to 20th of August 2014. Echocardiography was performed before, during and after the completion of therapy. Pegylated interferon once a week plus ribavirin therapy was given to the patients. Patients received 16-40 injections of pegylated interferon depending upon the decision of hepatologist. Patients with prior structural heart disease, patients who did not start the treatment or patients who did not turn up on follow up were excluded from the study. Results: A total of 102 patients planned to have interferon therapy were screened echocardiographically. One patient died after 5 injections due to infection (a non-cardiac cause). 46 patients completed the treatment and the follow up. None of the patients had any acute cardiac event. All patients had normal biventricular systolic function at the end of study. None of the patients had significant valvular heart disease or pulmonary hypertension. Reversal of E/A ratio or E/A ratio>2, parameters of diastolic dysfunction and mild pericardial effusion were noted in a statistically significant number of patients. Conclusion: Interferon therapy for HCV infection is cardiac safe in patients who have structurally normal heart. Female patients have propensity of adverse events like severe diastolic dysfunction and mild pericardial

Stability of human interferon-beta 1: oligomeric human interferon-beta 1 is inactive but is reactivated by monomerization.

Science.gov (United States)

Utsumi, J; Yamazaki, S; Kawaguchi, K; Kimura, S; Shimizu, H

1989-10-05

Human interferon-beta 1 is extremely stable is a low ionic strength solution of pH 2 such as 10 mM HCl at 37 degrees C. However, the presence of 0.15 M NaCl led to a remarkable loss of antiviral activity. The molecular-sieve high-performance liquid chromatography revealed that, whereas completely active human interferon-beta 1 eluted as a 25 kDa species (monomeric form), the inactivated preparation eluted primarily as a 90 kDa species (oligomeric form). The specific activity (units per mg protein) of the oligomeric form was approx. 10% of that of the monomeric form. This observation shows that oligomeric human interferon-beta 1 is apparently in an inactive form. When the oligomeric eluate was resolved by polyacrylamide gel containing sodium dodecyl sulphate (SDS), it appeared to be monomeric under non-reducing conditions. Monomerization of the oligomeric human interferon-beta 1 by treatment with 1% SDS, fully regenerated its antiviral activity. These results suggest that the inactivation of the human interferon-beta 1 preparation was caused by its oligomerization via hydrophobic interactions without the formation of intermolecular disulphide bonds. These oligomers can be dissociated by SDS to restore biological activity.

IL-12 and IL-18 Induction and Subsequent NKT Activation Effects of the Japanese Botanical Medicine Juzentaihoto

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Ken Taniguchi

2008-07-01

Full Text Available In this study, we first measured some cytokine concentrations in the serum of patients treated with Juzentaihoto (JTT. Of the cytokines measured interleukin (IL -18 was the most prominently up-regulated cytokine in the serum of patients under long term JTT administration. We next evaluated the effects of JTT in mice, focusing especially on natural killer T (NKT cell induction. Mice fed JTT were compared to control group ones. After sacrifice, the liver was fixed, embedded and stained. Transmission electron microscope (TEM observations were performed. Although the mice receiving the herbal medicine had same appearance, their livers were infiltrated with massive mononuclear cells, some of which were aggregated to form clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of IL-12 and IL-18 in the liver of JTT treated mice. To clarify what the key molecules that induce immunological restoration with JTT might be, we next examined in vitro lymphocyte cultures. Mononuclear cells isolated and prepared from healthy volunteers were cultured with and without JTT. Within 24 hours, JTT induced the IL-12 and IL-18 production and later (72 hours induction of interferon (IFN-gamma. Oral administration of JTT may induce the expression of IL-12 in the early stage, and IL-18 in the chronic stage, followed by NKT induction. Their activation, following immunological restoration could contribute to anti-tumor effects.

IL-12 and IL-18 induction and subsequent NKT activation effects of the Japanese botanical medicine Juzentaihoto.

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Fujiki, Kazuhiko; Nakamura, Masanori; Matsuda, Takako; Isogai, Mariko; Ikeda, Minako; Yamamoto, Yutaka; Kitamura, Mari; Sazaki, Naoko; Yakushiji, Fumiatsu; Suzuki, Shinji; Tomiyama, Junji; Uchida, Takashi; Taniguchi, Ken

2008-06-01

In this study, we first measured some cytokine concentrations in the serum of patients treated with Juzentaihoto (JTT). Of the cytokines measured interleukin (IL) -18 was the most prominently up-regulated cytokine in the serum of patients under long term JTT administration. We next evaluated the effects of JTT in mice, focusing especially on natural killer T (NKT) cell induction. Mice fed JTT were compared to control group ones. After sacrifice, the liver was fixed, embedded and stained. Transmission electron microscope (TEM) observations were performed. Although the mice receiving the herbal medicine had same appearance, their livers were infiltrated with massive mononuclear cells, some of which were aggregated to form clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of IL-12 and IL-18 in the liver of JTT treated mice. To clarify what the key molecules that induce immunological restoration with JTT might be, we next examined in vitro lymphocyte cultures. Mononuclear cells isolated and prepared from healthy volunteers were cultured with and without JTT. Within 24 hours, JTT induced the IL-12 and IL-18 production and later (72 hours) induction of interferon (IFN)-gamma. Oral administration of JTT may induce the expression of IL-12 in the early stage, and IL-18 in the chronic stage, followed by NKT induction. Their activation, following immunological restoration could contribute to anti-tumor effects.

Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis

DEFF Research Database (Denmark)

Börnsen, Lars; Christensen, Jeppe Romme; Ratzer, Rikke

2015-01-01

Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for......-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.......Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used...... for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels...

Interferon γ-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses.

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Thompson, Mikayla R; Sharma, Shruti; Atianand, Maninjay; Jensen, Søren B; Carpenter, Susan; Knipe, David M; Fitzgerald, Katherine A; Kurt-Jones, Evelyn A

2014-08-22

The interferon γ-inducible protein 16 (IFI16) has recently been linked to the detection of nuclear and cytosolic DNA during infection with herpes simplex virus-1 and HIV. IFI16 binds dsDNA via HIN200 domains and activates stimulator of interferon genes (STING), leading to TANK (TRAF family member-associated NF-κB activator)-binding kinase-1 (TBK1)-dependent phosphorylation of interferon regulatory factor (IRF) 3 and transcription of type I interferons (IFNs) and related genes. To better understand the role of IFI16 in coordinating type I IFN gene regulation, we generated cell lines with stable knockdown of IFI16 and examined responses to DNA and RNA viruses as well as cyclic dinucleotides. As expected, stable knockdown of IFI16 led to a severely attenuated type I IFN response to DNA ligands and viruses. In contrast, expression of the NF-κB-regulated cytokines IL-6 and IL-1β was unaffected in IFI16 knockdown cells, suggesting that the role of IFI16 in sensing these triggers was unique to the type I IFN pathway. Surprisingly, we also found that knockdown of IFI16 led to a severe attenuation of IFN-α and the IFN-stimulated gene retinoic acid-inducible gene I (RIG-I) in response to cyclic GMP-AMP, a second messenger produced by cyclic GMP-AMP synthase (cGAS) as well as RNA ligands and viruses. Analysis of IFI16 knockdown cells revealed compromised occupancy of RNA polymerase II on the IFN-α promoter in these cells, suggesting that transcription of IFN-stimulated genes is dependent on IFI16. These results indicate a broader role for IFI16 in the regulation of the type I IFN response to RNA and DNA viruses in antiviral immunity. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Interferon production and immune response induction in pathogenic rabies virus-infected mice

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Marcovistz, R; Leal, E C; De Souza Matos, D C [Departamento de Immunologia, Instituto Oswaldo Cruz, Caixa Postal 926, 21045 Rio de Janeiro (Brazil); Tsiang, H [Service Rage, Istitut Pasteur, Paris (France)

1994-08-01

Pathogenic parental rabies virus strain CVS (challenge virus standard) and its apathogenic variant RV194-2 were shown to differ in their ability to induce interferon (IFN) and immune response of the host. After intracerebral inoculation. IFN and antibody production was higher in the RV194-2 virus-infected mice than in the CVS infection. The enhancement of 2-5A synthetase activity, an IFN-mediated enzyme marker, showed biochemical evidence that IFN is active in both apathogenic and pathogenic infections. On the other hand, spontaneous proliferation in vitro of thymocytes and splenocytes from CVS virus-infected mice was strongly inhibited in contrast to the RV194-2 infection. In the CVS infection, the thymocyte proliferation However, in the RV194-2 infection, the thymocyte proliferation was higher than of the splenocytes. These results suggest a better performance of T-cell response to the RV194-2 infection. This fact can be critical for an enhancement of antibody production in the apathogenic infection and subsequent virus clearance from the brain of RV194-2 virus-infected mice. (author) 1 fig., 3 tabs., 32 refs.

Plasma membrane Toll-like receptor activation increases bacterial uptake but abrogates endosomal Lactobacillus acidophilus induction of interferon-β

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Boye, Louise; Welsby, Iain; Lund, Lisbeth Drozd

2016-01-01

Lactobacillus acidophilus induces a potent interferon-β (IFN-β) response in dendritic cells (DCs) by a Toll-like receptor 2 (TLR2) -dependent mechanism, in turn leading to strong interleukin-12 (IL-12) production. In the present study, we investigated the involvement of different types of endocyt...

[Pegylation and interferons in multiple sclerosis

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Diego Centonze

2016-07-01

Full Text Available Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs. [Article in Italian

Acetaminophen modulates the transcriptional response to recombinant interferon-beta.

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Aaron Farnsworth

Full Text Available BACKGROUND: Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-beta treatment. CD-1 mice were administered acetaminophen (APAP, interferon-beta (IFN-beta or a combination of IFN-beta+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-beta. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IkappaBK/NF-kappaB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. CONCLUSIONS/SIGNIFICANCE: A significant change in the transcriptional response was observed following co-administration of IFN-beta+APAP relative to IFN-beta treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-beta treatment.

Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

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Liu, Yu-Ching [Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan (China); Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Ho, Heng-Chien; Lee, Miau-Rong [Department of Biochemistry, China Medical University, Taichung 404, Taiwan (China); Lai, Kuang-Chi [Department of Surgery, China Medical University Beigang Hospital, Yunlin 651, Taiwan (China); School of Medicine, China Medical University, Taichung 404, Taiwan (China); Yeh, Chung-Min; Lin, Yueh-Min [Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan (China); Ho, Tin-Yun [School of Chinese Medicine, China Medical University, Taichung 404, Taiwan (China); Hsiang, Chien-Yun, E-mail: cyhsiang@mail.cmu.edu.tw [Department of Microbiology, China Medical University, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

2012-07-15

The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

International Nuclear Information System (INIS)

Liu, Yu-Ching; Ho, Heng-Chien; Lee, Miau-Rong; Lai, Kuang-Chi; Yeh, Chung-Min; Lin, Yueh-Min; Ho, Tin-Yun; Hsiang, Chien-Yun; Chung, Jing-Gung

2012-01-01

The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

Specificity, cross-talk and adaptation in Interferon signaling

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Zilman, Anton

Innate immune system is the first line of defense of higher organisms against pathogens. It coordinates the behavior of millions of cells of multiple types, achieved through numerous signaling molecules. This talk focuses on the signaling specificity of a major class of signaling molecules - Type I Interferons - which are also used therapeutically in the treatment of a number of diseases, such as Hepatitis C, multiple sclerosis and some cancers. Puzzlingly, different Interferons act through the same cell surface receptor but have different effects on the target cells. They also exhibit a strange pattern of temporal cross-talk resulting in a serious clinical problem - loss of response to Interferon therapy. We combined mathematical modeling with quantitative experiments to develop a quantitative model of specificity and adaptation in the Interferon signaling pathway. The model resolves several outstanding experimental puzzles and directly affects the clinical use of Type I Interferons in treatment of viral hepatitis and other diseases.

Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion

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Priya Luthra

2017-04-01

Full Text Available Ebola virus (EBOV protein VP35 inhibits production of interferon alpha/beta (IFN by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication.

Postinduction represssion of the β-interferon gene is mediated through two positive regulatory domains

International Nuclear Information System (INIS)

Whittemore, L.A.; Maniatis, T.

1990-01-01

Virus induction of the human β-interferon (β-IFN) gene results in an increase in the rate of β-IFN mRNA synthesis, followed by a rapid postinduction decrease. In this paper, the authors show that two β-IFN promoter elements, positive regulatory domains I and II (PRDI and PRDII), which are required for virus induction of the β-IFN gene are also required for the postinduction turnoff. Although protein synthesis is not necessary for activation, it is necessary for repression of these promoter elements. Examination of nuclear extracts from cells infected with virus reveals the presence of virus-inducible, cycloheximide-sensitive, DNA-binding activities that interact specifically with PRDI or PRDII. They propose that the postinduction repression of β-IFN gene transcription involves virus inducible repressors that either bind directly to the positive regulatory elements of the β-IFN promoter or inactivate the positive regulatory factors bound to PRDI and PRDII

Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.

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Seung Bum Park

Full Text Available Hepatitis C virus (HCV actively evades host interferon (IFN responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP and poly(IC. The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity.

Interferon in lyssavirus infection.

Science.gov (United States)

Rieder, Martina; Finke, Stefan; Conzelmann, Karl-Klaus

2012-01-01

Rabies is a zoonosis still claiming more than 50 000 human deaths per year. Typically, human cases are due to infection with rabies virus, the prototype of the Lyssavirus genus, but sporadic cases of rabies-like encephalitis caused by other lyssaviruses have been reported. In contrast to rabies virus, which has an extremely broad host range including many terrestrial warm-blooded animals, rabies-related viruses are associated predominantly with bats and rarely infect terrestrial species. In spite of a very close genetic relationship of rabies and rabies-related viruses, the factors determining the limited host range of rabies-related viruses are not clear. In the past years the importance of viral countermeasures against the host type I interferon system for establishment of an infection became evident. The rabies virus phosphoprotein (P) has emerged as a critical factor required for paralysing the signalling cascades leading to transcriptional activation of interferon genes as well as interferon signalling pathways, thereby limiting expression of antiviral and immune stimulatory genes. Comparative studies would be of interest in order to determine whether differential abilities of the lyssavirus P proteins contribute to the restricted host range of lyssaviruses.

Ester alkaloids from Cephalotaxus interfere with the 2'3'-cGAMP-induced type I interferon pathway in vitro.

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Gayoung Park

Full Text Available Dysregulated activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING pathway by self-DNA contributes to interferonopathy and promotes autoimmune diseases. To identify potential suppressors of STING-induced type I interferon (IFN induction, ethanol extracts of medicinal plants were screened for inhibitory activity against IFN-ß promoter activation. Notably, 70% ethanol extract of Cephalotaxus koreana specifically down-regulated STING-induced, but not TBK1- or IRF3-induced, IFN-ß promoter activity. The compounds exerting inhibitory activity specifically against STING-mediated IFN-ß promoter activation were identified as ester alkaloids isolated from the genus, Cephalotaxus, homoharringtonine and harringtonine. Furthermore, these two compounds inhibited 2'3'-cGAMP-induced IFN-stimulated gene expression and interaction between STING and TBK1. These suppressive effects were not observed with cephalotaxine devoid of the ester side-chain. Our data support the potential utility of homoharringtonine and harringtonine to treat STING-associated interferonopathy and autoimmune diseases.

Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a.

Science.gov (United States)

Rudick, R A; Pace, A; Rani, M R S; Hyde, R; Panzara, M; Appachi, S; Shrock, J; Maurer, S L; Calabresi, P A; Confavreux, C; Galetta, S L; Lublin, F D; Radue, E-W; Ransohoff, R M

2009-06-09

Findings from a small clinical study suggested that statins may counteract the therapeutic effects of interferon beta (IFNbeta) in patients with relapsing-remitting multiple sclerosis (RRMS). We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFNbeta-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of statins on efficacy of IFNbeta. SENTINEL was a prospective trial of patients with RRMS treated with natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFNbeta-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFNbeta-1a 30 microg. Clinical and MRI outcomes in patients treated with IM IFNbeta-1a only (no-statins group, n = 542) were compared with those of patients taking IM IFNbeta-1a and statins at doses used to treat hyperlipidemia (statins group, n = 40). No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-hyperintense lesions (p = 0.802) at 2 years. More patients in the statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the no-statins group. Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes. Statin therapy does not appear to affect clinical effects of IM interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.

Early Maternal Employment and Children's Vocabulary and Inductive Reasoning Ability: A Dynamic Approach.

Science.gov (United States)

Kühhirt, Michael; Klein, Markus

2018-03-01

This study investigates the relationship between early maternal employment history and children's vocabulary and inductive reasoning ability at age 5, drawing on longitudinal information on 2,200 children from the Growing Up in Scotland data. Prior research rarely addresses dynamics in maternal employment and the methodological ramifications of time-variant confounding. The present study proposes various measures to capture duration, timing, and stability of early maternal employment and uses inverse probability of treatment weighting to control for time-variant confounders that may partially mediate the effect of maternal employment on cognitive scores. The findings suggest only modest differences in the above ability measures between children who have been exposed to very different patterns of eary maternal employment, but with similar observed covariate history. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.

Thyroid hormonal disturbances related to treatment of hepatitis C with interferon-alpha and ribavirin

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Debora Lucia Seguro Danilovic

2011-01-01

Full Text Available OBJECTIVE: To characterize thyroid disturbances induced by interferon-alpha and ribavirin therapy in patients with chronic hepatitis C. INTRODUCTION: Interferon-alpha is used to treat chronic hepatitis C infections. This compound commonly induces both autoimmune and non-autoimmune thyroiditis. METHODS: We prospectively selected 26 patients with chronic hepatitis C infections. Clinical examinations, hormonal evaluations, and color-flow Doppler ultrasonography of the thyroid were performed before and during antiviral therapy. RESULTS: Of the patients in our study, 54% had no thyroid disorders associated with the interferon-alpha therapy but showed reduced levels of total T3 along with a decrease in serum alanine aminotransferase. Total T4 levels were also reduced at 3 and 12 months, but free T4 and thyroid stimulating hormone (TSH levels remained stable. A total of 19% of the subjects had autoimmune interferon-induced thyroiditis, which is characterized by an emerge of antithyroid antibodies or overt hypothyroidism. Additionally, 16% had non-autoimmune thyroiditis, which presents as destructive thyroiditis or subclinical hypothyroidism, and 11% remained in a state of euthyroidism despite the prior existence of antithyroidal antibodies. Thyrotoxicosis with destructive thyroiditis was diagnosed within three months of therapy, and ultrasonography of these patients revealed thyroid shrinkage and discordant change in the vascular patterns. DISCUSSION: Decreases in the total T3 and total T4 levels may be related to improvements in the hepatocellular lesions or inflammatory changes similar to those associated with nonthyroidal illnesses. The immune mechanisms and direct effects of interferon-alpha can be associated with thyroiditis. CONCLUSION: Interferon-alpha and ribavirin induce autoimmune and non-autoimmune thyroiditis and hormonal changes (such as decreased total T3 and total T4 levels, which occur despite stable free T4 and TSH levels. A thyroid

Literature systematic review on the ophthalmological side effects of interferons

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Yara Dadalti Fragoso

2011-08-01

Full Text Available Interferons alpha and beta have been used worldwide for a few decades, altering the natural history of several severe diseases including hepatitis C, cancer and immune-mediated conditions such as multiple sclerosis. The adverse events profile of interferons is well established, but only isolated reports of ophthalmological complications of interferon therapy have been published. The objective of this study was to carry out a literature systematic review on the subject, bringing to light the need for careful ophthalmological monitoring of patients undergoing interferon treatment. Nearly 500 cases of ophthalmological complications related to interferon have been reported. The most frequent findings were soft exudates, hemorrhages and retina ischemia.

Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone chronic hepatitis B. Protocol for a Cochrane Review

DEFF Research Database (Denmark)

Mellerup, M T; Krogsgaard, K; Mathurin, P

2000-01-01

Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon....

Respiratory syncytial virus mechanisms to interfere with type 1 interferons.

Science.gov (United States)

Barik, Sailen

2013-01-01

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family that consists of viruses with nonsegmented negative-strand RNA genome. Infection by these viruses triggers the innate antiviral response of the host, mainly type I interferon (IFN). Essentially all other viruses of this family produce IFN suppressor functions by co-transcriptional RNA editing. In contrast, RSV has evolved two unique nonstructural proteins, NS1 and NS2, to effectively serve this purpose. Together, NS1 and NS2 degrade or sequester multiple signaling proteins that affect both IFN induction and IFN effector functions. While the mechanism of action of NS1 and NS2 is a subject of active research, their effect on adaptive immunity is also being recognized. In this review, we discuss various aspects of NS1 and NS2 function with implications for vaccine design.

Type I Interferons Direct Gammaherpesvirus Host Colonization.

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Cindy S E Tan

2016-05-01

Full Text Available Gamma-herpesviruses colonise lymphocytes. Murid Herpesvirus-4 (MuHV-4 infects B cells via epithelial to myeloid to lymphoid transfer. This indirect route entails exposure to host defences, and type I interferons (IFN-I limit infection while viral evasion promotes it. To understand how IFN-I and its evasion both control infection outcomes, we used Mx1-cre mice to tag floxed viral genomes in IFN-I responding cells. Epithelial-derived MuHV-4 showed low IFN-I exposure, and neither disrupting viral evasion nor blocking IFN-I signalling markedly affected acute viral replication in the lungs. Maximising IFN-I induction with poly(I:C increased virus tagging in lung macrophages, but the tagged virus spread poorly. Lymphoid-derived MuHV-4 showed contrastingly high IFN-I exposure. This occurred mainly in B cells. IFN-I induction increased tagging without reducing viral loads; disrupting viral evasion caused marked attenuation; and blocking IFN-I signalling opened up new lytic spread between macrophages. Thus, the impact of IFN-I on viral replication was strongly cell type-dependent: epithelial infection induced little response; IFN-I largely suppressed macrophage infection; and viral evasion allowed passage through B cells despite IFN-I responses. As a result, IFN-I and its evasion promoted a switch in infection from acutely lytic in myeloid cells to chronically latent in B cells. Murine cytomegalovirus also showed a capacity to pass through IFN-I-responding cells, arguing that this is a core feature of herpesvirus host colonization.

early versus delayed induction of labour

African Journals Online (AJOL)

during labour versus 18 patients (52%) in the group that was induced .... (AMG) or a delayed induction group (DIG). Sealed .... Of the 7 CSs in the DIG, 3 were for fetal heart rate .... in mind that labour was never induced later than 48 hours.

AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA

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Yuki Nakaya

2017-07-01

Full Text Available Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs that stimulate the induction of interferons (IFNs and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING. Absent in melanoma 2 (AIM2-like receptors (ALRs have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

NARCIS (Netherlands)

Rudick, R.A.; Stuart, W.H.; Calabresi, P.A.; Confavreux, C.; Galetta, S.L.; Radue, E.W.; Lublin, F.D.; Weinstock-Guttman, B.; Wynn, D.R.; Lynn, F.; Panzara, M.A.; Sandrock, A.W.

2006-01-01

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies.

Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells.

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Jin, Shouheng; Tian, Shuo; Luo, Man; Xie, Weihong; Liu, Tao; Duan, Tianhao; Wu, Yaoxing; Cui, Jun

2017-10-19

Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatitis C virus and the controversial role of the interferon sensitivity determining region in the response to interferon treatment.

Science.gov (United States)

Torres-Puente, Manuela; Cuevas, José M; Jiménez-Hernández, Nuria; Bracho, María A; García-Robles, Inmaculada; Carnicer, Fernando; del Olmo, Juan; Ortega, Enrique; Moya, Andrés; González-Candelas, Fernando

2008-02-01

The degree of variability of the interferon sensitivity determining region (ISDR) in the hepatitis C virus (HCV) genome has been postulated to predict the response to interferon therapy, mainly in patients infected with subtype 1b, although this prediction has been the subject of a long controversy. This prediction has been tested by analyzing a cohort of 67 Spanish patients infected with HCV genotype 1, 23 of which were infected with subtype 1a and 44 with subtype 1b. A sample previous to therapy with alpha-interferon plus ribavirin was obtained and several clones (between 25 and 96) including the ISDR were sequenced from each patient. A significant correlation between mutations at the ISDR and response to treatment for subtype 1b patients, but not for those infected with subtype 1a, has been detected. Although the results suggest that the same relationship holds true for subtype 1a, lack of statistical power because of the small sample size of this subtype prevented firmer conclusions. However, identical ISDR sequences were found in responder and non-responder patients, suggesting that the stability of the ISDR sequence can occasionally help HCV to evade interferon therapy, although this is not a sufficient condition. More complex interactions, including the ISDR or not, are likely to exist and govern the HCV response to interferon treatment. (Copyright) 2007 Wiley-Liss, Inc.

Kaposi's sarcoma after alpha-interferon treatment for HIV-negative T ...

African Journals Online (AJOL)

Although interferon was successful in controlling the lymphoma the clinical course was complicated by the rapid development of aggressive, fatal Kaposi's sarcoma shortly after cessation of interferon treatment. It is suggested that the immunosuppressive effect of interferon therapy (or the T -cell lymphoma or both) may have ...

Interferon synthesis in mouse peritoneal cells damaged by x irradiation

Energy Technology Data Exchange (ETDEWEB)

Szolgay, E; T' alas, M

1976-01-01

NDV-induced interferon of peritoneal cells of irradiated (x-rays, 400 R) and control mice was investigated in vitro. Irradiation or treatment with hydroxyurea (10(-5) M) and mitomycin C (25 microng/ml) did not change interferon synthesis in spite of an 80 to 90% inhibition of 3H-thymidine incorporation. Increased doses of mitomycin C and treatment with actinomycin D and puromycin blocked interferon production. De novo interferon synthesis occurred in cells with damaged replicative activity of DNA caused by irradiation or by treatment with antimetabolites.

Laboratory evaluation of commercial interferon preparations

International Nuclear Information System (INIS)

Schoub, B.D.; Lyons, S.F.; Crespi, M.; Chiu, M.-N.; Lomnitzer, R.

1983-01-01

The antiviral, antiproliferative and natural killer-cell (NKC) stimulatory activities of four commercial therapeutic interferon preparations were assayed in a laboratory. The antiviral and antiproliferative activities of each preparation were relatively similar, but an unexpectedly high NKC stimulatory activity was found in one of them. In-house determination of antiviral activity and evaluation of the antiproliferative and NKC stimulation potential of interferon preparations are essential before rational clinical trials of this agent are carried out

Type I interferons in tuberculosis: Foe and occasionally friend.

Science.gov (United States)

Moreira-Teixeira, Lúcia; Mayer-Barber, Katrin; Sher, Alan; O'Garra, Anne

2018-05-07

Tuberculosis remains one of the leading causes of mortality worldwide, and, despite its clinical significance, there are still significant gaps in our understanding of pathogenic and protective mechanisms triggered by Mycobacterium tuberculosis infection. Type I interferons (IFN) regulate a broad family of genes that either stimulate or inhibit immune function, having both host-protective and detrimental effects, and exhibit well-characterized antiviral activity. Transcriptional studies have uncovered a potential deleterious role for type I IFN in active tuberculosis. Since then, additional studies in human tuberculosis and experimental mouse models of M. tuberculosis infection support the concept that type I IFN promotes both bacterial expansion and disease pathogenesis. More recently, studies in a different setting have suggested a putative protective role for type I IFN. In this study, we discuss the mechanistic and contextual factors that determine the detrimental versus beneficial outcomes of type I IFN induction during M. tuberculosis infection, from human disease to experimental mouse models of tuberculosis. © 2018 Moreira-Teixeira et al.

Cutaneous Adverse Events Associated with Interferon-β Treatment of Multiple Sclerosis

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Annette Kolb-Mäurer

2015-07-01

Full Text Available Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs.

Neuromyelitis optica-like pathology is dependent on type I interferon response.

Science.gov (United States)

Khorooshi, Reza; Wlodarczyk, Agnieszka; Asgari, Nasrin; Owens, Trevor

2013-09-01

Neuromyelitis optica is an antibody-mediated autoimmune inflammatory disease of the central nervous system. Reports have suggested that interferon beta which is beneficial for multiple sclerosis, exacerbates neuromyelitis optica. Our aim was to determine whether type I interferon plays a role in the formation of neuromyelitis optica lesions. Immunoglobulin G from a neuromyelitis optica patient was injected intracerebrally with human complement to type I interferon receptor deficient and wildtype mice. Loss of aquaporin-4 and glial fibrillary acidic protein was reduced in type I interferon receptor deficient mice brain. Our findings suggest that type I interferon signaling contributes to neuromyelitis optica pathogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

Interferon regulatory factor-7 modulates experimental autoimmune encephalomyelitis in mice

DEFF Research Database (Denmark)

Salem, Mohammad; Mony, Jyothi T; Lobner, Morten

2011-01-01

. Furthermore, IRF7-deficient mice developed more severe disease. Flow cytometric analysis showed that the extent of leukocyte infiltration into the CNS was higher in IRF7-deficient mice with significantly higher number of infiltrating macrophages and T cells, and the distribution of infiltrates within......ABSTRACT: BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with unknown etiology. Interferon-beta (IFN-beta), a member of the type I IFN family, is used as a therapeutic for MS and the IFN signaling pathway is implicated in MS susceptibility...... of MS-like disease in mice. Methods The role of IRF7 in development of EAE was studied by immunizing IRF7-KO and C57BL/6 (WT) mice with myelin oligodendrocyte glycoprotein using a standard protocol for the induction of EAE. We measured leukocyte infiltration and localization in the CNS using flow...

Tratamento de hemangioma gigante com interferon alfa: relato de dois casos Treatment of giant hemangioma with interferon-alpha: report of two cases

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Ana Julia Balau

2007-12-01

Full Text Available O objetivo do trabalho é descrever o uso de interferon alfa no tratamento de pacientes com hemangioma gigante. Os autores relatam e analisam dois casos de hemangioma gigante em tratamento com interferon alfa. IBS, 3 anos, em acompanhamento no Ambulatório de Hematologia desde um ano de idade com quadro de lesão angiomatosa em praticamente toda hemiface direita, acompanhada de sangramentos gengivais importantes. Após a realização de exames complementares (Angiorressonância magnética e feito o diagnóstico de hemangioma gigante em face, foi iniciado tratamento com prednisona e, posteriormente, associação com interferon alfa e observada importante melhora do quadro, resultando na diminuição dos episódios de sangramento e no tamanho do tumor. C.N.P., 12 anos, apresentando nódulo em região lateral de joelho esquerdo há 2 anos, com aumento progressivo do tamanho e dor local. Fez uso de prednisona e, sem melhora do quadro, introduzido interferon alfa com regressão importante do tamanho do tumor. O tratamento com interferon alfa deve ser considerado no tratamento de hemangiomas, pois apresenta bons resultados em relação à diminuição do tamanho do tumor e, conseqüentemente, reduz as intercorrências clínicas associadas à sua presença, principalmente os sangramentos.The aim of this study is to describe the treatment using interferon-alpha of giant hemangiomas in children. The authors report two cases of children presenting with giant hemangiomas treated using interferon-alpha and analyze the results. IBS, 3 years-old, has been followed up in Famema Hemathology Service since she was 1 year-old with a tumor on the face and persistent bleeding. After clinical and radiologic evaluations and suggested the diagnosis of giant hemangioma, she started treatment with interferon-alpha. A great clinical improvement was observed a reducing of the number of episodes of bleedings and a decrease in of the tumor size. CNP, 12 years-old, came to

Nonstructural 5A Protein of Hepatitis C Virus Interferes with Toll-Like Receptor Signaling and Suppresses the Interferon Response in Mouse Liver.

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Takeya Tsutsumi

Full Text Available The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver. Induction of the C-C motif chemokine ligand 2, 4, and 5 was also suppressed. Phosphorylation of the signal transducer and activator of transcription 3, which is activated by cytokines, was also reduced, and expression levels of interferon-stimulated genes, 2'-5' oligoadenylate synthase, interferon-inducible double-stranded RNA-activated protein kinase, and myxovirus resistance 1 were similarly suppressed. Since LPS binds to toll-like receptor 4 and stimulates the downstream pathway leading to induction of these genes, we examined the extracellular signal-regulated kinase and IκB-α. The phosphorylation levels of these molecules were reduced in transgenic mouse liver, indicating that the pathway upstream of the molecules was disrupted by NS5A. Further analyses revealed that the interaction between interleukin-1 receptor-associated kinase-1 and tumor necrosis factor receptor associated factor-6 was dispersed in transgenic mice, suggesting that NS5A may interfere with this interaction via myeloid differentiation primary response gene 88, which was shown to interact with NS5A. Since the gut microbiota, a source of LPS, is known to be associated with pathological conditions in liver diseases, our results suggest the involvement of NS5A in the pathogenesis of HCV infected-liver via the suppression of innate immunity.

Bilateral Ischemic Optic Neuropathy Developed under Interferon Therapy

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Fatih Selcukbiricik

2012-01-01

Full Text Available Introduction. Interferon is a glycoprotein produced by assigned cells of immune system. It has been used in many different diseases. Although flu-like syndrome, myalgia, rash, hypotension, thrombocytopenia and peripheral neuropathy due to interferon use are encountered frequently, ocular side effects are rare, generally mild and transient. Case Report. 47-year-old female patient, presented with a mass lesion in right renal pelvis. Right radical nephrectomy was applied and the histopathological examination was consistent with papillary renal cell carcinoma. Interferon alpha treatment was started subcutaneously at the dose of 5 MIU/3 times in a week. Four weeks after the interferon therapy, suddenly bilateral visual loss developed. We discussed the diagnosis, followup, and treatment of the patient who developed irreversible ischemic optic neuropathy and had no previous known primary systemic disease to cause this condition. Conclusion. We suggest that patients should be screened for risk factors causing optic ischemic neuropathy, before interferon therapy. Although there was no adequate information in the literature for the followup, patients should be monitorized before, 1 month after, and 2 months after the treatment. And if there is no complication, we suggest that they should be followed up at 3-month intervals.

Response of interferon alone and with ribavirin inpatients of chronic hepatitis C

International Nuclear Information System (INIS)

Niaz, A.

2003-01-01

Objective: The aim of the study was to compare the response of interferon alone and interferon plus ribavirin in patients of chronic hepatitis C. Results: At completion of treatment HCV-RNA levels in serum were not detectable in 15 of 20 (75%) patients who received interferon alpha and ribavirin combination therapy as compared to 10 of 20 (50%) patients who received interferon alpha alone. Only 1 patient became HCV RNA negative in the control group. Normalization of ALT concentration and histologic response was proportionate to the virological response. Conclusion: Combination therapy of interferon and ribavirin is more effective than treatment with interferon alone for minimizing viral load, improving ALT levels and histology. (author)

Homologous series of induced early mutants in Indica rice. Pt.3: The relationship between the induction of homologous series of early mutants and its different pedigree

International Nuclear Information System (INIS)

Chen Xiulan; Yang Hefeng; He Zhentian; Han Yuepeng; Liu Xueyu

2002-01-01

The percentage of homologous series of early mutants (PHSEM) induced by irradiation was closely related to its pedigree. This study showed that PHSEM for varieties with the same pedigree were similar, and there were three different level of dominance (high, low and normal) in the homologous series induced from different pedigree. The PHSEM for varieties derived form distant-relative-parents were higher than that derived from close-relative-parents. There was the dominance pedigree for the induction of homologous series of early mutants. IR8(Peta x DGWG), IR127 (Cpslo x Sigadis) and IR24 (IR8 x IR127) were dominant pedigree, and varieties derived from them could be easily induced the homologous series of early mutants

Induction of cell-mediated immunity during early stages of infection with intracellular protozoa

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Gazzinelli R.T.

1998-01-01

Full Text Available Toxoplasma gondii and Trypanosoma cruzi are intracellular parasites which, as part of their life cycle, induce a potent cell-mediated immunity (CMI maintained by Th1 lymphocytes and IFN-g. In both cases, induction of a strong CMI is thought to protect the host against rapid parasite multiplication and consequent pathology and lethality during the acute phase of infection. However, the parasitic infection is not eliminated by the immune system and the vertebrate host serves as a parasite reservoir. In contrast, Leishmania sp, which is a slow growing parasite, appears to evade induction of CMI during early stages of infection as a strategy for surviving in a hostile environment (i.e., inside the macrophages which are their obligatory niche in the vertebrate host. Recent reports show that the initiation of IL-12 synthesis by macrophages during these parasitic infections is a key event in regulating CMI and disease outcome. The studies reviewed here indicate that activation/inhibition of distinct signaling pathways and certain macrophage functions by intracellular protozoa are important events in inducing/modulating the immune response of their vertebrate hosts, allowing parasite and host survival and therefore maintaining parasite life cycles.

Early diagnosis of interferon-induced myocardial disorder in patients with chronic hepatitis C. Evaluation by myocardial imaging with 123I-BMIPP

International Nuclear Information System (INIS)

Kondo, Yuki; Yukinaka, Michiko; Nomura, Masahiro; Nakaya, Yutaka; Ito, Susumu

2000-01-01

Interferon (IFN) therapy for chronic hepatitis C is sometimes associated with cardiac complications. In the present study, we performed myocardial imaging with 123 I-labeled β-methyl-p-iodophenylpentadecanoic acid ( 123 I-BMIPP) in order to evaluate myocardial disorders caused by IFN. We studied 40 healthy subjects (H group) and 25 patients with chronic hepatitis C who had been treated with IFN (IFN group). A Holter electrocardiogram (ECG) was performed and the autonomic nervous function was assessed by analyzing the spectral variability and 1/f fluctuation of heart rate. Myocardial planner imaging with 123 I-BMIPP was performed to obtain the time activity curve for 20 min immediately after administration of 123 I-BMIPP (dynamic study). Early and delayed myocardial single photon emission computed tomography (SPECT) images were expressed as Bull's eyes and the myocardium was divided into four segments to calculate the washout rate for each segment on early and late SPECT images (early and late SPECT study). No significant differences in autonomic nervous function were observed between the two groups in heart rate variability. In a dynamic study, the reduction rate from the time activity curve was significantly higher in the IFN group compared with the H group (reduction rate, IFN group, 5.3±3.7% vs H group, 1.2±3.3%; P 123 I-BMIPP myocardial scintigraphy examination several months after IFN therapy. These results indicate that metabolic disorders of fatty acids caused by IFN therapy can be detected before abnormalities are observed by Holter-ECG or echocardiography. (author)

Early diagnosis of interferon-induced myocardial disorder in patients with chronic hepatitis C: evaluation by myocardial imaging with 123I-BMIPP.

Science.gov (United States)

Kondo, Y; Yukinaka, M; Nomura, M; Nakaya, Y; Ito, S

2000-01-01

Interferon (IFN) therapy for chronic hepatitis C is sometimes associated with cardiac complications. In the present study, we performed myocardial imaging with 123I-labeled beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) in order to evaluate myocardial disorders caused by IFN. We studied 40 healthy subjects (H group) and 25 patients with chronic hepatitis C who had been treated with IFN (IFN group). A Holter electrocardiogram (ECG) was performed and the autonomic nervous function was assessed by analyzing the spectral variability and 1/f fluctuation of heart rate. Myocardial planner imaging with 123I-BMIPP was performed to obtain the time activity curve for 20min immediately after administration of 123I-BMIPP (dynamic study). Early and delayed myocardial single photon emission computed tomography (SPECT) images were expressed as Bull's eyes and the myocardium was divided into four segments to calculate the washout rate for each segment on early and late SPECT images (early and late SPECT study). No significant differences in autonomic nervous function were observed between the two groups in heart rate variability. In a dynamic study, the reduction rate from the time activity curve was significantly higher in the IFN group compared with the H group (reduction rate, IFN group, 5.3 +/- 3.7% vs H group, 1.2 +/- 3.3%; P acids caused by IFN was reversed on the second 123I-BMIPP myocardial scintigraphy examination several months after IFN therapy. These results indicate that metabolic disorders of fatty acids caused by IFN therapy can be detected before abnormalities are observed by Holter-ECG or echocardiography.

Interferon-alpha mediates restriction of human immunodeficiency virus type-1 replication in primary human macrophages at an early stage of replication.

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Kelly M Cheney

2010-10-01

Full Text Available Type I interferons (IFNα and β are induced directly in response to viral infection, resulting in an antiviral state for the cell. In vitro studies have shown that IFNα is a potent inhibitor of viral replication; however, its role in HIV-1 infection is incompletely understood. In this study we describe the ability of IFNα to restrict HIV-1 infection in primary human macrophages in contrast to peripheral blood mononuclear cells and monocyte-derived dendritic cells. Inhibition to HIV-1 replication in cells pretreated with IFNα occurred at an early stage in the virus life cycle. Late viral events such as budding and subsequent rounds of infection were not affected by IFNα treatment. Analysis of early and late HIV-1 reverse transcripts and integrated proviral DNA confirmed an early post entry role for IFNα. First strand cDNA synthesis was slightly reduced but late and integrated products were severely depleted, suggesting that initiation or the nucleic acid intermediates of reverse transcription are targeted. The depletion of integrated provirus is disproportionally greater than that of viral cDNA synthesis suggesting the possibility of a least an additional later target. A role for either cellular protein APOBEC3G or tetherin in this IFNα mediated restriction has been excluded. Vpu, previously shown by others to rescue a viral budding restriction by tetherin, could not overcome this IFNα induced effect. Determining both the viral determinants and cellular proteins involved may lead to novel therapeutic approaches. Our results add to the understanding of HIV-1 restriction by IFNα.

Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection.

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Alan C-Y Hsu

Full Text Available Innate antiviral responses in bronchial epithelial cells (BECs provide the first line of defense against respiratory viral infection and the effectiveness of this response is critically dependent on the type I interferons (IFNs. However the importance of the antiviral responses in BECs during influenza infection is not well understood. We profiled the innate immune response to infection with H3N2 and H5N1 virus using Calu-3 cells and primary BECs to model proximal airway cells. The susceptibility of BECs to influenza infection was not solely dependent on the sialic acid-bearing glycoprotein, and antiviral responses that occurred after viral endocytosis was more important in limiting viral replication. The early antiviral response and apoptosis correlated with the ability to limit viral replication. Both viruses reduced RIG-I associated antiviral responses and subsequent induction of IFN-β. However it was found that there was constitutive release of IFN-β by BECs and this was critical in inducing late antiviral signaling via type I IFN receptors, and was crucial in limiting viral infection. This study characterizes anti-influenza virus responses in airway epithelial cells and shows that constitutive IFN-β release plays a more important role in initiating protective late IFN-stimulated responses during human influenza infection in bronchial epithelial cells.

Efficacy of dendritic cells matured early with OK-432 (Picibanil), prostaglandin E2, and interferon-alpha as a vaccine for a hormone refractory prostate cancer cell line.

Science.gov (United States)

Yoo, Changhee; Do, Hyun-Ah; Jeong, In Gab; Park, Hongzoo; Hwang, Jung-Jin; Hong, Jun Hyuk; Cho, Jin Seon; Choo, Myong-Soo; Ahn, Hanjong; Kim, Choung-Soo

2010-09-01

Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E(2) and interferon-alpha. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-alpha (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-alpha (T), TNF-alpha and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods.

Central Role of ULK1 in Type I Interferon Signaling

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Diana Saleiro

2015-04-01

Full Text Available We provide evidence that the Unc-51-like kinase 1 (ULK1 is activated during engagement of the type I interferon (IFN receptor (IFNR. Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE and IFNγ activation site (GAS elements and controls expression of key IFN-stimulated genes (ISGs. We identify ULK1 as an upstream regulator of p38α mitogen-activated protein kinase (MAPK and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses.

Type I interferon induction by Neisseria gonorrhoeae: Dual requirement of cyclic GMP-AMP synthase and Toll-like receptor 4

OpenAIRE

Andrade, Warrison A.; Agarwal, Sarika; Mo, Shunyan; Shaffer, Scott A.; Dillard, Joseph P.; Schmidt, Tobias; Hornung, Veit; Fitzgerald, Katherine A.; Kurt-Jones, Evelyn A.; Golenbock, Douglas T.

2016-01-01

The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2′3′-cGAMP and trigg...

Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon

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Patrícia Alessandra Dastoli

2011-02-01

Full Text Available OBJECTIVE: To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD: Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS: Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60% and the bigger reduction was 98.37%. Eleven patients had a reduction greater than 90%. Five patients had a tumor reduction between 75 and 90% and in three patients the tumors were reduced by less than 75%. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION: The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

Review of interferon beta-1b in the treatment of early and relapsing multiple sclerosis

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Damiano Paolicelli

2009-07-01

Full Text Available Damiano Paolicelli, Vita Direnzo, Maria TrojanoDepartment of Neurological and Psychiatric Sciences, University of Bari, Bari, ItalyAbstract: Multiple sclerosis (MS is the most common autoimmune illness of the central nervous system. For many years the inflammatory manifestations of MS were treated using only corticosteroids. Since the 1990s the results of several clinical trials with immunomodulatory agents have changed the therapeutic approach to this disease. Interferon beta (IFNβ-1b represents the pioneer of those therapies. There is growing evidence from clinical trials on relapsing-remitting MS and clinically isolated syndromes suggestive of MS that IFNβ-1b reduces the frequency and severity of relapses and the development of new and active brain lesions as assessed by magnetic resonance imaging. Long-term data suggest a persistent efficacy of IFNβ-1b on disease activity and a positive effect in slowing disability worsening. Furthermore a reduction of relapse rate and a slight positive effect on the progression were demonstrated when IFNβ-1b was administered to still-active secondary progressive MS. IFNβ-1b therapy is well tolerated and relatively free of long-term side effects. In spite of the emergence of new agents for the treatment of MS, IFNβ-1b still remains a first-line therapy with a fundamental role in all stages of the disease.Keywords: interferon beta-1b, relapsing-remitting multiple sclerosis, clinically isolated syndromes, efficacy, safety, neutralizing antibodies

Full Genome Sequence and sfRNA Interferon Antagonist Activity of Zika Virus from Recife, Brazil.

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Claire L Donald

2016-10-01

Full Text Available The outbreak of Zika virus (ZIKV in the Americas has transformed a previously obscure mosquito-transmitted arbovirus of the Flaviviridae family into a major public health concern. Little is currently known about the evolution and biology of ZIKV and the factors that contribute to the associated pathogenesis. Determining genomic sequences of clinical viral isolates and characterization of elements within these are an important prerequisite to advance our understanding of viral replicative processes and virus-host interactions.We obtained a ZIKV isolate from a patient who presented with classical ZIKV-associated symptoms, and used high throughput sequencing and other molecular biology approaches to determine its full genome sequence, including non-coding regions. Genome regions were characterized and compared to the sequences of other isolates where available. Furthermore, we identified a subgenomic flavivirus RNA (sfRNA in ZIKV-infected cells that has antagonist activity against RIG-I induced type I interferon induction, with a lesser effect on MDA-5 mediated action.The full-length genome sequence including non-coding regions of a South American ZIKV isolate from a patient with classical symptoms will support efforts to develop genetic tools for this virus. Detection of sfRNA that counteracts interferon responses is likely to be important for further understanding of pathogenesis and virus-host interactions.

Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis

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Dalbjerg, Sara Maria; Tsakiri, Anna; Fredriksen, Jette Lautrup

2016-01-01

Background Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis...... associated with Interferon-beta treatment. Case presentation We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved...... Interferon-beta-1-alpha therapy in patients with multiple sclerosis....

The value of 18F-FDG PET before and after induction chemotherapy for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy in oesophageal adenocarcinoma

International Nuclear Information System (INIS)

Rossum, Peter S.N. van; Fried, David V.; Zhang, Lifei; Court, Laurence E.; Hofstetter, Wayne L.; Ho, Linus; Meijer, Gert J.; Carter, Brett W.; Lin, Steven H.

2017-01-01

The purpose of our study was to determine the value of 18 F-FDG PET before and after induction chemotherapy in patients with oesophageal adenocarcinoma for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy (CRT). In 70 consecutive patients receiving a three-step treatment strategy of induction chemotherapy and preoperative chemoradiotherapy for oesophageal adenocarcinoma, 18 F-FDG PET scans were performed before and after induction chemotherapy (before preoperative CRT). SUV max , SUV mean , metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were determined at these two time points. The predictive potential of (the change in) these parameters for a poor pathologic response, progression-free survival (PFS) and overall survival (OS) was assessed. A poor pathologic response after induction chemotherapy and preoperative CRT was found in 27 patients (39 %). Patients with a poor pathologic response experienced less of a reduction in TLG after induction chemotherapy (p < 0.01). The change in TLG was predictive for a poor pathologic response at a threshold of -26 % (sensitivity 67 %, specificity 84 %, accuracy 77 %, PPV 72 %, NPV 80 %), yielding an area-under-the-curve of 0.74 in ROC analysis. Also, patients with a decrease in TLG lower than 26 % had a significantly worse PFS (p = 0.02), but not OS (p = 0.18). 18 F-FDG PET appears useful to predict a poor pathologic response as well as PFS early after induction chemotherapy in patients with oesophageal adenocarcinoma undergoing a three-step treatment strategy. As such, the early 18 F-FDG PET response after induction chemotherapy could aid in individualizing treatment by modification or withdrawal of subsequent preoperative CRT in poor responders. (orig.)

Whole blood interferon-gamma assay for baseline tuberculosis screening among Japanese healthcare students.

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Katsuyuki Hotta

Full Text Available BACKGROUND: The whole blood interferon-gamma assay (QuantiFERON-TB-2G; QFT has not been fully evaluated as a baseline tuberculosis screening test in Japanese healthcare students commencing clinical contact. The aim of this study was to compare the results from the QFT with those from the tuberculin skin test (TST in a population deemed to be at a low risk for infection with Mycobacterium tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Healthcare students recruited at Okayama University received both the TST and the QFT to assess the level of agreement between these two tests. The interleukin-10 levels before and after exposure to M tuberculosis-specific antigens (early-secreted antigenic target 6-kDa protein [ESAT-6] and culture filtrate protein 10 [CFP-10] were also measured. Of the 536 healthcare students, most of whom had been vaccinated with bacillus-Calmette-Guérin (BCG, 207 (56% were enrolled in this study. The agreement between the QFT and the TST results was poor, with positive result rates of 1.4% vs. 27.5%, respectively. A multivariate analysis also revealed that the induration diameter of the TST was not affected by the interferon-gamma concentration after exposure to either of the antigens but was influenced by the number of BCG needle scars (p = 0.046. The whole blood interleukin-10 assay revealed that after antigen exposure, the median increases in interleukin-10 concentration was higher in the subgroup with the small increase in interferon-gamma concentration than in the subgroup with the large increase in interferon-gamma concentration (0.3 vs. 0 pg/mL; p = 0.004. CONCLUSIONS/SIGNIFICANCE: As a baseline screening test for low-risk Japanese healthcare students at their course entry, QFT yielded quite discordant results, compared with the TST, probably because of the low specificity of the TST results in the BCG-vaccinated population. We also found, for the first time, that the change in the interleukin-10 level after exposure to

Retinopatia em paciente portador de hepatite C tratado com interferon peguilado e ribavirina: relato de caso Retinopathy in a patient with hepatitis C treated with pegylated interferon and ribavirin: case report

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Marcos Pereira de Ávila

2006-04-01

Full Text Available O interferon é uma citocina imunomoduladora utilizada no tratamento de diversas doenças, incluindo infecções crônicas pelo vírus da hepatite C. O interferon peguilado é uma nova forma de interferon, desenvolvida para aumentar o tempo de meia-vida da droga. Uma série de efeitos adversos têm sido associados ao uso do interferon, dentre eles a toxicidade ocular com desenvolvimento de retinopatia. As lesões oculares típicas incluem exsudatos algodonosos e hemorragias retinianas no pólo posterior, particularmente em torno do disco óptico. Descrevemos o caso de paciente tratado com associação de interferon peguilado e ribavirina com diminuição da acuidade visual e quadro oftalmológico compatível com retinopatia associada ao interferon. Quatro semanas após a suspensão do interferon, houve melhora da acuidade visual e diminuição importante das alterações retinianas.Interferon is an immunomodulating cytokine used to treat patients with different diseases, such as hepatitis C chronic infection. Pegylated interferon is a new type of interferon, developed to increase the half-life of the drug. Many side effects have been related to its use, including ocular toxicity and retinopathy. The most reported ocular findings are cotton-wool spots and hemorrhages located at the posterior pole and surrounding optic nerve head. We describe one case of pegylated interferon-associated retinopathy with visual loss. The patient had visual acuity improvement four weeks after discontinuation of the medication and the ocular findings became much more subtle.

Renal failure after treatment with interferon alpha 2b

NARCIS (Netherlands)

Roeloffzen, WWH; Hospers, GAP; De Vries, EGE; Navis, GJ

2002-01-01

Although there has been considerable experience with interferons in the treatment of malignancy and viral illnesses, acute renal failure as a side-effect of interferon treatment has rarely been reported. We present the case of a patient who developed acute on chronic renal failure 16 months after

Efficacy of Dendritic Cells Matured Early with OK-432 (Picibanil®), Prostaglandin E2, and Interferon-α as a Vaccine for a Hormone Refractory Prostate Cancer Cell Line

Science.gov (United States)

Yoo, Changhee; Do, Hyun-Ah; Jeong, In Gab; Park, Hongzoo; Hwang, Jung-Jin; Hong, Jun Hyuk; Cho, Jin Seon; Choo, Myong-Soo; Ahn, Hanjong

2010-01-01

Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil®) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E2 and interferon-α. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-α (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-α (T), TNF-α and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods. PMID:20808670

Early diagnosis of interferon-induced myocardial disorder in patients with chronic hepatitis C. Evaluation by myocardial imaging with {sup 123}I-BMIPP

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Kondo, Yuki; Yukinaka, Michiko; Nomura, Masahiro; Nakaya, Yutaka; Ito, Susumu [Tokushima Univ. (Japan). School of Medicine

2000-02-01

Interferon (IFN) therapy for chronic hepatitis C is sometimes associated with cardiac complications. In the present study, we performed myocardial imaging with {sup 123}I-labeled {beta}-methyl-p-iodophenylpentadecanoic acid ({sup 123}I-BMIPP) in order to evaluate myocardial disorders caused by IFN. We studied 40 healthy subjects (H group) and 25 patients with chronic hepatitis C who had been treated with IFN (IFN group). A Holter electrocardiogram (ECG) was performed and the autonomic nervous function was assessed by analyzing the spectral variability and 1/f fluctuation of heart rate. Myocardial planner imaging with {sup 123}I-BMIPP was performed to obtain the time activity curve for 20 min immediately after administration of {sup 123}I-BMIPP (dynamic study). Early and delayed myocardial single photon emission computed tomography (SPECT) images were expressed as Bull's eyes and the myocardium was divided into four segments to calculate the washout rate for each segment on early and late SPECT images (early and late SPECT study). No significant differences in autonomic nervous function were observed between the two groups in heart rate variability. In a dynamic study, the reduction rate from the time activity curve was significantly higher in the IFN group compared with the H group (reduction rate, IFN group, 5.3{+-}3.7% vs H group, 1.2{+-}3.3%; P<0.05). In the early and delayed myocardial SPECT study, the washout rate for the IFN group was significantly increased in all myocardial areas compared to that in the H group. However, the metabolic disorder of fatty acids caused by IFN was reversed on the second {sup 123}I-BMIPP myocardial scintigraphy examination several months after IFN therapy. These results indicate that metabolic disorders of fatty acids caused by IFN therapy can be detected before abnormalities are observed by Holter-ECG or echocardiography. (author)

Pegylated interferon and ribavirin promote early evolution of nonstructural 5A protein in individuals with hepatitis C who demonstrate a response to treatment.

Science.gov (United States)

Jain, Mamta K; Yuan, He-Jun; Adams-Huet, Beverley; Reeck, Amanda; Shelton, Janel; Attar, Nahid; Zhang, Song; Neumann, Avidan U; Carney, David S; Gale, Michael; Lee, William M

2009-09-15

Hepatitis C virus (HCV) quasispecies diversity is more likely to affect early viral decline during treatment of hepatitis C than is having human immunodeficiency virus (HIV) infection. We evaluated the influence of HCV therapy on changes in the nonstructural 5A (NS5A) protein. Fifteen patients with HCV genotype 1 infection with or without HIV infection were recruited for the present study, and the decrease in the HCV RNA level was measured at early time points. The evolution of HCV NS5A quasispecies within the first week was analyzed by comparing the clones observed at later times in the study with the baseline consensus sequence of individual patients. The response to therapy was defined as an early response (ER; ie, an HCV RNA level <615 IU/mL at week 4) or a slow response (SR; ie, a detectable HCV RNA level at week 4). HIV infection did not affect early viral kinetics. At baseline, lower diversity was seen in NS5A and in the amino and carboxyl termini of patients with an ER, compared with those with an SR. Rapid evolution of the NS5A genetic region occurred in patients with an ER (P = .01) but not in those with an SR (P = .73). The evolution was the result of an increase in the number of amino acid substitutions in the carboxyl region (P = .02) in patients with an ER. Selective pressure appears to result in more-marked changes in individuals with an ER than in those with an SR. The carboxyl terminus was subject to the most change and may be an important determinant of phenotypic resistance to interferon-based therapy.

Chemokine receptor CCR5 in interferon-treated multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, F; Kristiansen, T B; Wittenhagen, P

2007-01-01

To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta).......To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta)....

Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication

NARCIS (Netherlands)

Niedelman, Wendy; Sprokholt, Joris K.; Clough, Barbara; Frickel, Eva-Maria; Saeij, Jeroen P. J.

2013-01-01

The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate

Cell death of gamma interferon-stimulated human fibroblasts upon toxoplasma gondii infection induces early parasite egress and limits parasite replication

NARCIS (Netherlands)

Niedelman, W.; Sprokholt, J.K.; Clough, B.; Frickel, E.; Saeij, J.P.J.

2013-01-01

The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-¿) activation of both hematopoietic and nonhematopoietic cells. Although IFN-¿-induced innate

Interferon alfa with or without ribavirin for chronic hepatitis C

DEFF Research Database (Denmark)

Kjaergard, L L; Krogsgaard, K; Gluud, C

2001-01-01

To assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C.......To assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C....

Interferon-alpha administration enhances CD8+ T cell activation in HIV infection.

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Maura Manion

Full Text Available Type I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.To investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.The proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006. These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy. As plasma HIV levels fell with interferon therapy, this was correlated with a "paradoxical" increase in CD8+ T cell activation (p<0.001.Administration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection.

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice

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Lee Adam Wheeler

2016-05-01

Full Text Available Despite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3–4 weeks. Similarly intravaginal application of type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation, and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission but systemic interferons do not.

Both TLR2 and TRIF contribute to interferon-β production during Listeria infection.

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Camille Aubry

Full Text Available Synthesis of interferon-β (IFN-β is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-β synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-β production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, ΔpgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-β gene, requiring TLR2 and bacterial internalization. Induction of IFN-β was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-β gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-β gene expression.

Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells

International Nuclear Information System (INIS)

Miller, B.A.; Perrine, S.P.; Antognetti, G.; Perlmutter, D.H.; Emerson, S.G.; Sieff, C.; Faller, D.V.

1987-01-01

The effect of gamma-interferon on fetal hemoglobin synthesis by purified cord blood, fetal liver, and adult bone marrow erythroid progenitors was studied with a radioligand assay to measure hemoglobin production by BFU-E-derived erythroblasts. Coculture with recombinant gamma-interferon resulted in a significant and dose-dependent decrease in fetal hemoglobin production by neonatal and adult, but not fetal, BFU-E-derived erythroblasts. Accumulation of fetal hemoglobin by cord blood BFU-E-derived erythroblasts decreased up to 38.1% of control cultures (erythropoietin only). Synthesis of both G gamma/A gamma globin was decreased, since the G gamma/A gamma ratio was unchanged. Picograms fetal hemoglobin per cell was decreased by gamma-interferon addition, but picograms total hemoglobin was unchanged, demonstrating that a reciprocal increase in beta-globin production occurred in cultures treated with gamma-interferon. No toxic effect of gamma-interferon on colony growth was noted. The addition of gamma-interferon to cultures resulted in a decrease in the percentage of HbF produced by adult BFU-E-derived cells to 45.6% of control. Fetal hemoglobin production by cord blood, fetal liver, and adult bone marrow erythroid progenitors, was not significantly affected by the addition of recombinant GM-CSF, recombinant interleukin 1 (IL-1), recombinant IL-2, or recombinant alpha-interferon. Although fetal progenitor cells appear unable to alter their fetal hemoglobin program in response to any of the growth factors added here, the interaction of neonatal and adult erythroid progenitors with gamma-interferon results in an altered expression of globin genes

Interferon alfa and ribavirin induced hair changes

International Nuclear Information System (INIS)

Amir, S.; Taj, A.; Muhamud, T.H.; Iqbal, Z.; Yaqub, F.

2007-01-01

Combination therapy of Interferon alfa and ribavirin in chronic hepatitis C has well documented cutaneous adverse effects. Most interesting of these has been reported on hair physiology. This study was conducted to determine the frequency and pattern of adverse effects involving hair in patients receiving combination of interferon alfa 2a and ribavirin for chronic hepatitis C. The study was conducted in Department of Dermatology, Division of Medicine Shaikh Zayed Hospital. Thirty Eight patients who completed treatment with interferon alfa (3 MIU subcutaneously thrice weekly) and 1200 mg ribavirin daily for 24 weeks were enrolled in this single-center study. The patient's response and examination finding particularly regarding involvement of hair was noted on a Proforma. Thirty Two out of thirty eight (84%) patients noted adverse effects involving hair. The most frequent was diffuse hair loss and occurred in 27 patients (71%). Hypertrichosis of eyelashes (trichomegaly) and eyebrows (synophyrs) was observed in 18 (47%) and 16 (42%) patients respectively. Graying of hair was noted in 4 patients (11%), while discoloration of moustache hair was seen in 2 patients (5%). Epilation at the site of subcutaneous injection was noted in 10 patients (26%). Alopecia areata was reported in 2 patients (5%). It is concluded that adverse effects involving hair are frequent and varied (hair loss to excess hair growth) during combination therapy with Interferon alfa-2a and Ribavirin for chronic hepatitis C. (author)

Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon

NARCIS (Netherlands)

Poupon, R. E.; Bonnand, A. M.; Queneau, P. E.; Trépo, C.; Zarski, J. P. A.; Vetter, D.; Raabe, J. J.; Thieffin, G.; Larrey, D.; Grangé, J. D.; Capron, J. P.; Serfaty, L.; Chrétien, Y.; St Marc Girardin, M. F.; Mathiex-Fortunet, H.; Zafrani, E. S.; Guéchot, J.; Beuers, U.; Paumgartner, G.; Poupon, R.

2000-01-01

Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus

Interferon

CERN Multimedia

De Somer,P

1975-01-01

Le Prof.Pierre de Somer est né en Belgique et a fait ses études de médecine à l'Université de Louvin où il a obtenu en 1942 son diplôme. En 1961 il a été nommé professeur ordinaire d'hygiène et de microbiologie à cette même Université et depuis 1967 il est recteur de l'Université catholique flamande de Louvin, président de la société belge de microbiologie et expert de l'O.M.S. Il nous parle de l'interferon et de ses perspectives dans le traitement de maladies virales avec présentation des clichées.

Long-term effect of interferon plus ribavirin on hepatitis B surface antigen seroclearance in patients dually infected with hepatitis B and C viruses.

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Ming-Lun Yeh

Full Text Available BACKGROUND: Interferon-α/ribavirin combination therapy might promote hepatitis B surface antigen (HBsAg seroclearance in patients dually infected with hepatitis B and C viruses (HBV/HCV, but the long-term effect remains unclear. We aimed to investigate the rate of and the factors associated with HBsAg seroclearance during long-term follow-up after interferon-α/ribavirin combination therapy in HBV/HCV dually-infected patients. METHODOLOGY/PRINCIPAL FINDINGS: Eighty-one patients who received interferon-α/ribavirin combination therapy for 24 weeks with a follow-up period of >24 weeks were enrolled. HBV serological markers and HBV DNA were determined every 6 months. Early and late HBsAg seroclearance were defined as HBsAg loss in less or more than 6 months after end-of-treatment, respectively. Fifteen (18.5% patients had HBsAg seroclearance during a mean follow-up period of 3.4 (0.5-5.1 years. The 5-year cumulative incidence was 25.6%. Baseline cirrhosis and HBV DNA negativity 1 year after end-of-treatment were independently predictive of HBsAg seroclearance with an odds ratio (OR, 95% confidence intervals (CI of 16.6, 1.8-153 and 9.2, 1.4-62.1, respectively, by Cox regression hazard analysis. Four patients developed early and 11 developed late HBsAg seroclearance, respectively. Cox regression hazard analysis showed no factor was associated with early HBsAg seroclearance, whilst HBV DNA negativity 1 year after end-of-treatment was the only significant factor predicting late HBsAg loss (OR, 43.0; CI, 2.5-745. Five patients had HBsAg seroconversion with a 5-year cumulative incidence of 8.3%. HBV DNA negativity at baseline and one year after EOT had a trend for HBsAg seroconversion. HCV response did not correlate to HBsAg loss. CONCLUSIONS: We demonstrated that interferon-α/ribavirin had long-term effect on HBsAg seroclearance in dually HBV/HCV-infected patients. Baseline cirrhosis and seroclearance of HBV DNA 1 year after end-of-treatment were

STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors.

Science.gov (United States)

Deng, Liufu; Liang, Hua; Xu, Meng; Yang, Xuanming; Burnette, Byron; Arina, Ainhoa; Li, Xiao-Dong; Mauceri, Helena; Beckett, Michael; Darga, Thomas; Huang, Xiaona; Gajewski, Thomas F; Chen, Zhijian J; Fu, Yang-Xin; Weichselbaum, Ralph R

2014-11-20

Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

The value of {sup 18}F-FDG PET before and after induction chemotherapy for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy in oesophageal adenocarcinoma

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Rossum, Peter S.N. van [The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX (United States); University Medical Center Utrecht, Department of Radiation Oncology, Utrecht (Netherlands); Fried, David V.; Zhang, Lifei; Court, Laurence E. [The University of Texas MD Anderson Cancer Center, Department of Radiation Physics, Houston, TX (United States); Hofstetter, Wayne L. [The University of Texas MD Anderson Cancer Center, Department of Thoracic and Cardiovascular Surgery, Houston, TX (United States); Ho, Linus [The University of Texas MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Houston, TX (United States); Meijer, Gert J. [University Medical Center Utrecht, Department of Radiation Oncology, Utrecht (Netherlands); Carter, Brett W. [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Houston, TX (United States); Lin, Steven H. [The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX (United States)

2017-01-15

The purpose of our study was to determine the value of {sup 18}F-FDG PET before and after induction chemotherapy in patients with oesophageal adenocarcinoma for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy (CRT). In 70 consecutive patients receiving a three-step treatment strategy of induction chemotherapy and preoperative chemoradiotherapy for oesophageal adenocarcinoma, {sup 18}F-FDG PET scans were performed before and after induction chemotherapy (before preoperative CRT). SUV{sub max}, SUV{sub mean}, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were determined at these two time points. The predictive potential of (the change in) these parameters for a poor pathologic response, progression-free survival (PFS) and overall survival (OS) was assessed. A poor pathologic response after induction chemotherapy and preoperative CRT was found in 27 patients (39 %). Patients with a poor pathologic response experienced less of a reduction in TLG after induction chemotherapy (p < 0.01). The change in TLG was predictive for a poor pathologic response at a threshold of -26 % (sensitivity 67 %, specificity 84 %, accuracy 77 %, PPV 72 %, NPV 80 %), yielding an area-under-the-curve of 0.74 in ROC analysis. Also, patients with a decrease in TLG lower than 26 % had a significantly worse PFS (p = 0.02), but not OS (p = 0.18). {sup 18}F-FDG PET appears useful to predict a poor pathologic response as well as PFS early after induction chemotherapy in patients with oesophageal adenocarcinoma undergoing a three-step treatment strategy. As such, the early {sup 18}F-FDG PET response after induction chemotherapy could aid in individualizing treatment by modification or withdrawal of subsequent preoperative CRT in poor responders. (orig.)

The response of early neural genes to FGF signaling or inhibition of BMP indicate the absence of a conserved neural induction module

Directory of Open Access Journals (Sweden)

Rogers Crystal D

2011-12-01

Full Text Available Abstract Background The molecular mechanism that initiates the formation of the vertebrate central nervous system has long been debated. Studies in Xenopus and mouse demonstrate that inhibition of BMP signaling is sufficient to induce neural tissue in explants or ES cells respectively, whereas studies in chick argue that instructive FGF signaling is also required for the expression of neural genes. Although additional signals may be involved in neural induction and patterning, here we focus on the roles of BMP inhibition and FGF8a. Results To address the question of necessity and sufficiency of BMP inhibition and FGF signaling, we compared the temporal expression of the five earliest genes expressed in the neuroectoderm and determined their requirements for induction at the onset of neural plate formation in Xenopus. Our results demonstrate that the onset and peak of expression of the genes vary and that they have different regulatory requirements and are therefore unlikely to share a conserved neural induction regulatory module. Even though all require inhibition of BMP for expression, some also require FGF signaling; expression of the early-onset pan-neural genes sox2 and foxd5α requires FGF signaling while other early genes, sox3, geminin and zicr1 are induced by BMP inhibition alone. Conclusions We demonstrate that BMP inhibition and FGF signaling induce neural genes independently of each other. Together our data indicate that although the spatiotemporal expression patterns of early neural genes are similar, the mechanisms involved in their expression are distinct and there are different signaling requirements for the expression of each gene.

A novel mechanism of skin tumor promotion involving interferon-gamma (IFNγ)/signal transducer and activator of transcription-1 (Stat1) signaling.

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Bozeman, Ronald; Abel, Erika L; Macias, Everardo; Cheng, Tianyi; Beltran, Linda; DiGiovanni, John

2015-08-01

The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1(-/-) ) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1(-/-) mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. © 2014 Wiley Periodicals, Inc.

Mechanisms of regulation in the interferon factor 3 (IRF- 3) pathway

OpenAIRE

Limmer, Kirsten

2008-01-01

Interferon regulatory factor 3 (IRF-3) plays a critical role in the host cell response to both bacterial and viral infection. IRF-3 is activated by Toll-like receptors (TLRs) and cytoplasmic nucleic acid sensors, and serves to upregulate interferon beta and interferon stimulated genes (ISGs), thereby providing a quick and effective response to infection. In this work, two novel mechanisms of regulation in the IRF-3 pathway are revealed. The first part of this thesis work shows that upon bindi...

Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

Science.gov (United States)

Knuschke, Torben; Rotan, Olga; Bayer, Wibke; Kollenda, Sebastian; Dickow, Julia; Sutter, Kathrin; Hansen, Wiebke; Dittmer, Ulf; Lang, Karl S.; Epple, Matthias; Buer, Jan; Westendorf, Astrid M.

2018-01-01

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/−) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections. PMID:29740425

Interleukin 2 and alpha interferon induced in vitro modulation of spontaneous cell mediated cytotoxicity in patients with cancer of the uterine cervix undergoing radiotherapy

International Nuclear Information System (INIS)

Radhakrishna Pillai, M.; Balaram, P.; Padmanabhan, T.K.; Abraham, T.; Nair, M.K.; Regional Cancer Centre, Trivandrum

1989-01-01

In vitro modulation of spontaneous cell mediated cytotoxicity by interferon and interleukin 2 was carried out using peripheral blood lymphocytes from patients with cancer of the uterine cervix before and at different intervals after commencement of radiation treatment. A total of 150 patients with various stages of the disease were included and cytotoxicity was measured using the single cell cytotoxic assay. These results indicate a beneficial effect in vitro of interleukin 2 and interferon in augmenting spontaneous cell mediated cytotoxicity, a possibly vital antitumour immune mechanism in patients with relatively early cervix cancer. Natural killer cell, lymphokine activated killer cell and interferon activated killer cell activity was depressed immediately following radiotherapy. The activity of these cell types later on increased above pretreatment levels in patients with stages I, IIA and IIB. A similar rebound above pretreatment levels was not observed in patients with stages III and IV. (orig.)

Interferon alpha for the adjuvant treatment of cutaneous melanoma.

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Mocellin, Simone; Lens, Marko B; Pasquali, Sandro; Pilati, Pierluigi; Chiarion Sileni, Vanna

2013-06-18

Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists. To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma. We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials. We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II). Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates

The Roles of Parental Inductions, Moral Emotions, and Moral Cognitions in Prosocial Tendencies among Mexican American and European American Early Adolescents

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Carlo, Gustavo; Knight, George P.; McGinley, Meredith; Hayes, Rachel

2011-01-01

This study examined the relationships between parental inductions, sympathy, prosocial moral reasoning, and prosocial behaviors. A total of 207 early adolescents who self-identified as Mexican American (girls, n = 105; mean age = 10.91 years) and 108 who identified as European American (girls, n = 54; mean age = 11.07 years) completed measures of…

Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C

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Stephen E. Livingston

2016-03-01

Full Text Available Background: There have been few reports of hepatitis C virus (HCV treatment results with interferon-based regimens in indigenous populations. Objective: To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI population. Design: In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. Results: Sustained virologic response (SVR with standard interferon was 16.7% (3/18 and with standard interferon and ribavirin was 29.7% (11/37. Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%, including 10 of 46 with genotype 1 (21.7%, 38 of 51 with genotype 2 (74.5% and 13 of 22 with genotype 3 (59.1%. By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002, estimated duration of infection (p=0.034 and HCV genotype (p<0.0001. There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%. Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%. Conclusions: We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.

Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

LENUS (Irish Health Repository)

Enudi, W

2012-02-01

Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

LENUS (Irish Health Repository)

Enudi, W

2009-08-01

Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

Nonarteritic anterior ischemic optic neuropathy associated with interferon and ribavirin in a patient with hepatitis C.

Science.gov (United States)

Sharif, Walid; Sheikh, Khayam; De Silva, Ian; Elsherbiny, Samer

2017-04-01

To report a case of a temporal artery biopsy negative anterior ischemic optic neuropathy associated with a recently completed course of pegylated interferon 2 α with ribavirin for chronic hepatitis C. Despite the early presentation with symptoms and prompt treatment with systemic intravenous steroids the patient experienced deterioration of their optic neuropathy over the following few days. Although nonarteritic anterior ischemic optic neuropathy is a common disorder with known risk factors, the timing of onset of symptoms in our patient was suggestive of a possible etiology related to treatment with ribavirin and interferon 2 α, as found in the previously reported cases. There have been a few reported cases of the association between the use of interferon/ribavirin for treatment of chronic hepatitis with nonarteritic anterior ischemic optic neuropathy. In these cases stopping the drug caused some improvement of symptoms or halting the progression of optic neuropathy. Having reviewed the literature on previous cases, we postulate that there may be a dose related reaction to explain the delay and deterioration of vision in some cases despite stopping the drugs. We also advise that any person who is started on this treatment for chronic hepatitis are appropriately counselled as to the potential optic nerve side effect of the drug, based on the evidence reported in the literature.

Endogenous and recombinant type I interferons and disease activity in multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, Finn; Krakauer, Martin; Limborg, Signe

2012-01-01

the percentage of CD4+ T cells expressing CD71 and HLA-DR (activated T cells), and this was associated with an increased risk of clinical disease activity. In contrast, induction of CD71 and HLA-DR was not observed in untreated MS patients with evidence of endogenous type IFN I activity. In conclusion......Although treatment of multiple sclerosis (MS) with the type I interferon (IFN) IFN-ß lowers disease activity, the role of endogenous type I IFN in MS remains controversial. We studied CD4+ T cells and CD4+ T cell subsets, monocytes and dendritic cells by flow cytometry and analysed the relationship...... with endogenous type I IFN-like activity, the effect of IFN-ß therapy, and clinical and magnetic resonance imaging (MRI) disease activity in MS patients. Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells...

Newer Clinical Strategies for Combining Interferon and Cytotoxic Agents Against Solid Tumours and Hematological Malignancies

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Scott Wadler

1994-01-01

Full Text Available The role of interferons in the treatment of cancer continues to evolve. Despite limited single agent activity against solid tumours, interferons now appear to have an important role as modulators of the activity of a variety of cytotoxic drugs. Clinical benefits have been observed for combinations of interferons and alkylating agents against low grade lymphomas, interferons and dacarbazine against malignant melanoma, and interferons and 5-fluorouracil against gastrointestinal and genitourinary malignancies. Further progress will depend on a grealer understanding of the biology of the interaction.

fundTPL-2 – ERK1/2 Signaling Promotes Host Resistance against Intracellular Bacterial Infection by Negative Regulation of Type I Interferon Production3

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McNab, Finlay W.; Ewbank, John; Rajsbaum, Ricardo; Stavropoulos, Evangelos; Martirosyan, Anna; Redford, Paul S.; Wu, Xuemei; Graham, Christine M.; Saraiva, Margarida; Tsichlis, Philip; Chaussabel, Damien; Ley, Steven C.; O’Garra, Anne

2013-01-01

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1 and TNF-α, as well as IFN-γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. PMID:23842752

Ultraviolet radiation can either suppress or induce expression of intercellular adhesion molecule 1 (ICAM-1) on the surface of cultured human keratinocytes

International Nuclear Information System (INIS)

Norris, D.A.; Lyons, M.B.; Middleton, M.H.; Yohn, J.J.; Kashihara-Sawami, M.

1990-01-01

Interactions of the ligand/receptor pair LFA-1(CD11a/CD18) and ICAM-1(CD54) initiate and control the cell-cell interactions of leukocytes and interactions of leukocytes with parenchymal cells in all phases of the immune response. Induction of the intercellular adhesion molecule 1 (ICAM-1) on the surface of epidermal keratinocytes has been proposed as an important regulator of contact-dependent aspects of cutaneous inflammation. Ultraviolet radiation (UVR) also modifies cutaneous inflammation, producing both up- and down-regulation of contact hypersensitivity. We have found that UVR has a biphasic effect on the induction of keratinocyte CD54. Using immunofluorescence and FACS techniques to quantitate cell-surface CD54 staining, we have shown that UVR significantly (p less than 0.01) inhibits keratinocyte CD54 induction by gamma interferon 24 h after irradiation. However, at 48, 72, and 96 h after UVR, CD54 expression is significantly induced to levels even greater than are induced by gamma interferon (20 U/ml). In addition, at 48, 72, or 96 h following UVR (30-100 mJ/cm2), the gamma-interferon-induced CD54 expression on human keratinocytes is also strongly (p less than 0.05 to p less than 0.001) enhanced. In this cell-culture system, gamma interferon and TNF-alpha are both strong CD54 inducers and are synergistic, but GM-CSF, TFG-beta, and IL-1 have no direct CD54-inducing effects. Thus the effects of UVR on CD54 induction are biphasic, producing inhibition at 24 h and induction at 48, 72, and 96 h. This effect on CD54 may contribute to the biphasic effects of UVR on delayed hypersensitivity in vivo. The early inhibition of ICAM-1 by UVR may also contribute to the therapeutic effects of UVR. We also speculate that the late induction of ICAM-1 by UVR might be an important step in the induction of photosensitive diseases such as lupus erythematosus

EFFICACY OF INTRAPERITONEAL INTERFERON-α ADMINISTRATION FOR TREATMENT OF ENDOMETRIOSIS IN RATS

Directory of Open Access Journals (Sweden)

R. V. Pavlov

2006-01-01

Full Text Available Abstract. The article presents the results of intraperitoneal administration of recombinant rat interferon-α to twenty Wistar rats with experimentally induced endometriosis. The following criteria of treatment efficiency were applied: presence of ectopic endometrium in transplanted segments of cornu uteri, proliferative activity of endometrioid cells, features of vascularization and leucocyte infiltration within endometrial foci. It was shown that local application of interferon-α caused regression of endometrioid epithelial heterotopias in 50 per cent of the cases. If endometrioid epithelium was retained, its proliferative activity did significantly drop under interferon-α application. In all transplants derived from rats treated with interferon-α, the degree of vascularization is reduced, accompanied by increased leucocytic infiltration (due to lymphocytes, along with decreased contents of macrophages within leucocytic infiltrates.

Effects of adding ribavirin to interferon to treat chronic hepatitis C infection

DEFF Research Database (Denmark)

Brok, Jesper; Gluud, Lise L; Gluud, Christian

2005-01-01

Evidence shows that a combination therapy of ribavirin plus interferon clears hepatitis C virus from the blood in about 40% of patients with chronic hepatitis C infection, but the effects on clinical outcomes are unclear. We evaluated the beneficial and harmful effects of ribavirin plus interferon...... vs interferon alone for treatment of patients with chronic hepatitis C infection. Randomized trials were included irrespective of blinding, language, or publication status. Trials were identified through the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Library, MEDLINE....... In conclusion, the effect of ribavirin plus interferon on viral clearance may lead to reduced mortality and morbidity in patients with chronic hepatitis C infection. However, combination therapy is associated with increased risk for adverse events....

Interferon beta induces apoptosis in nasopharyngeal carcinoma cells via the TRAIL-signaling pathway.

Science.gov (United States)

Makowska, Anna; Wahab, Lora; Braunschweig, Till; Kapetanakis, Nikiforos-Ioannis; Vokuhl, Christian; Denecke, Bernd; Shen, Lian; Busson, Pierre; Kontny, Udo

2018-03-06

The combination of neoadjuvant chemotherapy, radiochemotherapy, and maintenance therapy with interferon beta (IFNβ) has led to superior results in the treatment of children and adolescents with nasopharyngeal carcinoma (NPC). However, nothing is known about the mechanism of the antitumor activity of IFNβ in NPC. Here, we investigate the role of IFNβ on apoptosis in NPC cells. Six NPC cell lines, one patient-derived NPC xenograft (PDX) and one SV40-transformed nasoepithelial cell line were used. Induction of apoptosis by IFNβ was measured by flow cytometric analysis of subG1-DNA-content, Hoechst 33258 staining and activation of caspase-3. Dissection of death ligand signaling pathways included measuring surface expression of its components by flow cytometry, activation by death ligands and neutralization with specific antibodies and siRNA. IFNβ induced apoptosis at concentrations achievable in humans in five of six NPC cell lines and in PDX cells but not in nasoepithelial cells. Inhibition of caspases-3 and -8 abrogated this effect suggesting IFNβ promoted apoptosis through the extrinsic pathway. IFNβ induced surface expression of TRAIL and TRAIL-R2 and the addition of an anti-TRAIL-antibody or transfection with TRAIL-siRNA blocked IFNβ-induced apoptosis. No induction of TRAIL-expression was noted in the IFNβ-resistant cell line. In conclusion, IFNβ leads to apoptosis in NPC cells in an autocrine way via the induction of TRAIL expression and subsequent activation of the TRAIL-signaling pathway. The mechanism described could at least partly explain the clinical benefit of IFNβ in the treatment of NPC. Further studies in a mouse-xenograft model are warranted to substantiate this effect in vivo .

Pegylated interferon alpha-2a and ribavirin combination therapy in HCV liver transplant recipients. Experience of 7 cases.

Science.gov (United States)

Iacob, Speranta; Gheorghe, Liana; Hrehoret, Doina; Becheanu, Gabriel; Herlea, Vlad; Popescu, Irinel

2008-06-01

Hepatitis C virus (HCV) related cirrhosis represents the leading indication for liver transplantation (LT) worldwide and HCV reinfection is the rule among transplant recipients. Combination therapy with interferon and ribavirin is the treatment of choice for established recurrent hepatitis C. To evaluate the efficacy and safety of the combination of pegylated interferon alpha-2a and ribavirin in LT recipients with histological recurrence of hepatitis C. Seven LT recipients with chronic hepatitis C recurrence were treated with peginterferon alpha-2a with an initial intended dose of 180 microg/week and an intended dose of ribavirin 800-1000 mg/day for at least 12 months and followed-up for at least 24 weeks. Early virological response rate was 57.1%. Three patients (42.8%) had end of treatment virological response and all had also sustained viral response (SVR). Five patients had end of treatment biological response, out of which 4 had also sustained biochemical response. Three patients had both SVR and sustained biochemical response. Four patients had end of treatment histological response, out of which 3 patients had also SVR. Cytopenia was the most common adverse event: anemia (57.1%), leucopenia/neutropenia (71.4%), thrombocytopenia (42.8%). Combination of pegylated interferon and ribavirin can be safely and successfully used in liver transplant recipients.

Neuromyelitis optica-like pathology is dependent on type I interferon response

DEFF Research Database (Denmark)

Khorooshi, Reza; Wlodarczyk, Agnieszka; Asgari, Nasrin

2013-01-01

Neuromyelitis optica is an antibody-mediated autoimmune inflammatory disease of the central nervous system. Reports have suggested that interferon beta which is beneficial for multiple sclerosis, exacerbates neuromyelitis optica. Our aim was to determine whether type I interferon plays a role in ...

Azathioprine versus Beta Interferons for Relapsing-Remitting Multiple Sclerosis: A Multicentre Randomized Non-Inferiority Trial

Science.gov (United States)

Massacesi, Luca; Tramacere, Irene; Amoroso, Salvatore; Battaglia, Mario A.; Benedetti, Maria Donata; Filippini, Graziella; La Mantia, Loredana; Repice, Anna; Solari, Alessandra; Tedeschi, Gioacchino; Milanese, Clara

2014-01-01

For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19–0.37) in the azathioprine and 0.39 (95% CI 0.30–0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61–0.95) in the azathioprine and 0.69 (95% CI 0.54–0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of �

Effects of Interferon-α/β on HBV Replication Determined by Viral Load

Science.gov (United States)

Tian, Yongjun; Chen, Wen-ling; Ou, Jing-hsiung James

2011-01-01

Interferons α and β (IFN-α/β) are type I interferons produced by the host to control microbial infections. However, the use of IFN-α to treat hepatitis B virus (HBV) patients generated sustained response to only a minority of patients. By using HBV transgenic mice as a model and by using hydrodynamic injection to introduce HBV DNA into the mouse liver, we studied the effect of IFN-α/β on HBV in vivo. Interestingly, our results indicated that IFN-α/β could have opposite effects on HBV: they suppressed HBV replication when viral load was high and enhanced HBV replication when viral load was low. IFN-α/β apparently suppressed HBV replication via transcriptional and post-transcriptional regulations. In contrast, IFN-α/β enhanced viral replication by inducing the transcription factor HNF3γ and activating STAT3, which together stimulated HBV gene expression and replication. Further studies revealed an important role of IFN-α/β in stimulating viral growth and prolonging viremia when viral load is low. This use of an innate immune response to enhance its replication and persistence may represent a novel strategy that HBV uses to enhance its growth and spread in the early stage of viral infection when the viral level is low. PMID:21829354

The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes

NARCIS (Netherlands)

de Jong, Tamarah D.; Lübbers, Joyce; Turk, Samina; Vosslamber, Saskia; Mantel, Elise; Bontkes, Hetty J.; van der Laken, Conny J.; Bijlsma, Johannes W.; van Schaardenburg, Dirkjan; Verweij, Cornelis L.

2016-01-01

The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature's functional consequences. The aim of

[Alpha interferon induced hyperthyroidism: a case report and review of the literature].

Science.gov (United States)

Maiga, I; Valdes-Socin, H; Thiry, A; Delwaide, J; Sidibe, A T; Beckers, A

2015-01-01

Treatment with alpha interferon in hepatitis C triggers a thyroid autoimmunity in a variable percentage of cases (2-8%). This complication raises some questions about its screening, the possibility to continue anti-viral therapy and thyroid treatment. Alpha interferon has an immunomodulatory effect on the thyroid, but also an inhibitory effect on thyroid hormone synthesis. This explains the occurrence of cases of thyroid dysfunction, which often remain undetected because of their latency. Factors predicting thyroid dysfunction with interferon use are: female sex, history of thyroid disease and previous autoimmunity. Several clinical aspects are encountered including hypothyroidism (the most frequent depending on the series) and hyperthyroidism related to Graves' disease. For their detection, a cooperation between general practionners, gastroenterologists and endocrinologists is mandatory thyroid function tests are requested before, during and after treatment,with alpha interferon. Therapeutic aspects of thyroid disorders range from simple monitoring to symptomatic treatment, such as thyroxine prescription in the presence of hypothyroidism. Antithyroid drugs radioactive iodine or thyroid surgery are used in cases of severe or persistent Graves' disease induced by alpha interferon.

Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

DEFF Research Database (Denmark)

Strickertsson, Jesper A B; Døssing, Kristina B V; Aabakke, Anna JM

2011-01-01

To investigate if and how the proinflammatory cytokine interferon ¿ (IFN¿) affects ghrelin expression in mice.......To investigate if and how the proinflammatory cytokine interferon ¿ (IFN¿) affects ghrelin expression in mice....

Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

DEFF Research Database (Denmark)

Strickertsson, Jesper A B; Døssing, Kristina B V; Aabakke, Anna JM

2011-01-01

To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice.......To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice....

The Use of Recombinant Feline Interferon Omega Therapy as an Immune-Modulator in Cats Naturally Infected with Feline Immunodeficiency Virus: New Perspectives

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Rodolfo Oliveira Leal

2016-10-01

Full Text Available Type I interferons (IFNs are well-known cytokines that, among their main functions, are key components of the host immune response against viral infections. Due to its immune modulation properties, they are commonly used in the therapeutic approach of various retroviral infections, namely human immunodeficiency virus (HIV and feline immunodeficiency virus (FIV. In HIV infection, it has been shown that IFN therapy limits early viral replication, particularly useful on post-exposure prophylaxis. In veterinary medicine, recombinant feline interferon omega (rFeIFN-ω was the first interferon licensed for use in cats. Several studies have recently shown that this compound seems to stimulate the innate immunity, decreasing clinical signs and co-infections in naturally FIV-infected cats. More than summarizing the main conclusions about rFeIFN-ω in cats, this review emphasizes the immune-modulation properties of IFN therapy, opening new perspectives for its use in retroviral infections. Either in FIV-infected cats or in HIV individuals, type I IFNs seem to induce an innate immune-modulation and should not be overlooked as a therapeutic option in retroviral infections.

The Use of Recombinant Feline Interferon Omega Therapy as an Immune-Modulator in Cats Naturally Infected with Feline Immunodeficiency Virus: New Perspectives.

Science.gov (United States)

Leal, Rodolfo Oliveira; Gil, Solange

2016-10-27

Type I interferons (IFNs) are well-known cytokines that, among their main functions, are key components of the host immune response against viral infections. Due to its immune modulation properties, they are commonly used in the therapeutic approach of various retroviral infections, namely human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV). In HIV infection, it has been shown that IFN therapy limits early viral replication, particularly useful on post-exposure prophylaxis. In veterinary medicine, recombinant feline interferon omega (rFeIFN-ω) was the first interferon licensed for use in cats. Several studies have recently shown that this compound seems to stimulate the innate immunity, decreasing clinical signs and co-infections in naturally FIV-infected cats. More than summarizing the main conclusions about rFeIFN-ω in cats, this review emphasizes the immune-modulation properties of IFN therapy, opening new perspectives for its use in retroviral infections. Either in FIV-infected cats or in HIV individuals, type I IFNs seem to induce an innate immune-modulation and should not be overlooked as a therapeutic option in retroviral infections.

Elevated levels of interferon-γ production by memory T cells do not promote transplant tolerance resistance in aged recipients.

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James I Kim

Full Text Available Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age aged male recipients (greater than 12 months of age transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients.

Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

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Torben Knuschke

2018-04-01

Full Text Available T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP nanoparticle (NP-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/− or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections.

The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.

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Baca Chan

2017-05-01

Full Text Available The type I interferon (IFN response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV that shuts down signaling following pattern recognition receptor (PRR sensing. Screening of an MCMV open reading frame (ORF library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR. Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR. M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.

DMPD: Molecular mechanisms of the anti-inflammatory functions of interferons. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 18086388 Molecular mechanisms of the anti-inflammatory functions of interferons. Ko....csml) Show Molecular mechanisms of the anti-inflammatory functions of interferons. PubmedID 18086388 Title ...Molecular mechanisms of the anti-inflammatory functions of interferons. Authors K

Kaposi's sarcoma after alpha-interferon treatment for HIV-negative T ...

African Journals Online (AJOL)

Abstract A 54-year-old HIV-negative patient suffering frOIn. T-cell lytnphoIna of Lennert's lytnphoIna (Lel) type was treated for 13 Inonths with interferon a-. 2b. While on treatment with interferon the patient. derrlOnstrated suppression of total and CD4+ lytn- phocytes to levels < 0,5 and 0,2 x 10911, respectively. Although ...

Interferons and their potential in the treatment of ocular inflammation

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Friederike Mackensen

2009-10-01

Full Text Available Friederike Mackensen,1 Regina Max,2 Matthias D Becker31Department of Ophthalmology, 2Department of Internal Medicine, Interdisciplinary Uveitis Center, University of Heidelberg, Germany; 3Department of Ophthalmology, Triemli Hospital Zürich, SwitzerlandAbstract: Since their discovery in the 1950s interferons have been the scope of investigation in many diseases as therapeutic as well as pathogenetic factors. We know they have immune stimulatory and immune regulatory effects. This apparently counter-intuitive mechanism can be summarized as immunomodulatory action and seems to be very effective in a number of ocular inflammatory diseases. We review the current knowledge of interferons in immunity and autoimmunity and show their use in clinical ophthalmologic practice.Keywords: interferon, uveitis, treatment, inflammation

Differential Delivery of Genomic Double-Stranded RNA Causes Reovirus Strain-Specific Differences in Interferon Regulatory Factor 3 Activation.

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Stuart, Johnasha D; Holm, Geoffrey H; Boehme, Karl W

2018-05-01

signaling pathways, leading to the activation of interferon regulatory factor 3 (IRF3) and NF-κB, key transcription factors required for IFN-I induction. Serotype 3 (T3) reoviruses induce significantly more IFN-I than serotype 1 (T1) strains. In this work, we found that differences in IFN-I production by T1 and T3 reoviruses correlate with differential IRF3 activation. Differences in IRF3 activation are not caused by a blockade of the IRF3 activation by a T1 strain. Rather, differences in events during the late stages of viral entry determine the capacity of reovirus to activate host IFN-I responses. Together, our work provides insight into mechanisms of IFN-I induction by nonenveloped viruses. Copyright © 2018 American Society for Microbiology.

Timing of induction of labor.

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Bacak, Stephen J; Olson-Chen, Courtney; Pressman, Eva

2015-10-01

Determining the optimal timing for induction of labor is critical in minimizing the risks to maternal and fetal health. While data are available to guide us in some clinical situations, such as hypertension and diabetes, many gaps in knowledge still exist in others, including cholestasis of pregnancy, fetal anomalies, and placental abruption. This review of the currently available literature assesses the risks and benefits of preterm and early term induction in a wide variety of maternal and fetal conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Sequence diversity of hepatitis C virus 6a within the extended interferon sensitivity-determining region correlates with interferon-alpha/ribavirin treatment outcomes.

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Zhou, Daniel X M; Chan, Paul K S; Zhang, Tiejun; Tully, Damien C; Tam, John S

2010-10-01

Studies on the association between sequence variability of the interferon sensitivity-determining region (ISDR) of hepatitis C virus and the outcome of treatment have reached conflicting results. In this study, 25 patients infected with HCV 6a who had received interferon-alpha/ribavirin combination treatment were analyzed for the sequence variations. 14 of them had the full genome sequences obtained from a previous study, whereas the other 11 samples were sequenced for the extended ISDR (eISDR). This eISDR fragment covers 192 bp (64 amino acids) upstream and 201 bp (67 amino acids) downstream from the ISDR previously defined for HCV 1b. The comparison between interferon-alpha resistance and response groups for the amino acid mutations located in the full genome (6 and 8 patients respectively) as well as the mutations located in the eISDR (10 and 15 patients respectively) showed that the mutations I2160V, I2256V, V2292I (Pc) 2010 Elsevier B.V. All rights reserved.

An Assay in Microtitre Plates for Absolute Abundance of Chicken Interferon Alpha Transcripts

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Renata Novak Kujundžić

2010-01-01

Full Text Available Immunosuppression of commercial chickens is a serious animal health and economic problem in the poultry industry. The major causes of the immunosuppression are viruses that suppress transcription of interferon genes, especially interferon alpha. There is a need for monitoring immunosuppression in commercially bred chickens. For this purpose, the absolute abundance of interferon alpha transcripts can be measured in blood of chickens by a suitable assay. Such an assay was used to estimate abundance of chicken interferon alpha in a sample of splenic cells induced with polyinosinic polycytidylic acid. The abundance measured was 29 ± 2 attomoles/µg total RNA. This assay can be performed in microtitre plates using samples collected from chickens in poultry houses.

Clinical and serological manifestations associated with interferon-α levels in childhood-onset systemic lupus erythematosus

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Mariana Postal

2012-01-01

Full Text Available OBJECTIVE: To determine the serum levels of interferon alpha in childhood-onset systemic lupus erythematosus patients, their first-degree relatives and healthy controls and to evaluate the associations between serum interferon alpha and disease activity, laboratory findings and treatment features. METHODS: We screened consecutive childhood-onset systemic lupus erythematosus patients in a longitudinal cohort at the pediatric rheumatology unit of the State University of Campinas between 2009 and 2010. All patients demonstrated disease onset before the age of 16. Disease status was assessed according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI. Interferon alpha levels were measured using an enzyme-linked immunoabsorbent assay. RESULTS: We included 57 childhood-onset systemic lupus erythematosus patients (mean age 17.33±4.50, 64 firstdegree relatives (mean age 39.95±5.66, and 57 healthy (mean age 19.30±4.97 controls. Serum interferon alpha levels were significantly increased in childhood-onset systemic lupus erythematosus patients compared to their firstdegree relatives and healthy controls. Interferon alpha levels were significantly increased in patients with positive dsDNA antibodies, patients with cutaneous vasculitis, patients with new malar rash and patients who were not receiving medication. Interferon alpha levels correlated with C3 levels and systemic lupus erythematosus Disease Activity Index scores. In addition, we observed an inverse correlation between patient age and interferon alpha levels. CONCLUSION: Interferon alpha may play a role in the pathogenesis of childhood-onset systemic lupus erythematosus, especially in cutaneous manifestations and dsDNA antibody formation. The observation that interferon alpha levels are increased in patients who are not taking medication should be investigated in

Reprogramming of murine macrophages through TLR2 confers viral resistance via TRAF3-mediated, enhanced interferon production.

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Darren J Perkins

Full Text Available The cell surface/endosomal Toll-like Receptors (TLRs are instrumental in initiating immune responses to both bacteria and viruses. With the exception of TLR2, all TLRs and cytosolic RIG-I-like receptors (RLRs with known virus-derived ligands induce type I interferons (IFNs in macrophages or dendritic cells. Herein, we report that prior ligation of TLR2, an event previously shown to induce "homo" or "hetero" tolerance, strongly "primes" macrophages for increased Type I IFN production in response to subsequent TLR/RLR signaling. This occurs by increasing activation of the transcription factor, IFN Regulatory Factor-3 (IRF-3 that, in turn, leads to enhanced induction of IFN-β, while expression of other pro-inflammatory genes are suppressed (tolerized. In vitro or in vivo "priming" of murine macrophages with TLR2 ligands increase virus-mediated IFN induction and resistance to infection. This priming effect of TLR2 is mediated by the selective upregulation of the K63 ubiquitin ligase, TRAF3. Thus, we provide a mechanistic explanation for the observed antiviral actions of MyD88-dependent TLR2 and further define the role of TRAF3 in viral innate immunity.

Higher Serum Uric Acid Levels in Multiple Sclerosis Patients After Longterm Interferon Beta Treatment

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Toncev Gordana

2017-10-01

Full Text Available Interferon beta is a safe and efficacious treatment for relapsing multiple sclerosis (MS. However, there is some evidence that uric acid, a scavenger of peroxynitrite, is involved in MS pathology and that increasing serum uric acid levels might have beneficial therapeutic effects. The aim of this study is to investigate serum uric acid levels in MS patients before and after long-term interferon beta treatment. Blood samples from 101 MS patients (53 receiving interferon beta 1a treatment and 48 receiving interferon beta 1b treatment; 28 male and 73 female; mean age at treatment onset 32,4±7,3 years; mean duration of disease at treatment onset 5,1±3,2 years; mean EDSS 2±1,3 before and after interferon beta treatment (mean treatment duration 3±2 years were analysed. Serum uric acid levels were measured using a quantitative enzymatic assay (Elitech Diagnostic, Sees, France. MS patients had significantly increased serum uric acid levels after treatment compared with those at the beginning of treatment (272,31±78,21 μmol/l vs. 210,17±53,65 μmol/l; p=0,019, Wilcoxon Mann-Whitney U-test. We did not find significant differences in serum uric acid levels between the interferon beta 1a and interferon beta 1b groups (p=0.98. These results indicate that one of the beneficial effects of interferon beta in MS might be based on the elevation of serum uric acid levels as a natural scavenger of peroxynitrite.

Interferon-Beta in Pediatric Multiple Sclerosis Patients: Safety in Short-Term Prescription

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Amir Hadi Maghzi

2012-02-01

Full Text Available Introduction: None of the approved immunomodulatory drugs in adults Multiple Sclerosis (MS patients have been officially approved for the pediatric patients and are currently used off-label in this population. Objectives: In this study, we evaluated the effectiveness and tolerability of intramuscular interferon beta1-a (Avonex® and subcutaneously injected interferon beta1-b (Betaferon® in children with definite relapsing-remitting MS (RRMS. Thirteen patients aged younger than 16, who were recently diagnosed with definite RRMS according to the McDonalds criteria, were enrolled in this study. Six patients were treated with Avonex® 30 μg, intramuscularly every week, and seven patients were treated with Betaferon® 250 μg, subcutaneously every other day. All patients were treated with adult doses; initially interferon-beta was prescribed with half dose, and it was increased to full adult dose steadily. Results: Eleven girls and two boys, mean (SD age of 14.7 (1.9 years, were studied. Following nine months of using interferon-beta, nine patients (69.2% had no relapses and the remaining four, experienced only one relapse. The mean EDSS score was decreased significantly after the study period. Conclusion: The present study provides reasonable data for the use of interferon-beta in Pediatric MS due to lack of short-term complications and safety. Studies with larger sample size and longer follow up duration are required to shed light on the long term impact of the interferon-beta therapy in children.

Erupção acneiforme aguda induzida por interferon beta-1b durante tratamento para esclerose múltipla Acute acneiform eruption induced by interferon beta-1b during treatment for multiple sclerosis

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Dário Júnior de Freitas Rosa

2011-04-01

Full Text Available Esclerose múltipla é uma doença inflamatória desmielinizante, com presumida origem autoimune, que afeta o sistema nervoso central. A principal modalidade terapêutica é baseada no uso de imunomoduladores, como o interferon beta, que são geralmente bem tolerados. As manifestações cutâneas secundárias ao interferon beta-1b são representadas, na maioria das vezes, por reações no local de sua aplicação subcutânea. Descrevemos o caso de uma paciente do sexo feminino que desenvolveu um quadro de erupção acneiforme pelo interferon beta-1b.Multiple sclerosis is an inflammatory demyelinating disease of presumed autoimmune origin that affects the central nervous system. The main form of therapy is based on the use of immunomodulators such as interferon beta, which are usually well tolerated. Skin manifestations resulting from treatment with interferon beta-1b consist principally of reactions at the site of subcutaneous application of the drug. The present case report describes a female patient who developed an acneiform eruption resulting from treatment with interferon beta-1b.

Oromucosal Administration of Interferon to Humans

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Manfred W. Beilharz

2010-01-01

Full Text Available The prevailing dogma is that, to be systemically effective, interferon-alpha (IFNα must be administered in sufficiently high doses to yield functional blood concentrations. Such an approach to IFNa therapy has proven effective in some instances, but high-dose parenteral IFNα therapy has the disadvantage of causing significant adverse events. Mounting evidence suggests that IFNα delivered into the oral cavity in low doses interacts with the oral mucosa in a unique manner to induce systemic host defense mechanisms without IFNα actually entering the circulation, thus reducing the potential for toxic side effects. A better understanding of the applications and potential benefits of this treatment modality are under active investigation. This paper provides a review of the relevant literature on the clinical use of the oromucosal route of administration of interferon, with an emphasis on the treatment of influenza.

Tumor inherent interferons: Impact on immune reactivity and immunotherapy.

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Brockwell, Natasha K; Parker, Belinda S

2018-04-19

Immunotherapy has revolutionized cancer treatment, with sustained responses to immune checkpoint inhibitors reported in a number of malignancies. Such therapeutics are now being trialed in aggressive or advanced cancers that are heavily reliant on untargeted therapies, such as triple negative breast cancer. However, responses have been underwhelming to date and are very difficult to predict, leading to an inability to accurately weigh up the benefit-to-risk ratio for their implementation. The tumor immune microenvironment has been closely linked to immunotherapeutic response, with superior responses observed in patients with T cell-inflamed or 'hot' tumors. One class of cytokines, the type I interferons, are a major dictator of tumor immune infiltration and activation. Tumor cell inherent interferon signaling dramatically influences the immune microenvironment and the expression of immune checkpoint proteins, hence regulators and targets of this pathway are candidate biomarkers of immunotherapeutic response. In support of a link between IFN signaling and immunotherapeutic response, the combination of type I interferon inducers with checkpoint immunotherapy has recently been demonstrated critical for a sustained anti-tumor response in aggressive breast cancer models. Here we review evidence that links type I interferons with a hot tumor immune microenvironment, response to checkpoint inhibitors and reduced risk of metastasis that supports their use as biomarkers and therapeutics in oncology. Copyright © 2018. Published by Elsevier Ltd.

Morning versus evening induction of labour for improving outcomes

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Bakker, Jannet J. H.; van der Goes, Birgit Y.; Pel, Maria; Mol, Ben Willem J.; van der Post, Joris A. M.

2013-01-01

Background Induction of labour is a common intervention in obstetric practice. Traditionally, inmost hospitals induction of labour with medication starts early in the morning, with the start of the working day for the day shift. In human and animal studies spontaneous onset of labour is proven to

Evaluation of Interferon-gamma Application for Recognition of Patients Afflicted by Non-healing Cutaneous Leishmaniasis

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Mohammad Moafi

2017-06-01

Full Text Available Introduction:Different studies undertaken in the animal modeling show that Interferon-gamma deficiency impairs healing process of Leishmania infection. It seems that the level of Interferon-gamma production could also affect the healing duration of Leishmania lesion in humans. The current study aims to investigate the possibility of Interferon-gamma application for recognition of cases afflicted by non-healing Leishmaniasis. Materials and methods: Peripheral blood mononuclear cells (PBMCs of 32 patients, who were afflicted by healing or non-healing Leishmaniasis, were isolated and the levels of interferon-gamma were determined, using ELISA method. Afterwards, the cut-off point of interferon-gamma to identify patients afflicted by non-healing Leishmaniasis was calculated through ROC-Curve analysis. Furthermore, Leishmanin Skin Test (LST was performed for every patient. Results: Levels of Interferon-gamma produced by PBMCs stimulated with Soluble Leishmania Antigen (SLA or Phytohemaglotinine were significantly higher in healing patients, compared with non-healing individuals (p

Trombose de veia central da retina em paciente usuária de interferon e ribavirina: relato de caso Central vein occlusion in a patient using interferon and ribavirin: case report

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John Helal Jr.

2006-08-01

Full Text Available O interferon alfa (INF alfa é droga atualmente utilizada no tratamento de várias doenças sistêmicas, como a hepatite C crônica. A ribavirina quando associada ao interferon alfa aumenta muito a resposta ao tratamento. Estima-se que a infecção crônica pelo vírus da hepatite C afete 170 milhões de pessoas no mundo, muitas delas em uso dessas medicações. A forma típica da retinopatia associada ao interferon alfa apresenta exsudatos algodonosos e hemorragias intra-retinianas. Há vários relatos de alterações oculares associadas ao uso do interferon alfa. Este trabalho descreve um caso de oclusão de veia central da retina em olho direito, com hemorragias no olho contralateral, em paciente usuária dessas medicações por dois anos. O caso descrito expõe em um dos olhos o quadro mais freqüente da retinopatia associada ao uso de interferon alfa (hemorragias de fundo e no olho contralateral, uma apresentação muito mais atípica (trombose de veia central da retina. O quadro fundoscópico apresentou melhora com a interrupção da medicação.Interferon and ribavirin are medications widely used in the treatment of some systemic diseases, mainly hepatitis C. Ribavirin when associated with interferon increases the rate of success of this treatment. There are about 170 million patients with chronic hepatitis C in the world, many in use of these medications. The classic associated retinopathy is described as cotton wool exudates and hemorrhages. Since the first reports, several different ocular disturbances were described in association with interferon. The present case shows a patient whose right eye presented with central retinal vein occlusion and whose left eye presented the typical findings of hemorrhages; prompt resolution after the medications were discontinued.

Interferons in the central nervous system

DEFF Research Database (Denmark)

Owens, Trevor; Khorooshi, Reza M. H.; Wlodarczyk, Agnieszka

2014-01-01

Interferons (IFNs) are implicated as an important component of the innate immune system influencing viral infections, inflammation, and immune surveillance. We review here the complex biological activity of IFNs in the central nervous system (CNS) and associated glial–immune interactions...

Herpes simplex virus infection is sensed by both Toll-like receptors and retinoic acid-inducible gene- like receptors, which synergize to induce type I interferon production

DEFF Research Database (Denmark)

Rasmussen, Simon B; Jensen, Søren B; Nielsen, Christoffer

2009-01-01

The innate antiviral response is initiated by pattern recognition receptors, which recognize viral pathogen-associated molecular patterns. Here we show that retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) in cooperation with Toll-like receptor (TLR) 9 is required for expression of type I...... interferons (IFNs) after infection with herpes simplex virus (HSV). Our work also identified RNase L as a critical component in IFN induction. Moreover, we found that TLR9 and RLRs activate distinct, as well as overlapping, intracellular signalling pathways. Thus, RLRs are important for recognition of HSV...

cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice.

Science.gov (United States)

Ruangkiattikul, Nanthapon; Nerlich, Andreas; Abdissa, Ketema; Lienenklaus, Stefan; Suwandi, Abdulhadi; Janze, Nina; Laarmann, Kristin; Spanier, Julia; Kalinke, Ulrich; Weiss, Siegfried; Goethe, Ralph

2017-10-03

Type I interferons (IFN-I), such as IFN-α and IFN-β are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-β than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focused on the obligate pathogen Mycobacterium avium ssp paratuberculosis (MAP) and the opportunistic M. smegmatis. Viability of both bacteria was required for induction of IFN-β in macrophages. Both bacteria induced IFN-β via the cGAS-STING-TBK1-IRF3/7-pathway of IFN-β activation. Stronger phosphorylation of TBK1 and higher amounts of extracellular bacterial DNA in the macrophage cytosol were found in M. smegmatis infected macrophages than in MAP infected macrophages. After intraperitoneal infection of mice, a strong Ifnb induction by M. smegmatis correlated with clearance of the bacteria. In contrast, MAP only induced weak Ifnb expression which correlated with bacterial persistence and increased number of granulomas in the liver. In mice lacking the type I interferon receptor we observed improved survival of M. smegmatis while survival of MAP was similar to that in wildtype mice. On the other hand, treatment of MAP infected wildtype mice with the IFN-I inducer poly(I:C) or recombinant IFN-β impaired the survival of MAP. This indicates an essential role of IFN-I in clearing infections by MAP and M. smegmatis. The expression level of IFN-I is decisive for transient versus persistent NTM infection.

Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis - A case report.

Science.gov (United States)

Dalbjerg, Sara Maria; Tsakiri, Anna; Frederiksen, Jette Lautrup

2016-07-01

Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis associated with Interferon-beta treatment. We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved. Clinicians should be aware of the possibility of rhabdomyolysis occurring during Interferon-beta-1-alpha therapy. In cases where patients complain of severe myalgia, and in particular if weakness is reported, creatine kinase activity should be measured to prevent irreversible rhabdomyolysis during Interferon-beta-1-alpha therapy in patients with multiple sclerosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Activation of type III interferon genes by pathogenic bacteria in infected epithelial cells and mouse placenta.

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Hélène Bierne

Full Text Available Bacterial infections trigger the expression of type I and II interferon genes but little is known about their effect on type III interferon (IFN-λ genes, whose products play important roles in epithelial innate immunity against viruses. Here, we studied the expression of IFN-λ genes in cultured human epithelial cells infected with different pathogenic bacteria and in the mouse placenta infected with Listeria monocytogenes. We first showed that in intestinal LoVo cells, induction of IFN-λ genes by L. monocytogenes required bacterial entry and increased further during the bacterial intracellular phase of infection. Other Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis, also induced IFN-λ genes when internalized by LoVo cells. In contrast, Gram-negative bacteria Salmonella enterica serovar Typhimurium, Shigella flexneri and Chlamydia trachomatis did not substantially induce IFN-λ. We also found that IFN-λ genes were up-regulated in A549 lung epithelial cells infected with Mycobacterium tuberculosis and in HepG2 hepatocytes and BeWo trophoblastic cells infected with L. monocytogenes. In a humanized mouse line permissive to fetoplacental listeriosis, IFN-λ2/λ3 mRNA levels were enhanced in placentas infected with L. monocytogenes. In addition, the feto-placental tissue was responsive to IFN-λ2. Together, these results suggest that IFN-λ may be an important modulator of the immune response to Gram-positive intracellular bacteria in epithelial tissues.

Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate

DEFF Research Database (Denmark)

Abrahamsson, Jonas; Forestier, Erik; Heldrup, Jesper

2011-01-01

To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.......To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course....

Interferon alpha association with neuromyelitis optica

DEFF Research Database (Denmark)

Asgari, Nasrin; Voss, Anne; Steenstrup, Troels

2013-01-01

Interferon-alpha (IFN- α ) has immunoregulatory functions in autoimmune inflammatory diseases. The goal of this study was to determine occurrence and clinical consequences of IFN- α in neuromyelitis optica (NMO) patients. Thirty-six NMO and 41 multiple sclerosis (MS) patients from a population...

Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype.

Science.gov (United States)

Schulte, Barbara M; Gielen, Paul R; Kers-Rebel, Esther D; Prosser, Amy C; Lind, Katharina; Flodström-Tullberg, Malin; Tack, Cees J; Elving, Lammy D; Adema, Gosse J

2016-09-01

In children at risk for type 1 diabetes, innate immune activity is detected before seroconversion. Enterovirus infections have been linked to diabetes development, and a polymorphism (A946T) in the innate immune sensor recognizing enterovirus RNA, interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5, predisposes to disease. We hypothesized that the strength of innate antienteroviral responses is affected in autoimmune type 1 diabetes patients and linked to the A946T polymorphism. We compared induction of interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in healthy individuals and diabetes patients upon stimulation with enterovirus, enterovirus-antibody complexes, or ligands mimicking infection in relation to the A946T polymorphism. Overall, PBMCs of diabetes patients and healthy donors showed comparable ISG induction upon stimulation. No differences were observed in DCs. Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls. These data imply an intrinsic difference in the responses to enterovirus and enterovirus-antibody complexes in diabetes patients carrying a TT risk genotype compared to heterozygotes that may influence control of enterovirus clearance.

Oxidative Modification of Blood Serum Proteins in Multiple Sclerosis after Interferon Beta and Melatonin Treatment

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Monika Adamczyk-Sowa

2017-01-01

Full Text Available Multiple sclerosis (MS is a disease involving oxidative stress (OS. This study was aimed at examination of the effect of melatonin supplementation on OS parameters, especially oxidative protein modifications of blood serum proteins, in MS patients. The study included 11 control subjects, 14 de novo diagnosed MS patients with the relapsing-remitting form of MS (RRMS, 36 patients with RRMS receiving interferon beta-1b (250 μg every other day, and 25 RRMS patients receiving interferon beta-1b plus melatonin (5 mg daily. The levels of N′-formylkynurenine, kynurenine, dityrosine, carbonyl groups, advanced glycation products (AGEs, advanced oxidation protein products (AOPP, and malondialdehyde were elevated in nontreated RRSM patients. N′-Formylkynurenine, kynurenine, AGEs, and carbonyl contents were decreased only in the group treated with interferon beta plus melatonin, while dityrosine and AOPP contents were decreased both in the group of patients treated with interferon beta and in the group treated with interferon beta-1b plus melatonin. These results demonstrate that melatonin ameliorates OS in MS patients supporting the view that combined administration of interferon beta-1b and melatonin can be more effective in reducing OS in MS patients than interferon beta-1b alone.

DMPD: Interferon gene regulation: not all roads lead to Tolls. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 16095970 Interferon gene regulation: not all roads lead to Tolls. Jefferies CA, Fit...zgerald KA. Trends Mol Med. 2005 Sep;11(9):403-11. (.png) (.svg) (.html) (.csml) Show Interferon gene regulation: not all roads... lead to Tolls. PubmedID 16095970 Title Interferon gene regulation: not all roads lead to

The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon

Science.gov (United States)

Fernández de Marco, María del Mar; Alejo, Alí; Hudson, Paul; Damon, Inger K.; Alcami, Antonio

2010-01-01

Variola virus (VARV) caused smallpox, one of the most devastating human diseases and the first to be eradicated, but its deliberate release represents a dangerous threat. Virulent orthopoxviruses infecting humans, such as monkeypox virus (MPXV), could fill the niche left by smallpox eradication and the cessation of vaccination. However, immunomodulatory activities and virulence determinants of VARV and MPXV remain largely unexplored. We report the molecular characterization of the VARV- and MPXV-secreted type I interferon-binding proteins, which interact with the cell surface after secretion and prevent type I interferon responses. The proteins expressed in the baculovirus system have been purified, and their interferon-binding properties characterized by surface plasmon resonance. The ability of these proteins to inhibit a broad range of interferons was investigated to identify potential adaptation to the human immune system. Furthermore, we demonstrate by Western blot and activity assays the expression of the type I interferon inhibitor during VARV and MPXV infections. These findings are relevant for the design of new vaccines and therapeutics to smallpox and emergent virulent orthopoxviruses because the type I interferon-binding protein is a major virulence factor in animal models, vaccination with this protein induces protective immunity, and its neutralization prevents disease progression.—Fernández de Marco, M. M., Alejo, A., Hudson, P., Damon, I. K., Alcami, A. The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon. PMID:20019241

Interferon-alpha triggers B cell effector 1 (Be1 commitment.

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Marie-Ghislaine de Goër de Herve

Full Text Available B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells producing a Th-1-like cytokine pattern and the other (Be2 producing a Th-2-like pattern. IL-12 and IFN-γ play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-α triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-γ gene imprinting factors. IFN-α primed naive B-cells for IFN-γ production and increased IFN-γ gene responsiveness to IL-12. IFN-γ continues this polarization by re-inducing T-bet and up-regulating IL-12Rβ2 expression. IFN-α and IFN-γ therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-α, IFN-γ and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.

Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice

NARCIS (Netherlands)

Poosti, Fariba; Bansal, Ruchi; Yazdani, Saleh; Prakash, Jai; Beljaars, Leonie; van den Born, Jacob; de Borst, Martin H.; van Goor, Harry; Hillebrands, Jan-Luuk; Poelstra, Klaas

2016-01-01

Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-gamma is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-gamma is hampered due to inflammation-mediated systemic side effects. We used an interferon-gamma

Microassay for interferon, using [3H]uridine, microculture plates, and a multiple automated sample harvester.

Science.gov (United States)

Richmond, J Y; Polatnick, J; Knudsen, R C

1980-01-01

A microassay for interferon is described which uses target cells grown in microculture wells, [3H]uridine to measure vesicular stomatitis virus replication in target cells, and a multiple automated sample harvester to collect the radioactively labeled viral ribonucleic acid onto glass fiber filter disks. The disks were placed in minivials, and radioactivity was counted in a liquid scintillation spectrophotometer. Interferon activity was calculated as the reciprocal of the highest titer which inhibited the incorporation of [3H]uridine into viral ribonucleic acid by 50%. Interferon titers determined by the microassay were similar to the plaque reduction assay when 100 plaque-forming units of challenge vesicular stomatitis virus was used. However, it was found that the interferon titers decreased approximately 2-fold for each 10-fold increase in the concentration of challenge vesicular stomatitis virus when tested in the range of 10(2) to 10(5) plaque-forming units. Interferon titers determined by the microassay show a high degree of repeatability, and the assay can be used to measure small and large numbers of interferon samples. PMID:6155105

Delirium after interleukin-2 and alpha-interferon therapy for renal cell carcinoma

NARCIS (Netherlands)

Van Steijn, JHM; Nieboer, P; Hospers, GAP; De Vries, EGE; Mulder, NH

2001-01-01

A 55-year-old man receiving alpha-interferon and interieukin-2 therapy for renal cell carcinoma presented with seizures and delirium. A CT-scan of the cerebrum did not reveal any disorder. Both alpha-interferon and interleukin-2 were stopped Treatment with steroids led to complete regression of

Induction immunosuppressive therapies in renal transplantation.

Science.gov (United States)

Gabardi, Steven; Martin, Spencer T; Roberts, Keri L; Grafals, Monica

2011-02-01

Induction immunosuppressive therapies for patients undergoing renal transplantation are reviewed. The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplantation. Induction therapy is often considered essential to optimize outcomes, particularly in patients at high risk for poor short-term outcomes. All of the induction immunosuppressive agents currently used are biological agents and are either monoclonal (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) or polyclonal (antithymocyte globulin [equine] or antithymocyte globulin [rabbit]) antibodies. Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent. Basiliximab is not considered as potent an immunosuppressive agent but has a much more favorable adverse-effect profile compared with antithymocyte globulin (rabbit) and is most commonly used in patients at low risk for acute rejection. Rituximab is being studied for use as induction therapy but to date has not demonstrated any significant benefits over placebo. While head-to-head data are available comparing most induction agents, the final decision on the most appropriate induction therapy for a transplant recipient is highly dependent on preexisting medical conditions, donor characteristics, and the maintenance immunosuppressive regimen to be used. No standard induction immunosuppressive regimen exists for patients undergoing renal transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. The choice of regimen depends on the preferences of clinicians and institutions.

Renal thrombotic microangiopathy caused by interferon beta-1a treatment for multiple sclerosis

Directory of Open Access Journals (Sweden)

Mahe J

2013-08-01

Full Text Available Julien Mahe,1 Aurélie Meurette,2 Anne Moreau,3 Caroline Vercel,2 Pascale Jolliet1,4 1Clinical Pharmacology Department, Institute of Biology, University Hospital, Nantes, France; 2Clinical Nephrology and Immunology Department, University Hospital, Nantes, France; 3Laboratory of Pathology, University Hospital, Nantes, France; 4EA 4275 Biostatistics, Pharmacoepidemiology and Subjective Measures in Health Sciences, University of Nantes, Nantes, France Abstract: Interferon beta-1a is available as an immunomodulating agent for relapsing forms of multiple sclerosis. Common side effects include flu-like symptoms, asthenia, anorexia, and administration site reaction. Kidney disorders are rarely reported. In this study we describe the case of a woman who has been undergoing treatment with interferon beta-1a for multiple sclerosis for 5 years. She developed a hemolytic-uremic syndrome with intravascular hemolysis in a context of severe hypertension. A kidney biopsy showed a thrombotic microangiopathy. This observation highlights an uncommon side effect of long-term interferon beta-1a therapy. Pathophysiological mechanisms leading to this complication might be explained by the antiangiogenic activity of interferon. Keywords: thrombotic microangiopathy, interferon beta, hemolytic-uremic syndrome, antiangiogenic activity

Influence of Interferon-Alpha Combined with Chemo (Radio Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

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Svetlana Karakhanova

2014-03-01

Full Text Available Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.

[Expression of gamma interferon during HPV and Chlamydia trachomatis infection in cervical samples].

Science.gov (United States)

Colín-Ferreyra, María Del Carmen; Mendieta-Zerón, Hugo; Romero-Figueroa, María Del Socorro; Martínez-Madrigal, Migdania; Martínez-Pérez, Sergio; Domínguez-García, María Victoria

2015-02-01

The aim of this study was to mesure the expression of gamma interferon in HPV and Chlamydia trachomatis infection in squamous intraepithelial lesions. Samples from 100 patients diagnosed by colposcopy with or without squamous intraepithelial lesions were used in the present study. Each patient was found to be infected by HPV and C.trachomatis. Relative gamma interferon mRNA expression was assessed using a real-time reverse transcriptase PCR assay (RT-PCR). The relative units of expression of gamma interferon mRNA were 13, 1.8 and 0.3, for HPV and C.trachomatis co-infection, or HPV or C.trachomatis infection, respectively. HPV and C.trachomatis could overstimulate the expression of gamma interferon. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.

Science.gov (United States)

Holmes, J A; Congiu, M; Bonanzinga, S; Sandhu, M K; Kia, Y H; Bell, S J; Nguyen, T; Iser, D M; Visvanathan, K; Sievert, W; Bowden, D S; Desmond, P V; Thompson, A J

2015-08-01

The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype. © 2015 John Wiley & Sons Ltd.

Joseph Henry’s role in the discovery of electromagnetic induction

International Nuclear Information System (INIS)

Smith, Glenn S

2017-01-01

The discovery of electromagnetic induction in the early part of the 19th century is one of the greatest scientific achievements of all time, and it has had tremendous technological consequences. The credit for this discovery rightfully goes to the great English experimental physicist Michael Faraday. However, the American physicist Joseph Henry made some observations comparable to Faraday’s at nearly the same time, and for that reason, Faraday and Henry are often considered to be co-discoverers of some aspects of electromagnetic induction. We examine Henry’s early research on electromagnetism, starting from his efforts to improve the electromagnet, which led directly to his investigations of induction. We describe his earliest experiments on both mutual and self-induction, and pay particular attention to the relationship of Henry’s research to that of Faraday. The approach is one in which the experiments are described and then analysed using modern theory and terminology. (paper)

Increase in neutrophil Fc gamma receptor I expression following interferon gamma treatment in rheumatoid arthritis.

Science.gov (United States)

Goulding, N J; Knight, S M; Godolphin, J L; Guyre, P M

1992-04-01

The therapeutic potential of interferon gamma (IFN gamma) in a number of disease states is still being explored, but progress is hampered by the lack of a suitable measure of in vivo biological activity. To assess the in vivo biological effects of recombinant human IFN gamma (rhIFN gamma), 14 patients were studied in a randomised, prospective, double blind, placebo controlled trial of this cytokine for the treatment of rheumatoid arthritis. The levels of Fc gamma receptors on peripheral blood neutrophils were measured at baseline and after 21 days of once daily, subcutaneous injections of rhIFN gamma or placebo. An induction of neutrophil Fc gamma receptor type I (Fc gamma RI) was seen in the group of patients receiving recombinant human rhIFN gamma but not in those receiving placebo. No change in the expression of Fc gamma RII or Fc gamma RIII was detected. The amount of induction of Fc gamma RI detected on the neutrophils of patients receiving rhIFN gamma did not correlate with clinical measures of response at either 21 days or at the end of the study (24 weeks). No significant clinical responses were observed in the rhIFN gamma group at these times. These data confirm that the reported in vitro effect of IFN gamma on human neutrophil Fc receptor expression can be reproduced in vivo.

Pulmonary abnormalities caused by interferon with or without herbal drug. CT and radiographic findings

International Nuclear Information System (INIS)

Ikezoe, Junpei; Kohno, Nobuaki; Johkoh, Takeshi; Kozuka, Takahiro; Kawase, Ichiro; Ebara, Hidemi; Kamisako, Toshinori; Adachi, Yukihiko.

1995-01-01

Chest radiographic and CT findings of acute diffuse interstitial lung disease due to interferon administration were reviewed. The subjects were 5 patients who were treated with interferon alone (n=4) or combined with traditional herbal drug treatment (n=one) for chronic hepatitis C. Respiratory symptoms consisted of cough (n=4), fever (n=4), dyspnea (n=3), and chest pain (n=one). CT findings were peripherally predominant non-segmental consolidation (n=3) with or without ground-glass opacities, and intralobular reticulation with ground-glass opacities (n=2). Neither honeycombing nor lung distortion was observed on CT. Chest radiographs showed airspace consolidation with or without ground-glass opacities (n=4) and reticulonodular lesions with ground-glass opacities (n=one). Although radiological findings of interferon-induced lung abnormalities were not uniform, it appears that these findings reflect lung hypersensitivity to interferon. Recognizing radiographic and CT findings of interferon-induced lung abnormalities is required because they are likely to occur associated with increasing use of this drug in the clinical setting. (N.K.)

Pulmonary abnormalities caused by interferon with or without herbal drug. CT and radiographic findings

Energy Technology Data Exchange (ETDEWEB)

Ikezoe, Junpei; Kohno, Nobuaki; Johkoh, Takeshi; Kozuka, Takahiro; Kawase, Ichiro [Osaka Univ. (Japan). Faculty of Medicine; Ebara, Hidemi; Kamisako, Toshinori; Adachi, Yukihiko

1995-02-01

Chest radiographic and CT findings of acute diffuse interstitial lung disease due to interferon administration were reviewed. The subjects were 5 patients who were treated with interferon alone (n=4) or combined with traditional herbal drug treatment (n=one) for chronic hepatitis C. Respiratory symptoms consisted of cough (n=4), fever (n=4), dyspnea (n=3), and chest pain (n=one). CT findings were peripherally predominant non-segmental consolidation (n=3) with or without ground-glass opacities, and intralobular reticulation with ground-glass opacities (n=2). Neither honeycombing nor lung distortion was observed on CT. Chest radiographs showed airspace consolidation with or without ground-glass opacities (n=4) and reticulonodular lesions with ground-glass opacities (n=one). Although radiological findings of interferon-induced lung abnormalities were not uniform, it appears that these findings reflect lung hypersensitivity to interferon. Recognizing radiographic and CT findings of interferon-induced lung abnormalities is required because they are likely to occur associated with increasing use of this drug in the clinical setting. (N.K.).

DMPD: Toll-like receptors and Type I interferons. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available m. 2007 May 25;282(21):15319-23. Epub 2007 Mar 29. (.png) (.svg) (.html) (.csml) Show Toll-like receptors and Type I interferons. Pub...medID 17395581 Title Toll-like receptors and Type I interferons. Authors Uematsu S,

Alpha interferon therapy in Danish haemophiliac patients with chronic hepatitis C

DEFF Research Database (Denmark)

Laursen, A L; Scheibel, E; Ingerslev, Jørgen

1998-01-01

Following a survey among all Danish haemophiliac patients 49 HIV-negative patients with chronic hepatitis C were offered enrollment in a randomized controlled open label study comparing two different maintenance regimens following standard interferon-alpha-2b treatment. Dose modifications...... and biochemical response after 6 months of follow up. Overall, the individualized treatment regimen did not seem to offer any advantage over the fixed dose regimen. The response to alpha interferon treatment in Danish haemophiliac patients with chronic hepatitis C immediately after treatment is comparable...... and treatment discontinuation were based upon changes in transaminase levels. Forty-seven patients enrolled received 3 MU of alpha interferon thrice weekly (TIW) for 3 months. Twenty-six nonresponders had their dose increased to 6 MU TIW for an additional 3 months, while 21 responding patients continued on 3 MU...

Interferon Gamma in African Trypanosome Infections: Friends or Foes?

Science.gov (United States)

Wu, Hui; Liu, Gongguan; Shi, Meiqing

2017-01-01

African trypanosomes cause fatal infections in both humans and livestock. Interferon gamma (IFN-γ) plays an essential role in resistance to African trypanosomes. However, increasing evidence suggests that IFN-γ, when excessively synthesized, also induces immunopathology, enhancing susceptibility to the infection. Thus, production of IFN-γ must be tightly regulated during infections with African trypanosomes to ensure that a robust immune response is elicited without tissue destruction. Early studies have shown that secretion of IFN-γ is downregulated by interleukin 10 (IL-10). More recently, IL-27 has been identified as a negative regulator of IFN-γ production during African trypanosome infections. In this review, we discuss the current state of our understanding of the role of IFN-γ in African trypanosome infections. We have focused on the cellular source of IFN-γ, its beneficial and detrimental effects, and mechanisms involved in regulation of its production, highlighting some recent advances and offering some perspectives on future directions.

Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection

DEFF Research Database (Denmark)

Petrucci, Roberta; Abu Amer, Nabil; Gurgel, Ricardo Queiroz

2008-01-01

BACKGROUND: Children in contact with adults with pulmonary tuberculosis (TB) are at risk for infection and disease progression, and chemoprophylaxis may reduce this risk. The identification of infection is based on the tuberculin skin test (TST) and interferon-gamma (INF-gamma) release assays...

IRF3 and type I interferons fuel a fatal response to myocardial infarction.

Science.gov (United States)

King, Kevin R; Aguirre, Aaron D; Ye, Yu-Xiang; Sun, Yuan; Roh, Jason D; Ng, Richard P; Kohler, Rainer H; Arlauckas, Sean P; Iwamoto, Yoshiko; Savol, Andrej; Sadreyev, Ruslan I; Kelly, Mark; Fitzgibbons, Timothy P; Fitzgerald, Katherine A; Mitchison, Timothy; Libby, Peter; Nahrendorf, Matthias; Weissleder, Ralph

2017-12-01

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.

DMPD: The interferon regulatory factor family in host defense: mechanism of action. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17502370 The interferon regulatory factor family in host defense: mechanism of acti....html) (.csml) Show The interferon regulatory factor family in host defense: mechanism of action. PubmedID 1...7502370 Title The interferon regulatory factor family in host defense: mechanism

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis.

Science.gov (United States)

Laperchia, Claudia; Tesoriero, Chiara; Seke-Etet, Paul F; La Verde, Valentina; Colavito, Valeria; Grassi-Zucconi, Gigliola; Rodgers, Jean; Montague, Paul; Kennedy, Peter G E; Bentivoglio, Marina

2017-08-01

Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease. The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness. The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis.

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis.

Directory of Open Access Journals (Sweden)

Claudia Laperchia

2017-08-01

Full Text Available Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease.The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi, but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness.The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African

E2F/Rb Family Proteins Mediate Interferon Induced Repression of Adenovirus Immediate Early Transcription to Promote Persistent Viral Infection.

Directory of Open Access Journals (Sweden)

Yueting Zheng

2016-01-01

Full Text Available Interferons (IFNs are cytokines that have pleiotropic effects and play important roles in innate and adaptive immunity. IFNs have broad antiviral properties and function by different mechanisms. IFNs fail to inhibit wild-type Adenovirus (Ad replication in established cancer cell lines. In this study, we analyzed the effects of IFNs on Ad replication in normal human cells. Our data demonstrate that both IFNα and IFNγ blocked wild-type Ad5 replication in primary human bronchial epithelial cells (NHBEC and TERT-immortalized normal human diploid fibroblasts (HDF-TERT. IFNs inhibited the replication of divergent adenoviruses. The inhibition of Ad5 replication by IFNα and IFNγ is the consequence of repression of transcription of the E1A immediate early gene product. Both IFNα and IFNγ impede the association of the transactivator GABP with the E1A enhancer region during the early phase of infection. The repression of E1A expression by IFNs requires a conserved E2F binding site in the E1A enhancer, and IFNs increased the enrichment of the E2F-associated pocket proteins, Rb and p107, at the E1A enhancer in vivo. PD0332991 (Pabociclib, a specific CDK4/6 inhibitor, dephosphoryles pocket proteins to promote their interaction with E2Fs and inhibited wild-type Ad5 replication dependent on the conserved E2F binding site. Consistent with this result, expression of the small E1A oncoprotein, which abrogates E2F/pocket protein interactions, rescued Ad replication in the presence of IFNα or IFNγ. Finally, we established a persistent Ad infection model in vitro and demonstrated that IFNγ suppresses productive Ad replication in a manner dependent on the E2F binding site in the E1A enhancer. This is the first study that probes the molecular basis of persistent adenovirus infection and reveals a novel mechanism by which adenoviruses utilize IFN signaling to suppress lytic virus replication and to promote persistent infection.

Early histological, hormonal, and molecular changes during pineapple (Ananas comosus (L.) Merrill) artificial flowering induction.

Science.gov (United States)

Espinosa, Maita Eulalia Ávila; Moreira, Rafael Oliveira; Lima, André Almeida; Ságio, Solange Aparecida; Barreto, Horllys Gomes; Luiz, Sara Lazara Pérez; Abreu, Carlos Eduardo Aragón; Yanes-Paz, Ermis; Ruíz, Yanelis Capdesuñer; González-Olmedo, Justo Lorenzo; Chalfun-Júnior, Antonio

2017-02-01

Natural flowering can cause serious scheduling problems in the pineapple (Ananas comosus) industry and increase harvest costs. Pineapple flowering is thought to be triggered by increased ethylene levels and artificial forcing of pineapple flowering is a common practice to promote flowering synchronisation. However, little is known about the early hormonal and molecular changes of pineapple flowering induction and development. Here, we aimed to analyse the molecular, hormonal, and histological changes during artificial pineapple flowering by Ethrel ® 48 treatment. Histological analyses of the shoot apical meristem, leaf gibberellic acid (GA 3 ), and ethylene quantification were carried out during the first 72h after Ethrel ® 48 treatment. Expression profiles from ethylene biosynthesis (AcACS2 and AcACO1), gibberellin metabolism (AcGA2-ox1 and AcDELLA1), and flower development (FT-like gene (AcFT), LFY-like gene (AcLFY), and a PISTILLATA-like gene (AcPI)) genes were analysed during the first 24h after Ethrel ® 48 treatment. Differentiation processes of the shoot apical meristem into flower buds were already present in the first 72h after Ethrel ® 48 treatment. Ethrel ® 48 lead to a reduction in GA 3 levels, probably triggered by elevated ethylene levels and the positive regulation AcGA2-ox1. AcLFY activation upon Ethrel ® 48 may also have contributed to the reduction of GA 3 levels and, along with the up-regulation of AcPI, are probably associated with the flower induction activation. AcFT and AcDELLA1 do not seem to be regulated by GA 3 and ethylene. Decreased GA 3 and increased ethylene levels suggest an accumulation of AcDELLA1, which may display an important role in pineapple flowering induction. Thus, this study shows that molecular, hormonal, and histological changes are present right after Ethrel ® 48 treatment, providing new insights into how pineapple flowering occurs under natural conditions. Copyright © 2016 Elsevier GmbH. All rights reserved.

Evaluation of Interferon-gamma Application for Recognition of Patients Afflicted by Non-healing Cutaneous Leishmaniasis

OpenAIRE

Mohammad Moafi; Hossein Rezvan; Roya Sherkat; Sayyed Hamid Zarkesh-Esfahani; Roya Taleban; Ali Asilian; Mohammad Ali Nilforoushzadeh; Fariba Jaffary; Marjan Mansourian; Fatemeh Sokhanvari; Nazli Ansari

2017-01-01

Introduction:Different studies undertaken in the animal modeling show that Interferon-gamma deficiency impairs healing process of Leishmania infection. It seems that the level of Interferon-gamma production could also affect the healing duration of Leishmania lesion in humans. The current study aims to investigate the possibility of Interferon-gamma application for recognition of cases afflicted by non-healing Leishmaniasis. Materials and methods: Peripheral blood mononuclear cells (PBMCs) of...

TANK-Binding Kinase 1 (TBK1 Isoforms Negatively Regulate Type I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation

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Yi Wei Hu

2018-01-01

Full Text Available TANK-binding kinase 1 (TBK1 is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-β signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I and mitochondria antiviral-signaling protein (MAVS. However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s exist in teleost fish. In this study, we identify two alternatively spliced isoforms of TBK1 from zebrafish, termed TBK1_tv1 and TBK1_tv2. Both TBK1_tv1 and TBK1_tv2 contain an incomplete STKc_TBK1 domain. Moreover, the UBL_TBK1_like domain is also missing for TBK1_tv2. TBK1_tv1 and TBK1_tv2 are expressed in zebrafish larvae. Overexpression of TBK1_tv1 and TBK1_tv2 inhibits RIG-I-, MAVS-, TBK1-, and IRF3-mediated activation of IFN promoters in response to spring viremia of carp virus infection. Also, TBK1_tv1 and TBK1_tv2 inhibit expression of IFNs and IFN-stimulated genes induced by MAVS and TBK1. Mechanistically, TBK1_tv1 and TBK1_tv2 competitively associate with TBK1 and IRF3 to disrupt the formation of a functional TBK1-IRF3 complex, impeding the phosphorylation of IRF3 mediated by TBK1. Collectively, these results demonstrate that TBK1 spliced isoforms are dominant negative regulators in the RIG-I/MAVS/TBK1/IRF3 antiviral pathway by targeting the functional TBK1-IRF3 complex formation. Identification and functional characterization of piscine TBK1 spliced isoforms may contribute to understanding the role of TBK1 expression in innate antiviral response.

Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection

DEFF Research Database (Denmark)

Petrucci, Roberta; Abu Amer, Nabil; Gurgel, Ricardo Queiroz

2008-01-01

BACKGROUND: Children in contact with adults with pulmonary tuberculosis (TB) are at risk for infection and disease progression, and chemoprophylaxis may reduce this risk. The identification of infection is based on the tuberculin skin test (TST) and interferon-gamma (INF-gamma) release assays. Ot...

A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.

Science.gov (United States)

Rascio, Federica; Pontrelli, Paola; Accetturo, Matteo; Oranger, Annarita; Gigante, Margherita; Castellano, Giuseppe; Gigante, Maddalena; Zito, Anna; Zaza, Gianluigi; Lupo, Antonio; Ranieri, Elena; Stallone, Giovanni; Gesualdo, Loreto; Grandaliano, Giuseppe

2015-09-01

Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control

Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis

DEFF Research Database (Denmark)

Polman, Chris H; Bertolotto, Antonio; Deisenhammer, Florian

2010-01-01

in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs......The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts...... and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual...

Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C.

Science.gov (United States)

Lee, Jae-Won; Kim, Won; Kwon, Eun-Kyung; Kim, Yuri; Shin, Hyun Mu; Kim, Dong-Hyun; Min, Chan-Ki; Choi, Ji-Yeob; Lee, Won-Woo; Choi, Myung-Sik; Kim, Byeong Gwan; Cho, Nam-Hyuk

2017-01-01

Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.

DMPD: Interferons at age 50: past, current and future impact on biomedicine. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 18049472 Interferons at age 50: past, current and future impact on biomedicine. Bor...975-90. (.png) (.svg) (.html) (.csml) Show Interferons at age 50: past, current and future impact on biomedicine.... PubmedID 18049472 Title Interferons at age 50: past, current and future impact on biomedicine

Clinical Value of Thyrotropin Receptor Antibodies for the Differential Diagnosis of Interferon Induced Thyroiditis.

Science.gov (United States)

Benaiges, D; Garcia-Retortillo, M; Mas, A; Cañete, N; Broquetas, T; Puigvehi, M; Chillarón, J J; Flores-Le Roux, J A; Sagarra, E; Cabrero, B; Zaffalon, D; Solà, R; Pedro-Botet, J; Carrión, J A

2016-01-01

The clinical value of thyrotropin receptor antibodies for the differential diagnosis of thyrotoxicosis induced by pegylated interferon-alpha remains unknown. We analyzed the diagnostic accuracy of thyrotropin receptor antibodies in the differential diagnosis of thyrotoxicosis in patients with chronic hepatitis C (CHC) receiving pegylated interferon-alpha plus ribavirin. Retrospective analysis of 274 patients with CHC receiving pegylated interferon-alpha plus ribavirin. Interferon-induced thyrotoxicosis was classified according to clinical guidelines as Graves disease, autoimmune and non- autoimmune destructive thyroiditis. 48 (17.5%) patients developed hypothyroidism, 17 (6.2%) thyrotoxicosis (6 non- autoimmune destructive thyroiditis, 8 autoimmune destructive thyroiditis and 3 Graves disease) and 22 "de novo" thyrotropin receptor antibodies (all Graves disease, 2 of the 8 autoimmune destructive thyroiditis and 17 with normal thyroid function). The sensitivity and specificity of thyrotropin receptor antibodies for Graves disease diagnosis in patients with thyrotoxicosis were 100 and 85%, respectively. Patients with destructive thyroiditis developed hypothyroidism in 87.5% of autoimmune cases and in none of those with a non- autoimmune etiology (pthyroid scintigraphy for the differential diagnosis of thyrotoxicosis in CHC patients treated with pegylated interferon. © Georg Thieme Verlag KG Stuttgart · New York.

Identification of distal silencing elements in the murine interferon-A11 gene promoter.

Science.gov (United States)

Roffet, P; Lopez, S; Navarro, S; Bandu, M T; Coulombel, C; Vignal, M; Doly, J; Vodjdani, G

1996-08-01

The murine interferon-A11 (Mu IFN-A11) gene is a member of the IFN-A multigenic family. In mouse L929 cells, the weak response of the gene's promoter to viral induction is due to a combination of both a point mutation in the virus responsive element (VRE) and the presence of negatively regulating sequences surrounding the VRE. In the distal part of the promoter, the negatively acting E1E2 sequence was delimited. This sequence displays an inhibitory effect in either orientation or position on the inducibility of a virus-responsive heterologous promoter. It selectively represses VRE-dependent transcription but is not able to reduce the transcriptional activity of a VRE-lacking promoter. In a transient transfection assay, an E1E2-containing DNA competitor was able to derepress the native Mu IFN-A11 promoter. Specific nuclear factors bind to this sequence; thus the binding of trans-regulators participates in the repression of the Mu IFN-A11 gene. The E1E2 sequence contains an IFN regulatory factor (IRF)-binding site. Recombinant IRF2 binds this sequence and anti-IRF2 antibodies supershift a major complex formed with nuclear extracts. The protein composing the complex is 50 kDa in size, indicating the presence of IRF2 or antigenically related proteins in the complex. The Mu IFN-A11 gene is the first example within the murine IFN-A family, in which a distal promoter element has been identified that can negatively modulate the transcriptional response to viral induction.

Resistance-Associated NS5A Variants of Hepatitis C Virus Are Susceptible to Interferon-Based Therapy.

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Jun Itakura

Full Text Available The presence of resistance-associated variants (RAVs of hepatitis C virus (HCV attenuates the efficacy of direct acting antivirals (DAAs. The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4% at baseline which significantly decreased to 29.7% (0.16%- 98.3% within 7 days of initiation of treatment (p = 0.023. The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4% and a marked reduction of more than 10% was observed in 14 cases (48.7%. HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day than the Y93 wild type (-3.35±1.0 logIU/mL/day (p<0.001.Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.

Resistance-Associated NS5A Variants of Hepatitis C Virus Are Susceptible to Interferon-Based Therapy.

Science.gov (United States)

Itakura, Jun; Kurosaki, Masayuki; Higuchi, Mayu; Takada, Hitomi; Nakakuki, Natsuko; Itakura, Yoshie; Tamaki, Nobuharu; Yasui, Yutaka; Suzuki, Shoko; Tsuchiya, Kaoru; Nakanishi, Hiroyuki; Takahashi, Yuka; Maekawa, Shinya; Enomoto, Nobuyuki; Izumi, Namiki

2015-01-01

The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy. Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined. By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001). Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.

A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice.

Science.gov (United States)

Martín, V; Pascual, E; Avia, M; Rangel, G; de Molina, A; Alejo, A; Sevilla, N

2016-01-06

Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Celiac disease onset after pegylated interferon and ribavirin treatment of chronic hepatitis C Doença celíaca após tratamento de hepatite C crônica com interferon peguilado e ribavirina

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Elson V. Martins Jr.

2004-06-01

Full Text Available AIM: Report of a case of a woman patient who developed celiac disease after pegylated interferon alpha-2a and ribavirin use for chronic hepatitis C. PATIENT AND METHOD: A 34-year-old woman with chronic hepatitis C, genotype 3, receiving pegylated interferon alpha-2a and ribavirin for 6 months, developed progressive malaise and anemia 6 months after the end of treatment. RESULT: Additional investigation revealed duodenal villous atrophy and positivity for anti-endomysium and anti-gliadin antibodies. Celiac disease diagnosis was performed and symptoms and laboratory abnormalities improved after gluten-free diet. CONCLUSION: Celiac disease must be ruled out in patients with malabsorption complaints in or after interferon (or pegylated interferon therapy. Screening for celiac disease with detection of anti-endomysium antibodies would be done in susceptible patients.OBJETIVO: Relatar caso de doença celíaca ocorrendo após uso de interferon peguilado e ribavirina em paciente com hepatite C crônica. PACIENTE E MÉTODO: Mulher de 34 anos com hepatite C crônica, genótipo 3, tratada com interferon peguilado alfa-2a e ribavirina durante 6 meses, desenvolveu quadro de astenia e anemia após 6 meses do término do tratamento. RESULTADO: Investigação complementar revelou atrofia vilositária à biopsia duodenal e detecção de anticorpos anti-endomísio e anti-gliadina, realizando-se diagnóstico de doença celíaca. Dieta isenta de glúten foi instituída, observando-se boa resposta clínica e laboratorial. CONCLUSÃO: Doença celíaca deve ser afastada em pacientes com quadro de má absorção durante ou após uso de interferon (ou interferon peguilado. Rastreamento de doença celíaca através da realização de anticorpo anti-endomísio pode ser considerado em populações susceptíveis.

Diagnostics for induction accelerators

International Nuclear Information System (INIS)

Fessenden, T.J.

1996-04-01

The induction accelerator was conceived by N. C. Christofilos and first realized as the Astron accelerator that operated at LLNL from the early 1960's to the end of 1975. This accelerator generated electron beams at energies near 6 MeV with typical currents of 600 Amperes in 400 ns pulses. The Advanced Test Accelerator (ATA) built at Livermore's Site 300 produced 10,000 Ampere beams with pulse widths of 70 ns at energies approaching 50 MeV. Several other electron and ion induction accelerators have been fabricated at LLNL and LBNL. This paper reviews the principal diagnostics developed through efforts by scientists at both laboratories for measuring the current, position, energy, and emittance of beams generated by these high current, short pulse accelerators. Many of these diagnostics are closely related to those developed for other accelerators. However, the very fast and intense current pulses often require special diagnostic techniques and considerations. The physics and design of the more unique diagnostics developed for electron induction accelerators are presented and discussed in detail

Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy.

Science.gov (United States)

Schmidt, M; Hochhaus, A; König-Merediz, S A; Brendel, C; Proba, J; Hoppe, G J; Wittig, B; Ehninger, G; Hehlmann, R; Neubauer, A

2000-10-01

Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML. Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro-stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-alpha therapy and in 47 additional CML samples taken during IFN-alpha therapy. IRF4 expression was then correlated with cytogenetic response to IFN-alpha. IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-alpha therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-alpha therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-alpha, a good response was associated with high IRF4 expression. IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-alpha therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-alpha in CML.

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

DEFF Research Database (Denmark)

Khorooshi, Reza; Mørch, Marlene Thorsen; Holm, Thomas Hellesøe

2015-01-01

show elevated levels of Type I IFNs in the central nervous system (CNS), suggesting a role for endogenous Type I IFN during inflammation. However, the therapeutic benefit of Type I IFN produced in the CNS remains to be established. The aim of this study was to examine whether experimentally induced CNS......-endogenous Type I IFN influences EAE. Using IFN-β reporter mice, we showed that direct administration of polyinosinic-polycytidylic acid (poly I:C), a potent inducer of IFN-β, into the cerebrospinal fluid induced increased leukocyte numbers and transient upregulation of IFN-β in CD45/CD11b-positive cells located...... in the meninges and choroid plexus, as well as enhanced IFN-β expression by parenchymal microglial cells. Intrathecal injection of poly I:C to mice showing first symptoms of EAE substantially increased the normal disease-associated expression of IFN-α, IFN-β, interferon regulatory factor-7 and IL-10 in CNS...

Whole-exome sequencing reveals a rare interferon gamma receptor 1 mutation associated with myasthenia gravis.

Science.gov (United States)

Qi, Guoyan; Liu, Peng; Gu, Shanshan; Yang, Hongxia; Dong, Huimin; Xue, Yinping

2018-04-01

Our study is aimed to explore the underlying genetic basis of myasthenia gravis. We collected a Chinese pedigree with myasthenia gravis, and whole-exome sequencing was performed on the two affected siblings and their parents. The candidate pathogenic gene was identified by bioinformatics filtering, which was further verified by Sanger sequencing. The homozygous mutation c.G40A (p.V14M) in interferon gamma receptor 1was identified. Moreover, the mutation was also detected in 3 cases of 44 sporadic myasthenia gravis patients. The p.V14M substitution in interferon gamma receptor 1 may affect the signal peptide function and the translocation on cell membrane, which could disrupt the binding of the ligand of interferon gamma and antibody production, contributing to myasthenia gravis susceptibility. We discovered that a rare variant c.G40A in interferon gamma receptor 1 potentially contributes to the myasthenia gravis pathogenesis. Further functional studies are needed to confirm the effect of the interferon gamma receptor 1 on the myasthenia gravis phenotype.

Modulation of interferon-γ synthesis by the effects of lignin-like enzymatically polymerized polyphenols on antigen-presenting cell activation and the subsequent cell-to-cell interactions.

Science.gov (United States)

Yamanaka, Daisuke; Motoi, Masuro; Ishibashi, Ken-ichi; Miura, Noriko N; Adachi, Yoshiyuki; Ohno, Naohito

2013-12-15

Lignin-like polymerized polyphenols strongly activate lymphocytes and induce cytokine synthesis. We aimed to characterise the mechanisms of action of polymerized polyphenols on immunomodulating functions. We compared the reactivity of leukocytes from various organs to that of polymerized polyphenols. Splenocytes and resident peritoneal cavity cells (PCCs) responded to polymerized polyphenols and released several cytokines, whereas thymocytes and bone-marrow cells showed no response. Next, we eliminated antigen-presenting cells (APCs) from splenocytes to study their involvement in cytokine synthesis. We found that APC-negative splenocytes showed significantly reduced cytokine production induced by polymerized polyphenols. Additionally, adequate interferon-γ (IFN-γ) induction by polymerized polyphenols was mediated by the coexistence of APCs and T cells because the addition of T cells to PCCs increased IFN-γ production. Furthermore, inhibition of the T cell-APC interaction using neutralising antibodies significantly decreased cytokine production. Thus, cytokine induction by polymerized polyphenols was mediated by the interaction between APCs and T cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development of a cultivation process for the enhancement of human interferon alpha 2b production in the oleaginous yeast, Yarrowia lipolytica

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Gasmi Najla

2011-11-01

Full Text Available Abstract Background As an oleaginous yeast, Yarrowia lipolytica is able to assimilate hydrophobic substrates. This led to the isolation of several promoters of key enzymes of this catabolic pathway. Less is known about the behavior of Y. lipolytica in large bioreactors using these substrates. There is therefore a lack of established know-how concerning high cell density culture protocols of this yeast. Consequently, the establishment of suitable induction conditions is required, to maximize recombinant protein production under the control of these promoters. Results Human interferon α2b (huIFN α2b production in Yarrowia lipolytica was used as a model for the enhancement of recombinant protein production under the control of the oleic acid (OA-inducible promoter POX2. Cell viability and heterologous protein production were enhanced by exponential glucose feeding, to generate biomass before OA induction. The optimal biomass level before induction was determined (73 g L-1, and glucose was added with oleic acid during the induction phase. Several oleic acid feeding strategies were assessed. Continuous feeding with OA at a ratio of 0.02 g OA per g dry cell weight increased huIFNα2b production by a factor of 1.88 (425 mg L-1 and decreased the induction time (by a factor of 2.6, 21 h. huIFN α2b degradation by an aspartic protease secreted by Y. lipolytica was prevented by adding pepstatin (10 μM, leading to produce a 19-fold more active huIFN α2b (26.2 × 107 IU mg-1. Conclusion Y. lipolytica, a generally regarded as safe (GRAS microorganism is one of the most promising non conventional yeasts for the production of biologically active therapeutic proteins under the control of hydrophobic substrate-inducible promoter.

Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

Directory of Open Access Journals (Sweden)

Alecia Seliga

2018-02-01

Full Text Available The Kallikrein–Kinin System (KKS, comprised of kallikreins (klks, bradykinins (BKs angiotensin-converting enzyme (ACE, and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand, R848 (TLR7 ligand, or recombinant IFN-α to induce interferon-stimulated genes (ISGs and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein, or captopril (an ACE inhibitor. BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice, and in human PBMCs, especially the induction of Irf7 gene (p < 0.05, the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs. BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10, the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2, suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.

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Conrad, Curdin; Di Domizio, Jeremy; Mylonas, Alessio; Belkhodja, Cyrine; Demaria, Olivier; Navarini, Alexander A; Lapointe, Anne-Karine; French, Lars E; Vernez, Maxime; Gilliet, Michel

2018-01-02

Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2-5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.

Interferon Treatment of Multiple Sclerosis

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Alajbegovic, Azra; Deljo, Dervis; Alajbegovic, Salem; Djelilovic-Vranic, Jasminka; Todorovic, Ljubica; Tiric-Campara, Merita

2012-01-01

Introduction: In the treatment of Multiple Sclerosis (MS) differ: treatment of relapse, treatment slow the progression of the disease (immunomodulators and immunosuppression), and symptomatic treatment. The aim: The aim of this study is to analyze the application of interferon therapy in the treatment of MS-E: Process the disease, patients with multiple sclerosis who have passed the commission for multiple sclerosis at the Neurology Clinic of Clinical Center of Sarajevo University as a refere...

The human adenovirus type 5 E1B 55 kDa protein obstructs inhibition of viral replication by type I interferon in normal human cells.

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Jasdave S Chahal

Full Text Available Vectors derived from human adenovirus type 5, which typically lack the E1A and E1B genes, induce robust innate immune responses that limit their therapeutic efficacy. We reported previously that the E1B 55 kDa protein inhibits expression of a set of cellular genes that is highly enriched for those associated with anti-viral defense and immune responses, and includes many interferon-sensitive genes. The sensitivity of replication of E1B 55 kDa null-mutants to exogenous interferon (IFN was therefore examined in normal human fibroblasts and respiratory epithelial cells. Yields of the mutants were reduced at least 500-fold, compared to only 5-fold, for wild-type (WT virus replication. To investigate the mechanistic basis of such inhibition, the accumulation of viral early proteins and genomes was compared by immunoblotting and qPCR, respectively, in WT- and mutant-infected cells in the absence or presence of exogenous IFN. Both the concentration of viral genomes detected during the late phase and the numbers of viral replication centers formed were strongly reduced in IFN-treated cells in the absence of the E1B protein, despite production of similar quantities of viral replication proteins. These defects could not be attributed to degradation of entering viral genomes, induction of apoptosis, or failure to reorganize components of PML nuclear bodies. Nor was assembly of the E1B- and E4 Orf6 protein- E3 ubiquitin ligase required to prevent inhibition of viral replication by IFN. However, by using RT-PCR, the E1B 55 kDa protein was demonstrated to be a potent repressor of expression of IFN-inducible genes in IFN-treated cells. We propose that a primary function of the previously described transcriptional repression activity of the E1B 55 kDa protein is to block expression of IFN- inducible genes, and hence to facilitate formation of viral replication centers and genome replication.

Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells

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Lesinski, Gregory B; Zimmerer, Jason M; Kreiner, Melanie; Trefry, John; Bill, Matthew A; Young, Gregory S; Becknell, Brian; Carson, William E III

2010-01-01

Endogenously produced interferons can regulate the growth of melanoma cells and are administered exogenously as therapeutic agents to patients with advanced cancer. We investigated the role of negative regulators of interferon signaling known as suppressors of cytokine signaling (SOCS) in mediating interferon-resistance in human melanoma cells. Basal and interferon-alpha (IFN-α) or interferon-gamma (IFN-γ)-induced expression of SOCS1 and SOCS3 proteins was evaluated by immunoblot analysis in a panel of n = 10 metastatic human melanoma cell lines, in human embryonic melanocytes (HEM), and radial or vertical growth phase melanoma cells. Over-expression of SOCS1 and SOCS3 proteins in melanoma cells was achieved using the PINCO retroviral vector, while siRNA were used to inhibit SOCS1 and SOCS3 expression. Tyr 701 -phosphorylated STAT1 (P-STAT1) was measured by intracellular flow cytometry and IFN-stimulated gene expression was measured by Real Time PCR. SOCS1 and SOCS3 proteins were expressed at basal levels in melanocytes and in all melanoma cell lines examined. Expression of the SOCS1 and SOCS3 proteins was also enhanced following stimulation of a subset of cell lines with IFN-α or IFN-γ. Over-expression of SOCS proteins in melanoma cell lines led to significant inhibition of Tyr 701 -phosphorylated STAT1 (P-STAT1) and gene expression following stimulation with IFN-α (IFIT2, OAS-1, ISG-15) or IFN-γ (IRF1). Conversely, siRNA inhibition of SOCS1 and SOCS3 expression in melanoma cells enhanced their responsiveness to interferon stimulation. These data demonstrate that SOCS proteins are expressed in human melanoma cell lines and their modulation can influence the responsiveness of melanoma cells to IFN-α and IFN-γ

Ikaros is degraded by proteasome-dependent mechanism in the early phase of apoptosis induction

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He, Li-Cai; Xu, Han-Zhang; Gu, Zhi-Min; Liu, Chuan-Xu; Chen, Guo-Qiang; Wang, Yue-Fei; Wen, Dong-Hua; Wu, Ying-Li

2011-01-01

Research highlights: → Chemotherapeutic drugs or UV treatment reduces Ikaros prior to caspase-3 activation. → Etoposide treatment does not alter the mRNA but shortens the half-life of Ikaros. → MG132 or epoxomicin but not calpeptin inhibits etoposide-induced Ikaros degradation. → Overexpression of Ikaros accelerates etoposide-induced apoptosis in NB4 cells. -- Abstract: Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. In this work, we found that chemotherapeutic drugs or ultraviolet radiation (UV) treatment could reduce the expression of full-length Ikaros (IK1) protein in less than 3 h in leukemic NB4, Kasumi-1 and Jurkat cells, prior to the activation of caspase-3. Etoposide treatment could not alter the mRNA level of IK1 but it could shorten the half-life of IK1. Co-treatment with the proteasome inhibitor MG132 or epoxomicin but not calpain inhibitor calpeptin inhibited etoposide-induced Ikaros downregulation. Overexpression of IK1 could accelerate etoposide-induced apoptosis in NB4 cells, as evidenced by the increase of Annexin V positive cells and the more early activation of caspase 3. To our knowledge, this is the first report to show that upon chemotherapy drugs or UV treatment, IK1 could be degraded via the proteasome system in the early phase of apoptosis induction. These data might shed new insight on the role of IK1 in apoptosis and the post-translational regulation of IK1.

Hypothyroidism In Hepatitis C Patients On Pegylated Interferon Therapy.

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Hameed, Muhammad Asim; Mehmood, Asif; Farooq, Muhammad Ahsan; Tayyab, Ghias Un Nabi; Haq Toor, Israr Ul

2016-01-01

Chronic hepatitis has become a major health problem all over the world especially in the third world countries. The most common cause of chronic hepatitis in Pakistan is hepatitis C which can lead Toliver cirrhosis and hepatocellular carcinoma. In Pakistan Pegylated Interferon Alpha is still corner stone of therapy for chronic hepatitis C. One of the major side effects of this therapy is the development of thyroid dysfunction, i.e., hypothyroidism and hyperthyroidism. This study was done to assess the frequency of hypothyroidism in hepatitis C patients after three months of pegylated interferon therapy. This study was conducted from 1st October 2013 to 31st march 2014 at outpatients department (OPD) of Gastroenterology and Hepatology, Lahore General Hospital Lahore. Descriptive case series study design was used. The sample of 200 patients was taken from the patients who visited OPD and fulfil the inclusion criteria of the study. Serum thyroid stimulating hormone level (TSH) was done before and after completion of three months therapy at centre for Nuclear Medicine (CENUM) laboratory, Mayo Hospital, Lahore by immune-radiometric assay (IRMA) and patients having TSH>4.0 mIU/L (normal range: 0.2-4.0 mIU/L) were considered hypothyroid. The mean age of the patients was 36.29±8.5 years. One hundred and twenty-three (61.5%) were male and 77 (38.5%) were female. After 3 months of interferon therapy, 163 (81.5%) patients were euthyroid and 37(18.5%) patients were having thyroid dysfunction. There were total 29 (14.5%) hypothyroid patients; 8 (27.6%) were male and 21 (72.4%) female. It is concluded from this study that frequency of hypothyroidism in patients with chronic hepatitis C was 14.5% after treatment with pegylated interferon therapy for 3 months. Female patients were more prone to develop hypothyroidism as compared to male patients.

Interferon status at the women with recurrent genital herpes in combined liposomal RNA treatment

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A. Sh. Makhmutkhodzhayev

2012-01-01

Full Text Available The aim of this study was the estimation of the influence of liposomal ribonucleic acid (RNA medicine «Liprina» on interferon status of women with recurrent genital herpes. In this study 60 women were included, who combined (acyclovir and Liprina, n = 40 or monoterapy with acyclovir (n = 20 were received. The levels of serum interferon alpha and gamma along with cervical virus elimination were estimated. The medicine «Liprina» increased the therapy efficiency of the women with genital herpes, that perhaps related with endogen interferon production amplification.

Dissecting interferon-induced transcriptional programs in human peripheral blood cells.

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Simon J Waddell

2010-03-01

Full Text Available Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1 compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs elicited by 6 major mediators of the immune response: interferons alpha, beta, omega and gamma, IL12 and TNFalpha; and (2 characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes to IFNgamma stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNgamma and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFalpha stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNgamma, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings.

Kinetic and metabolic studies on the priming effect of interferon in L cells

International Nuclear Information System (INIS)

Rosztoczy, I.

1977-01-01

In cultures primed by interferon pretreatment before stimulation by polyriboinosinic-polyribocytidylic acid interferon was detected one hour earlier, its production followed an enhanced pattern and became resistant to actinomycin D 30 min sooner than in unprimed cultures. The kinetics of development of the primed state was found to be a time- and dose-dependent phenomenon. The continuous presence of interferon during the pretreatment period was not required for the development of the primed state. Actinomycin D at a concentration inhibitory for nuclear RNA synthesis did not influence the development of priming. Higher concentrations of the drug and long term α-amanitin or cycloheximide pretreatments, inhibitory for heterogeneous nuclear RNA synthesis, prevented the establishment of the primed state. (author)

Dampened STING-Dependent Interferon Activation in Bats.

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Xie, Jiazheng; Li, Yang; Shen, Xurui; Goh, Geraldine; Zhu, Yan; Cui, Jie; Wang, Lin-Fa; Shi, Zheng-Li; Zhou, Peng

2018-03-14

Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat-specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir. Copyright © 2018 Elsevier Inc. All rights reserved.

Production of interferon-gamma by in vivo tumor-sensitized T cells: Association with active antitumor immunity

International Nuclear Information System (INIS)

Bursuker, I.; Pearce, M.T.

1990-01-01

The state of active immunity to Meth A fibrosarcoma in mice immunized with an admixture of Meth A cells and Propionibacterium acnes is associated with possession by the host of spleen cells capable of producing interferon-gamma (IFN-gamma) upon in vitro restimulation with irradiated tumor cells. The ability of spleen cells from immunized mice to produce IFN-gamma in response to irradiated Meth A cells decays as active antitumor immunity is replaced by a state of immunological memory. The IFN-producing cells are L3T4+Ly2+, cyclophosphamide-sensitive and radiosensitive T cells, as determined by their sensitivity to corresponding monoclonal antibodies and complement. The induction of IFN-gamma production by in vivo tumor-sensitized T cells is tumor specific, in that spleen cells from mice immunized against Meth A fibrosarcoma can produce IFN in response to irradiated Meth A cells but not in response to another syngeneic tumor M109 lung carcinoma

A case of reversible dilated cardiomyopathy after alpha-interferon therapy in a patient with renal cell carcinoma.

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Kuwata, Akiko; Ohashi, Masuo; Sugiyama, Masaya; Ueda, Ryuzo; Dohi, Yasuaki

2002-12-01

A 47-year-old man with renal cell carcinoma underwent nephrectomy, and postoperative chemotherapy was performed with recombinant alpha-interferon. Five years later, he experienced dyspnea during physical exertion. An echocardiogram revealed dilatation and systolic dysfunction of the left ventricle, and thallium-201 myocardial scintigraphy showed diffuse heterogeneous perfusion. We diagnosed congestive heart failure because of cardiomyopathy induced by alpha-interferon therapy. Withdrawal of interferon therapy and the combination of an angiotensin-converting enzyme inhibitor, diuretics, and digitalis improved left ventricular systolic function. Furthermore, myocardial scintigraphy using [123I] beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) or [123 I]metaiodobenzylguanidine (123I-MIBG) revealed normal perfusion after the improvement of congestive heart failure. This is a rare case of interferon-induced cardiomyopathy that resulted in normal myocardial images in 123I-BMIPP and 123I-MIBG scintigrams after withdrawal of interferon therapy.

Interferon-γ and NF-κB mediate nitric oxide production by mesenchymal stromal cells

International Nuclear Information System (INIS)

Oh, I.; Ozaki, K.; Sato, K.; Meguro, A.; Tatara, R.; Hatanaka, K.; Nagai, T.; Muroi, K.; Ozawa, K.

2007-01-01

Mesenchymal stromal cells (MSCs) have been shown to have an immunosuppressive effect. Previously, we demonstrated that nitric oxide (NO) is one of the immunomodulatory mediators of MSCs. We herein show that primary mouse bone marrow MSCs and three cell lines that mimic MSCs suppress both differentiation and proliferation in Th1 condition, whereas the suppression in Th2 condition is mild. NO production is inversely correlated with T cell proliferation in Th1 and Th2 conditions. NO is highly induced in Th1 and minimally induced in Th2. Moreover, an inhibitor of NO synthase restores both proliferation and interferon-γ (IFN-γ) production in Th1 condition. Furthermore, an anti-IFN-γ antibody strongly inhibits NO production and an inhibitor of NF-κB reduces the level of induction of inducible NO synthase (iNOS) in MSCs. Taken together, our results suggest that NO plays a significant role in the modification of Th1 and Th2 differentiation by MSCs, and that both IFN-γ and NF-κB are critical for NO production by MSCs

Evidence of a Transition from Perceptual to Category Induction in 3- to 9-Year-Old Children

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Badger, Julia R.; Shapiro, Laura R.

2012-01-01

We examined whether inductive reasoning development is better characterized by accounts assuming an early category bias versus an early perceptual bias. We trained 264 children aged 3 to 9 years to categorize novel insects using a rule that directly pitted category membership against appearance. This was followed by an induction task with…

Effect of alpha interferon on glucose and alanine transport by rat renal brush border membrane vesicles

International Nuclear Information System (INIS)

Batuman, V.; Chadha, I.

1990-01-01

To investigate the pathogenetic mechanisms of interferon nephrotoxicity, we studied the effect of recombinant interferon alfa-2b on the uptake of 14 C-D-glucose and 14 C-L-alanine by rat renal brush-border-membrane vesicles. Interferon significantly inhibited 20 sec. sodium-dependent and 5 and 10 min. equilibrium uptake of both glucose and alanine. The inhibitory effect was dose dependent with maximum effect achieved at interferon concentration of 5 x 10 -8 M in the uptake media. The half-maximal inhibitory concentrations, IC 50 , of interferon on glucose uptake was 1.8 x 10 -8 M, and 5.4 x 10 -9 M on alanine uptake. Dixon plot analysis of uptake data was consistent with pure non-competitive inhibition. The inhibition constants, K i , 1.5 x 10 -8 M for glucose uptake, and 7.3 x 10 -9 M for alanine uptake, derived from Dixon plots were in close agreement with the IC 50 s calculated from the semilog dose response curves. These observations reveal that direct interactions at the proximal tubule cell membrane are involved in the pathogenesis of interferon nephrotoxicity, and that its mechanism of nephrotoxicity is similar to that of other low molecular weight proteins

La Crosse bunyavirus nonstructural protein NSs serves to suppress the type I interferon system of mammalian hosts.

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Blakqori, Gjon; Delhaye, Sophie; Habjan, Matthias; Blair, Carol D; Sánchez-Vargas, Irma; Olson, Ken E; Attarzadeh-Yazdi, Ghassem; Fragkoudis, Rennos; Kohl, Alain; Kalinke, Ulrich; Weiss, Siegfried; Michiels, Thomas; Staeheli, Peter; Weber, Friedemann

2007-05-01

La Crosse virus (LACV) is a mosquito-transmitted member of the Bunyaviridae family that causes severe encephalitis in children. For the LACV nonstructural protein NSs, previous overexpression studies with mammalian cells had suggested two different functions, namely induction of apoptosis and inhibition of RNA interference (RNAi). Here, we demonstrate that mosquito cells persistently infected with LACV do not undergo apoptosis and mount a specific RNAi response. Recombinant viruses that either express (rLACV) or lack (rLACVdelNSs) the NSs gene similarly persisted and were prone to the RNAi-mediated resistance to superinfection. Furthermore, in mosquito cells overexpressed LACV NSs was unable to inhibit RNAi against Semliki Forest virus. In mammalian cells, however, the rLACVdelNSs mutant virus strongly activated the antiviral type I interferon (IFN) system, whereas rLACV as well as overexpressed NSs suppressed IFN induction. Consequently, rLACVdelNSs was attenuated in IFN-competent mouse embryo fibroblasts and animals but not in systems lacking the type I IFN receptor. In situ analyses of mouse brains demonstrated that wild-type and mutant LACV mainly infect neuronal cells and that NSs is able to suppress IFN induction in the central nervous system. Thus, our data suggest little relevance of the NSs-induced apoptosis or RNAi inhibition for growth or pathogenesis of LACV in the mammalian host and indicate that NSs has no function in the insect vector. Since deletion of the viral NSs gene can be fully complemented by inactivation of the host's IFN system, we propose that the major biological function of NSs is suppression of the mammalian innate immune response.

Distinct Effects of Type I and III Interferons on Enteric Viruses

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Harshad Ingle

2018-01-01

Full Text Available Interferons (IFNs are key host cytokines in the innate immune response to viral infection, and recent work has identified unique roles for IFN subtypes in regulating different aspects of infection. Currently emerging is a common theme that type III IFNs are critical in localized control of infection at mucosal barrier sites, while type I IFNs are important for broad systemic control of infections. The intestine is a particular site of interest for exploring these effects, as in addition to being the port of entry for a multitude of pathogens, it is a complex tissue with a variety of cell types as well as the presence of the intestinal microbiota. Here we focus on the roles of type I and III IFNs in control of enteric viruses, discussing what is known about signaling downstream from these cytokines, including induction of specific IFN-stimulated genes. We review viral strategies to evade IFN responses, effects of IFNs on the intestine, interactions between IFNs and the microbiota, and briefly discuss the role of IFNs in controlling viral infections at other barrier sites. Enhanced understanding of the coordinate roles of IFNs in control of viral infections may facilitate development of antiviral therapeutic strategies; here we highlight potential avenues for future exploration.

Polymorphism in the interferon-{alpha} gene family

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Golovleva, I.; Lundgren, E.; Beckman, L. [Univ. of Umea (Sweden); Kandefer-Szerszen, M. [Maria Curie-Sklodowska Univ., Lublin (Poland)

1996-09-01

A pronounced genetic polymorphism of the interferon type I gene family has been assumed on the basis of RFLP analysis of the genomic region as well as the large number of sequences published compared to the number of loci. However, IFNA2 is the only locus that has been carefully analyzed concerning gene frequency, and only naturally occurring rare alleles have been found. We have extended the studies on a variation of expressed sequences by studying the IFNA1, IFNA2, IFNA10, IFNA13, IFNA14, and IFNA17 genes. Genomic white-blood-cell DNA from a population sample of blood donors and from a family material were screened by single-nucleotide primer extension (allele-specific primer extension) of PCR fragments. Because of sequence similarities, in some cases {open_quotes}nested{close_quotes} PCR was used, and, when applicable, restriction analysis or control sequencing was performed. All individuals carried the interferon-{alpha} 1 and interferon-{alpha} 13 variants but not the LeIF D variant. At the IFNA2 and IFNA14 loci only one sequence variant was found, while in the IFNA10 and IFNA17 groups two alleles were detected in each group. The IFNA10 and IFNA17 alleles segregated in families and showed a close fit to the Hardy-Weinberg equilibrium. There was a significant linkage disequilibrium between IFNA10 and IFNA17 alleles. The fact that the extent of genetic polymorphism was lower than expected suggests that a majority of the previously described gene sequences represent nonpolymorphic rare mutants that may have arisen in tumor cell lines. 44 refs., 4 figs., 4 tabs.

Inductive differentiation of two neural lineages reconstituted in a microculture system from Xenopus early gastrula cells.

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Mitani, S; Okamoto, H

1991-05-01

Neural induction of ectoderm cells has been reconstituted and examined in a microculture system derived from dissociated early gastrula cells of Xenopus laevis. We have used monoclonal antibodies as specific markers to monitor cellular differentiation from three distinct ectoderm lineages in culture (N1 for CNS neurons from neural tube, Me1 for melanophores from neural crest and E3 for skin epidermal cells from epidermal lineages). CNS neurons and melanophores differentiate when deep layer cells of the ventral ectoderm (VE, prospective epidermis region; 150 cells/culture) and an appropriate region of the marginal zone (MZ, prospective mesoderm region; 5-150 cells/culture) are co-cultured, but not in cultures of either cell type on their own; VE cells cultured alone yield epidermal cells as we have previously reported. The extent of inductive neural differentiation in the co-culture system strongly depends on the origin and number of MZ cells initially added to culture wells. The potency to induce CNS neurons is highest for dorsal MZ cells and sharply decreases as more ventrally located cells are used. The same dorsoventral distribution of potency is seen in the ability of MZ cells to inhibit epidermal differentiation. In contrast, the ability of MZ cells to induce melanophores shows the reverse polarity, ventral to dorsal. These data indicate that separate developmental mechanisms are used for the induction of neural tube and neural crest lineages. Co-differentiation of CNS neurons or melanophores with epidermal cells can be obtained in a single well of co-cultures of VE cells (150) and a wide range of numbers of MZ cells (5 to 100). Further, reproducible differentiation of both neural lineages requires intimate association between cells from the two gastrula regions; virtually no differentiation is obtained when cells from the VE and MZ are separated in a culture well. These results indicate that the inducing signals from MZ cells for both neural tube and neural

IMMUNOMODULATING THERAPY BY RECOMBINANT ALPHA-2B INTERFERON AMONG CHILDREN WITH TIMOMEGALIA

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L.A. Nikulin

2007-01-01

Full Text Available The study of the enlarged thymus gland syndrome is extremely important for understanding of the immune system formation and functioning mechanisms. the purpose of this study is to conduct clinical and immunological analysis of the children, suffering from the syndrome of the enlarged thymus gland II and III degrees, who received recombinant alpha2b interferon (in suppositories. The revealed changes in the immune sys tem during timomegalia are complex and conducive to the development of the infectious and inflammatory diseases among infants, thus, determining the necessity for the adequate immune correction. The application of the recombinant alpha 2b interferon among such children allows one to uncover the immunomodulating effects, normalizing the imbalances in the immune system of children with timomegalia.Key words: timomegalia, alpha 2b interferon, immunity, immune correction, children.

Early discharge following birth

DEFF Research Database (Denmark)

Nilsson, Ingrid M. S.; Kronborg, Hanne; Knight, Christopher H.

2017-01-01

.26–0.48) and primiparous compared to multiparous had an OR of 0.22 (CI 0.17–0.29) for early discharge. Other predictors for early discharge were: no induction of labour, no epidural painkiller, bleeding less than 500 ml during delivery, higher gestational age, early expected discharge and positive breastfeeding experience...

Glycosaminoglycans mediate retention of the poxvirus type I interferon binding protein at the cell surface to locally block interferon antiviral responses

Science.gov (United States)

Montanuy, Imma; Alejo, Ali; Alcami, Antonio

2011-01-01

Eradication of smallpox was accomplished 30 yr ago, but poxviral infections still represent a public health concern due to the potential release of variola virus or the emergence of zoonotic poxviruses, such as monkeypox virus. A critical determinant of poxvirus virulence is the inhibition of interferons (IFNs) by the virus-encoded type I IFN-binding protein (IFNα/βBP). This immunomodulatory protein is secreted and has the unique property of interacting with the cell surface in order to prevent IFN-mediated antiviral responses. However, the mechanism of its attachment to the cell surface remains unknown. Using surface plasmon resonance and cell-binding assays, we report that the IFNα/βBP from vaccinia virus, the smallpox vaccine, interacts with cell surface glycosaminoglycans (GAGs). Analysis of the contribution of different regions of the protein to cell surface binding demonstrated that clusters of basic residues in the first immunoglobulin domain mediate GAG interactions. Furthermore, mutation of the GAG-interaction motifs does not affect its IFN-binding and -blocking capacity. Functional conservation of GAG-binding sites is demonstrated for the IFNα/βBP from variola and monkeypox viruses, extending our understanding of immune modulation by the most virulent human poxviruses. These results are relevant for the design of improved vaccines and intervention strategies.—Montanuy, I., Alejo, A., Alcami, A. Glycosaminoglycans mediate retention of the poxvirus type I interferon binding protein at the cell surface to locally block interferon antiviral responses. PMID:21372110

DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...hways mediating type I interferon gene expression. PubmedID 17904888 Title Signalling pathways...R, Slater L, Johnston SL. Microbes Infect. 2007 Sep;9(11):1245-51. Epub 2007 Jul 1. (.png) (.svg) (.html) (.csml) Show Signalling pat

Study on homologous series of induced early mutants in Indica rice Ⅱ. the relationship between the homologous series of early mutants induced and the ecotype in Indica rice

International Nuclear Information System (INIS)

Chen Xiulan; Yang Hefeng; He Zhentian; Han Yuepeng; Liu Xueyu

2001-01-01

The induced mutation in light sensitivity of the Indica rice leads to induction of the homologous series of early mutants along with the variation of ecological character and the ecoclimate. The induction of mutants was closely related to the ecotype of Indica rice, the homologous series of early mutants in different level were derived from the different ecotype of the Indica rice, otherwise, the similar homologous series of early mutants were derived from the same ecotypic variety. The induction of the early ecotypic variety derived from the homologous series of early mutants provides the basis and possibility for accelerating the development of the new cultivars. (authors)

Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease.

Science.gov (United States)

Rice, Gillian I; Melki, Isabelle; Frémond, Marie-Louise; Briggs, Tracy A; Rodero, Mathieu P; Kitabayashi, Naoki; Oojageer, Anthony; Bader-Meunier, Brigitte; Belot, Alexandre; Bodemer, Christine; Quartier, Pierre; Crow, Yanick J

2017-02-01

Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of >2.466, is considered as abnormal). Results were correlated with genetic and clinical data. Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69

Diagnostics for induction accelerators

International Nuclear Information System (INIS)

Fessenden, T.J.

1997-01-01

The induction accelerator was conceived by N. C. Christofilos and first realized as the Astron accelerator that operated at Lawrence Livermore National Laboratory (LLNL) from the early 1960s to the end of 1975. This accelerator generated electron beams at energies near 6 MeV with typical currents of 600 Amperes in 400-ns pulses. The Advanced Test Accelerator (ATA) built at Livermore close-quote s Site 300 produced 10,000-Ampere beams with pulse widths of 70 ns at energies approaching 50 MeV. Several other electron and ion induction accelerators have been fabricated at LLNL and Lawrence Berkeley National Laboratory (LBNL). This paper reviews the principal diagnostics developed through efforts by scientists at both laboratories for measuring the current, position, energy, and emittance of beams generated by these high-current, short-pulse accelerators. Many of these diagnostics are closely related to those developed for other accelerators. However, the very fast and intense current pulses often require special diagnostic techniques and considerations. The physics and design of the more unique diagnostics developed for electron induction accelerators are presented and discussed in detail. copyright 1997 American Institute of Physics

Antiproliferative activity of recombinant human interferon-λ2 ...

African Journals Online (AJOL)

Antiproliferative activity of recombinant human interferon-λ2 expressed in stably ... The representing 26 kDa protein band of IFN-λ2 was detected by SDS-PAGE and ... The antiproliferative activity of hIFN-λ2 was determined by MTT assay.

Is the use of IL28B genotype justified in the era of interferon-free treatments for hepatitis C?

Science.gov (United States)

Kanda, Tatsuo; Nakamoto, Shingo; Yokosuka, Osamu

2015-01-01

In 2009, several groups reported that interleukin-28B (IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus (HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferon-free 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28B favorable alleles, importance of IL28B will be reduced with availability of oral interferon free regimen. PMID:26279979

Crystallization and preliminary X-ray analysis of Ebola VP35 interferon inhibitory domain mutant proteins

International Nuclear Information System (INIS)

Leung, Daisy W.; Borek, Dominika; Farahbakhsh, Mina; Ramanan, Parameshwaran; Nix, Jay C.; Wang, Tianjiao; Prins, Kathleen C.; Otwinowski, Zbyszek; Honzatko, Richard B.; Helgeson, Luke A.; Basler, Christopher F.; Amarasinghe, Gaya K.

2010-01-01

Three mutant forms of Ebola VP35 interferon inhibitory domain were crystallized in three different space groups. VP35 is one of seven structural proteins encoded by the Ebola viral genome and mediates viral replication, nucleocapsid formation and host immune suppression. The C-terminal interferon inhibitory domain (IID) of VP35 is critical for dsRNA binding and interferon inhibition. The wild-type VP35 IID structure revealed several conserved residues that are important for dsRNA binding and interferon antagonism. Here, the expression, purification and crystallization of recombinant Zaire Ebola VP35 IID mutants R312A, K319A/R322A and K339A in space groups P6 1 22, P2 1 2 1 2 1 and P2 1 , respectively, are described. Diffraction data were collected using synchrotron sources at the Advanced Light Source and the Advanced Photon Source

The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy

Directory of Open Access Journals (Sweden)

Janina Bruening

2017-01-01

Full Text Available The human interferon (IFN response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs, are an essential component of the innate immune response to hepatitis C virus (HCV. In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.

Long term survival with the combination of interferon and chemotherapy in metastatic melanoma

International Nuclear Information System (INIS)

Karagoz, B.; Bilgi, O.; Ozgun, A.; Emirzeoglu, L.; Celika, S.; Ozet, A.

2015-01-01

The prognosis of metastatic melanoma is poor. Pre-targeted treatment era, the combination of interferon-α (IF-α) plus chemotherapy had been used and have generally short response duration. Herein, we present a metastatic melanoma case that achieved long-term durable complete response (CR) IF-α plus chemotherapy and IF-α maintenance therapy and had lower Regulatory T (Treg) cells. A fifty-year old woman was admitted to the hospital with metastatic melanoma. Lactate dehydrogenase (LDH) level was 660 U/L. The percentage of CD4+CD25+ Treg cells was 2.4% in CD4+ lymphocytes. The IF-α plus chemotherapy and IF-α maintenance were administered. After six courses of chemotherapy, CR was achieved. Vitiligo and hypothyroidism occurred. The patient has remained in CR for approximately 7 years until second pleural metastases were detected and death. The patient has positive prognostic factors such as induction of auto immunity, small tumor volume, mild elevated LDH level, and lower Treg cell percentage. She survived long term with CR after IF-α treatment with concurrent chemotherapy and maintenance. IF-α plus chemotherapy may be a treatment option for metastatic melanoma in selected cases who cannot reach new targeted drugs

NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

Science.gov (United States)

Jiang, Zhaozhao; Fortune, Sarah M.; Coulombe, Francois; Behr, Marcel A.; Fitzgerald, Katherine A.; Sassetti, Christopher M.; Kelliher, Michelle A.

2009-01-01

While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNα and IFNβ, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system. PMID:19578435

DMPD: Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 15031527 Toll-like receptor 3: a link between toll-like receptor, interferon and virus... (.csml) Show Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. PubmedID 1503...1527 Title Toll-like receptor 3: a link between toll-like receptor, interferon and virus

A 2-week pretreatment with 13-cis-retinoic acid + interferon-α-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers

International Nuclear Information System (INIS)

Dunst, J.; Haensgen, G.; Becker, A.; Krause, U.; Fuechsel, G.; Koehler, U.

1998-01-01

Background: We have evaluated the tumor tissue pO 2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-α-2a prior to and during radiotherapy. Patients and methods: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-α-2a (IFN-α-2a) as part of a phase-II protocol. cRA/IFN-α-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6x10 6 IU IFN-α-2a subcutaneously daily). After this indicution period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-α-2a-treatment was continued with 50% of the daily doses. Tumor tissue pO 2 -measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO 2 -histograph. Results: In 11 out of the 22 patients, pO 2 -measurements were performed prior to the cRA/IFN-induction therapy. The median pO 2 of these untreated tumors was 17.7±16.3 mm Hg. The relative frequency of hypoxic readings with pO 2 -values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3±21.0%). After the 2-week induction period with cRA/IFN, the median pO 2 had increased from 17.7pm16.3 mm Hg to 27.6±19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO 2 of 10 mm Hg or less), the median pO 2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO 2 increased from 6.3±2.7 mm Hg to 27.0±5.6 mm Hg (p=0.004, t-test for paired samples). The frequency of hypoxic readings (pO 2 -values 2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. Conclusions: Pretreatment with cRA/IFN improves oxygenation of

Hypothyroidism in hepatitis c patients on pegylated interferon therapy

International Nuclear Information System (INIS)

Hameed, M.A.; Mehmood, A.; Farooq, M.A.; Nabi, G.U.; Toor, I. H.

2017-01-01

Chronic hepatitis has become a major health problem all over the world especially in the third world countries. The most common cause of chronic hepatitis in Pakistan is hepatitis C which can lead to liver cirrhosis and hepatocellular carcinoma. In Pakistan Pegylated Interferon Alpha is still corner stone of therapy for chronic hepatitis C. One of the major side effect of this therapy is the development of thyroid dysfunction, i.e., hypothyroidism and hyperthyroidism. This study was done to assess the frequency of hypothyroidism in hepatitis C patients after three months of pegylated interferon therapy. Method: This study was conducted from 1st October 2013 to 31st march 2014 at outpatients department (OPD) of Gastroenterology and Hepatology, Lahore General Hospital Lahore. Descriptive case series study design was used. The sample of 200 patients was taken from the patients who visited OPD and fulfil the inclusion criteria of the study. Serum thyroid stimulating hormone level (TSH) was done before and after completion of three months therapy at centre for Nuclear Medicine (CENUM) laboratory, Mayo Hospital, Lahore by immune-radiometric assay (IRMA) and patients having TSH>4.0 mIU/L (normal range: 0.2-4.0 mIU/L) were considered hypothyroid. Results: The mean age of the patients was 36.29+-8.5 years. One hundred and twenty-three (61.5 percent) were male and 77 (38.5 percent) were female. After 3 months of interferon therapy, 163 (81.5 percent) patients were euthyroid and 37(18.5 percent) patients were having thyroid dysfunction. There were total 29 (14.5 percent) hypothyroid patients; 8 (27.6 percent) were male and 21 (72.4 percent) female. Conclusion: It is concluded from this study that frequency of hypothyroidism in patients with chronic hepatitis C was 14.5 percent after treatment with pegylated interferon therapy for 3 months. Female patients were more prone to develop hypothyroidism as compared to male patients. (author)

Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation.

Science.gov (United States)

Brasseit, Jennifer; Kwong Chung, Cheong K C; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

2018-01-01

Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1 -/- recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1 -/- recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.

Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation.

Science.gov (United States)

Razaghi, Ali; Owens, Leigh; Heimann, Kirsten

2016-12-20

Human interferon gamma is a cytokine belonging to a diverse group of interferons which have a crucial immunological function against mycobacteria and a wide variety of viral infections. To date, it has been approved for treatment of chronic granulomatous disease and malignant osteopetrosis, and its application as an immunotherapeutic agent against cancer is an increasing prospect. Recombinant human interferon gamma, as a lucrative biopharmaceutical, has been engineered in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human interferon gamma is commonly expressed in Escherichia coli, marketed as ACTIMMUNE ® , however, the resulting product of the prokaryotic expression system is unglycosylated with a short half-life in the bloodstream; the purification process is tedious and makes the product costlier. Other expression systems also did not show satisfactory results in terms of yields, the biological activity of the protein or economic viability. Thus, the review aims to synthesise available information from previous studies on the production of human interferon gamma and its glycosylation patterns in different expression systems, to provide direction to future research in this field. Copyright © 2016 Elsevier B.V. All rights reserved.

Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11.

Science.gov (United States)

Li, Manqing; Kao, Elaine; Gao, Xia; Sandig, Hilary; Limmer, Kirsten; Pavon-Eternod, Mariana; Jones, Thomas E; Landry, Sebastien; Pan, Tao; Weitzman, Matthew D; David, Michael

2012-11-01

In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial.

Science.gov (United States)

Demiroglu, H; Ozcebe, O I; Barista, I; Dündar, S; Eldem, B

2000-02-19

Sight-threatening eye involvement is a serious complication of Behçet's disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçet's disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

DEFF Research Database (Denmark)

Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M

2007-01-01

The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas......-mediated signaling during early implantation. Here we show that ESCs are primarily resistant to Fas-mediated apoptosis independently of their state of hormonal differentiation. Pre-treatment of ESCs with interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha sensitizes them to become apoptotic upon stimulation...... of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN-gamma and TNF-alpha was accompanied by a significant upregulation of Fas and FLICE...

Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis.

Science.gov (United States)

Shirani, Afsaneh; Zhao, Yinshan; Karim, Mohammad Ehsanul; Evans, Charity; Kingwell, Elaine; van der Kop, Mia L; Oger, Joel; Gustafson, Paul; Petkau, John; Tremlett, Helen

2012-07-18

Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0

The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold.

Science.gov (United States)

Zhang, Adrianna P P; Bornholdt, Zachary A; Liu, Tong; Abelson, Dafna M; Lee, David E; Li, Sheng; Woods, Virgil L; Saphire, Erica Ollmann

2012-02-01

Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan) and nonpathogenic to humans (Reston). These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.

The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold.

Directory of Open Access Journals (Sweden)

Adrianna P P Zhang

2012-02-01

Full Text Available Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan and nonpathogenic to humans (Reston. These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.

Kinetic inductance detectors for far-infrared spectroscopy

International Nuclear Information System (INIS)

Barlis, A.; Aguirre, J.; Stevenson, T.

2016-01-01

The star formation mechanisms at work in the early universe remain one of the major unsolved problems of modern astrophysics. Many of the luminous galaxies present during the period of peak star formation (at redshift of about 2.5) were heavily enshrouded in dust, which makes observing their properties difficult at optical wavelengths. However, many spectral lines exist at far-infrared wavelengths that serve as tracers of star formation. Here, we describe a detector system suitable for a balloon-borne spectroscopic intensity mapping experiment at far-infrared wavelengths. The system uses lumped-element kinetic inductance detectors (KIDs), which have the potential to achieve high sensitivity and low noise levels. KIDs consist of separate capacitive and inductive elements, and use the inductive element as the radiation absorber. We describe the design considerations, fabrication process, and readout scheme for a prototype LEKID array of 1600 pixels. - Highlights: • We describe a concept for a balloon-borne telescope for far-IR wavelengths. • Telescope would use high-sensitivity kinetic inductance detectors. • Design considerations and fabrication process for prototype detectors.

Kinetic inductance detectors for far-infrared spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Barlis, A., E-mail: abarlis@physics.upenn.edu [University of Pennsylvania Department of Physics and Astronomy, Philadelphia, Pennsylvania (United States); Aguirre, J. [University of Pennsylvania Department of Physics and Astronomy, Philadelphia, Pennsylvania (United States); Stevenson, T. [NASA Goddard Space Flight Center, Greenbelt, Maryland (United States)

2016-07-11

The star formation mechanisms at work in the early universe remain one of the major unsolved problems of modern astrophysics. Many of the luminous galaxies present during the period of peak star formation (at redshift of about 2.5) were heavily enshrouded in dust, which makes observing their properties difficult at optical wavelengths. However, many spectral lines exist at far-infrared wavelengths that serve as tracers of star formation. Here, we describe a detector system suitable for a balloon-borne spectroscopic intensity mapping experiment at far-infrared wavelengths. The system uses lumped-element kinetic inductance detectors (KIDs), which have the potential to achieve high sensitivity and low noise levels. KIDs consist of separate capacitive and inductive elements, and use the inductive element as the radiation absorber. We describe the design considerations, fabrication process, and readout scheme for a prototype LEKID array of 1600 pixels. - Highlights: • We describe a concept for a balloon-borne telescope for far-IR wavelengths. • Telescope would use high-sensitivity kinetic inductance detectors. • Design considerations and fabrication process for prototype detectors.

JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa.

Science.gov (United States)

Boor, Patrick P C; de Ruiter, Petra E; Asmawidjaja, Patrick S; Lubberts, Erik; van der Laan, Luc J W; Kwekkeboom, Jaap

2017-10-01

Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

MicroRNA-302a suppresses influenza A virus-stimulated interferon regulatory factor-5 expression and cytokine storm induction.

Science.gov (United States)

Chen, Xueyuan; Zhou, Li; Peng, Nanfang; Yu, Haisheng; Li, Mengqi; Cao, Zhongying; Lin, Yong; Wang, Xueyu; Li, Qian; Wang, Jun; She, Yinglong; Zhu, Chengliang; Lu, Mengji; Zhu, Ying; Liu, Shi

2017-12-29

During influenza A virus (IAV) infection, cytokine storms play a vital and critical role in clinical outcomes. We have previously reported that microRNA (miR)-302c regulates IAV-induced IFN expression by targeting the 3'-UTR of nuclear factor κB (NF-κB)-inducing kinase. In the current study, we found that miR-302a, another member of the miR-302 cluster, controls the IAV-induced cytokine storm. According to results from cell-based and knockout mouse models, IAV induces a cytokine storm via interferon regulatory factor-5 (IRF-5). We also found that IAV infection up-regulates IRF-5 expression and that IRF-5 in turn promotes IAV replication. Furthermore, we observed that IRF-5 is a direct target of miR-302a, which down-regulated IRF-5 expression by binding its 3'-UTR. Moreover, IAV increased IRF-5 expression by down-regulating miR-302a expression. Interestingly, miR-302a inhibited IAV replication. In IAV-infected patients, miR-302a expression was down-regulated, whereas IRF-5 expression was up-regulated. Taken together, our work uncovers and defines a signaling pathway implicated in an IAV-induced cytokine storm. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

DMPD: Fifty years of interferon research: aiming at a moving target. [Dynamic Macrophage Pathway CSML Database

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Full Text Available mmunity. 2006 Sep;25(3):343-8. (.png) (.svg) (.html) (.csml) Show Fifty years of interferon research: aiming at a moving target. Pubm...edID 16979566 Title Fifty years of interferon research: aiming at a moving target.

Interferon-gamma treatment kinetics among patients with active ...

African Journals Online (AJOL)

Introduction: Interferon-γ (IFN-γ) is essential for defence against Mycobacterium tuberculosis; however, levels in patients with active tuberculosis (TB) and changes during treatment have not been documented in our tuberculosis patients in Nigeria, hence this study has been carried out. Objective: To determine variations, ...

Transplantation Tolerance Induction: Cell Therapies and their Mechanisms

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Joseph R Scalea

2016-03-01

Full Text Available Cell based therapies have been studied extensively in the context of transplantation tolerance induction. The most successful protocols have relied on transfusion of bone marrow prior to the transplantation of a renal allograft. However, it is not clear that stem cells found in bone marrow are required in order to render a transplant candidate immunologically tolerant. Accordingly, mesenchymal stem cells, regulatory myeloid cells, T regulatory cells, and other cell types, are being tested as possible routes to tolerance induction, in the absence of donor derived stem cells. Early data with each of these cell types have been encouraging. However, the induction regimen capable of achieving consistent tolerance, whilst avoiding unwanted sided effects, and which is scalable to the human patient, has yet to be identified. Here we present the status of investigations of various tolerogenic cell types and the mechanistic rationale for their use in in tolerance induction protocols.

Interferon Lambda Genetics and Biology in Regulation of Viral Control

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Emily A. Hemann

2017-12-01

Full Text Available Type III interferons, also known as interferon lambdas (IFNλs, are the most recent addition to the IFN family following their discovery in 2003. Initially, IFNλ was demonstrated to induce expression of interferon-stimulated genes and exert antiviral properties in a similar manner to type I IFNs. However, while IFNλ has been described to have largely overlapping expression and function with type I IFNs, it has become increasingly clear that type III IFNs also have distinct functions from type I IFNs. In contrast to type I IFNs, whose receptor is ubiquitously expressed, type III IFNs signal and function largely at barrier epithelial surfaces, such as the respiratory and gastrointestinal tracts, as well as the blood–brain barrier. In further support of unique functions for type III IFNs, single nucleotide polymorphisms in IFNL genes in humans are strongly associated with outcomes to viral infection. These biological linkages have also been more directly supported by studies in mice highlighting roles of IFNλ in promoting antiviral immune responses. In this review, we discuss the current understanding of type III IFNs, and how their functions are similar to, and different from, type I IFN in various immune cell subtypes and viral infections.

Interferon Lambda: A New Sword in Cancer Immunotherapy

Science.gov (United States)

Lasfar, Ahmed; Abushahba, Walid; Balan, Murugabaskar; Cohen-Solal, Karine A.

2011-01-01

The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λ proteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λ receptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy. PMID:22190970

Synthesis and processing in Escherichia coli of human leucocyte interferon fused with the signal sequence of Bacillus amyloliquefaciens a-amylase

International Nuclear Information System (INIS)

Sorokin, A.V.; Avakov, A.S.; Bogush, V.G.

1985-01-01

Earlier, the authors reported cloning of the alpha-amylase gene of B. amyloliquefaciens in B. subtilis and E. coli. Currently, the authors report results on the expression of the hybrid gene consisting of the DNA fragment coding for the leader part of B. amyloliquefaciens alpha-amylase and the structural part of the human interferon alpha-2 in E. coli cells. This gene contains an additional methionine codon at the 5'-terminal, which codes for the interferon structure (without its own signal peptide). The interferon gene was inserted into plasmid /sub p/TG 278 at the cleavage site of EcoRI. The structure of the plasmid thus obtained the signal peptide of amylase, five amino acids (Val-Gly-Glu-Phe-Met), and the structural part of the interferon. The E. coli C600 cells carrying plasmid pTGA6 were used to study interferon secretions. The interferon activity was determined radioimmunologically with the use of monoclonal anti-bodies NK2

Onset of Celiac Disease after Treatment of Chronic Hepatitis C with Interferon Based Triple Therapy

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Amandeep Singh

2015-01-01

Full Text Available Background. Patients treated with interferon (IFN based therapies may develop exacerbation of autoimmune disease. We herein present the case of a 53-year-old female patient who developed celiac disease (CD as a result of triple therapy (interferon, ribavirin, and boceprevir for chronic HCV. Case. 53-year-old Caucasian female with past medical history of IV drug abuse was referred for abnormal LFTs. Laboratory data showed HCV RNA of 4,515,392 IU/mL, HCV genotype 1a, with normal LFTs. She was treated with 4 weeks of pegylated interferon alfa-2a plus ribavirin, followed by triple therapy using boceprevir for a total of 28 weeks. Approximately 4 weeks after initiation of triple therapy patient developed loose nonbloody bowel movements and was also found to have anemia. Biopsies from first and second portions of the duodenum were consistent with CD. The patient was treated with a gluten-free diet. Her intestinal symptoms improved and the hemoglobin returned to normal. Conclusion. Chronic HCV patients being treated with interferon alfa can develop celiac disease during or after therapy. For patients with positive autoantibodies, all-oral-IFN-free regimens should be considered. Celiac disease should be considered in patients who develop CD-like symptoms while on and shortly after cessation of interferon alfa therapy.

Opposing roles for interferon regulatory factor-3 (IRF-3 and type I interferon signaling during plague.

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Ami A Patel

Full Text Available Type I interferons (IFN-I broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production.

Interferon γ-Induced Nuclear Interleukin-33 Potentiates the Release of Esophageal Epithelial Derived Cytokines.

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Jing Shan

Full Text Available Esophageal epithelial cells are an initiating cell type in esophageal inflammation, playing an essential role in the pathogenesis of gastroesophageal reflux disease (GERD. A new tissue-derived cytokine, interleukin-33 (IL-33, has been shown to be upregulated in esophageal epithelial cell nuclei in GERD, taking part in mucosal inflammation. Here, inflammatory cytokines secreted by esophageal epithelial cells, and their regulation by IL-33, were investigated.In an in vitro stratified squamous epithelial model, IL-33 expression was examined using quantitative RT-PCR, western blot, ELISA, and immunofluorescence. Epithelial cell secreted inflammatory cytokines were examined using multiplex flow immunoassay. IL-33 was knocked down with small interfering RNA (siRNA in normal human esophageal epithelial cells (HEECs. Pharmacological inhibitors and signal transducers and activators of transcription 1 (STAT1 siRNA were used to explore the signaling pathways.Interferon (IFNγ treatment upregulated nuclear IL-33 in HEECs. Furthermore, HEECs can produce various inflammatory cytokines, such as IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1, regulated on activation normal T-cell expressed and presumably secreted (RANTES, and granulocyte-macrophage colony-stimulating factor (GM-CSF in response to IFNγ. Nuclear, but not exogenous IL-33, amplified IFN induction of these cytokines. P38 mitogen-activated protein kinase (MAPK and janus protein tyrosine kinases (JAK/STAT1 were the common signaling pathways of IFNγ-mediated induction of IL-33 and other cytokines.Esophageal epithelial cells can actively participate in GERD pathogenesis through the production of various cytokines, and epithelial-derived IL-33 might play a central role in the production of these cytokines.

Henipaviruses Employ a Multifaceted Approach to Evade the Antiviral Interferon Response

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Megan L. Shaw

2009-12-01

Full Text Available Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other paramyxoviruses, their ability to evade the host interferon (IFN response is conferred by the P gene. The henipavirus P gene encodes four proteins; the P, V, W and C proteins, which have all been described to inhibit the antiviral response. Further studies have revealed that these proteins have overlapping but unique properties which enable the virus to block multiple signaling pathways in the IFN response. The best characterized of these is the JAK-STAT signaling pathway which is targeted by the P, V and W proteins via an interaction with the transcription factor STAT1. In addition the V and W proteins can both limit virus-induced induction of IFN but they appear to do this via distinct mechanisms that rely on unique sequences in their C-terminal domains. The ability to generate recombinant Nipah viruses now gives us the opportunity to determine the precise role for each of these proteins and address their contribution to pathogenicity. Additionally, the question of whether these multiple anti-IFN strategies are all active in the different mammalian hosts for henipaviruses, particularly the fruit bat reservoir, warrants further exploration.

A Successful Induction of Lactation in Surrogate Pregnancy with Metoclopramide and Review of Lactation Induction

OpenAIRE

Elahe Mirzaaga; Arezoo Arabipoor; Mitra Frotan; Marzieh Shiva

2010-01-01

In surrogate pregnancies genetic parents have little opportunity for early bonding with their infants,either prenatally (in utero) or during the immediate postnatal period. Procedures commonlyused to induce lactation include both pharmacologic and nonpharmacologic methods, often incombination. Studies reporting induced lactation are sparse, due to the rarity of augmentedlactation. Here we report a case of lactation induction following a surrogate pregnancy. Othermethods that can be used to au...

Induction of cytoplasmic petite in yeast by guanidine hydrochloride

International Nuclear Information System (INIS)

Villa, L.L.; Juliani, M.H.

1980-01-01

We have studied the induction of p - mutants by guanidine hydrochloride (GuHCL) in combination with other known inducers; ethidium bromide (EB), berenil and ultraviolet light. Competition was observed when cells were simultaneously treated with optimal concentrations of EB and GuHCL; on the other hand, treatment of cells with EB in the presence of non-inducing concentrations of GuHCL resulted in the stimulation of p - induction by EB. Furthermore, using a strain which upon treatment with high EB concentrations shows recovery of respiratory competence, the presence of GuHCL did not interfere either with the early phase of induction or with the recovery phase, but it did interfere in a competitive fashion with the final irreversible phase of EB induction. In the case of berenil, a synergistic effect was seen when cells were pretreated with GuHCL. A synergistic induction was also observed when cells were submitted to UV prior to GuHCL treatment. These results suggest that GuHCL, EB and berenil act via some common step in their p - induction pathways. Moreover, GuHCL may somehow be decreasing the efficiency of dark repair of ultraviolet lesions on mitochondrial DNA. (orig.)

Interferon-beta in multiple sclerosis. Can we control its costs?

Science.gov (United States)

Tolley, K H; Whynes, D K

1997-03-01

The recent licensing of interferon-beta for use in patients with multiple sclerosis has caused concern, in view of the equivocal evidence of efficacy, pressure of public expectation towards its use and the high expected cost if widespread use were to be sanctioned. Whether such alarm is justified remains a moot point. Owing to the limited range of circumstances of proven efficacy and the lack of cost-effectiveness data, it remains unclear whether sanctioned usage will proliferate to the anticipated extent. Unit costs may well fall in the future owing to competition in the pharmaceutical market. Interferon-beta is simply one example of a growing trend in actively promoted high-cost preparations over which rationing decisions will have to be reached.

Impending anterior ischemic optic neuropathy with elements of retinal vein occlusion in a patient on interferon for polycythemia vera

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Rue KS

2012-10-01

Full Text Available Kelly S Rue, Louis K Hirsch, Alfredo A SadunDepartment of Neuro-Ophthalmology, Doheny Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, CA, USAAbstract: We describe the course and likely pathophysiology of impending anterior ischemic optic neuropathy (AION and retinal vein occlusion in a 56-year-old man with polycythemia vera managed with interferon alpha for 2 years. Our patient presented with decreased vision, scintillating scotomata, and floaters. Fundus examination findings and results of a fluorescein angiogram led to the diagnosis of impending AION and retinal vein occlusion. Considering that both polycythemia vera and interferon have possible influences on vascular occlusion and optic disc edema, we stopped interferon treatment and immediately attempted to treat the polycythemia vera empirically with pentoxifylline and any interferon-associated inflammation with prednisone. Our patient experienced complete resolution of fundus abnormalities and return of normal vision within 3 weeks, which may be attributed to our successful treatment of both etiologies. Thus, further study is warranted to elucidate the treatment of both polycythemia vera and interferon-induced impending AION.Keywords: optic disc edema, interferon alpha, vascular occlusion, Roth spot, autoantibody, pentoxifylline

Clinical and virological effects of high-dose recombinant interferon-alpha in disseminated AIDS-related Kaposi's sarcoma

NARCIS (Netherlands)

de Wit, R.; Schattenkerk, J. K.; Boucher, C. A.; Bakker, P. J.; Veenhof, K. H.; Danner, S. A.

1988-01-01

The effectiveness and antiretroviral activities of interferon-alpha in AIDS-related Kaposi's sarcoma was assessed in a non-randomised, phase-II clinical trial. 28 patients were treated with high-dose (27-36 MU) human recombinant interferon-alpha 2a subcutaneously every day for 8 weeks. In patients

Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN.

Science.gov (United States)

Kilday, John-Paul; Caldarelli, Massimo; Massimi, Luca; Chen, Robert Hsin-Hung; Lee, Yi Yen; Liang, Muh-Lii; Parkes, Jeanette; Naiker, Thuran; van Veelen, Marie-Lise; Michiels, Erna; Mallucci, Conor; Pettorini, Benedetta; Meijer, Lisethe; Dorfer, Christian; Czech, Thomas; Diezi, Manuel; Schouten-van Meeteren, Antoinette Y N; Holm, Stefan; Gustavsson, Bengt; Benesch, Martin; Müller, Hermann L; Hoffmann, Anika; Rutkowski, Stefan; Flitsch, Joerg; Escherich, Gabriele; Grotzer, Michael; Spoudeas, Helen A; Azquikina, Kristian; Capra, Michael; Jiménez-Guerra, Rolando; MacDonald, Patrick; Johnston, Donna L; Dvir, Rina; Constantini, Shlomi; Kuo, Meng-Fai; Yang, Shih-Hung; Bartels, Ute

2017-10-01

Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha. European Société Internationale d'Oncologie Pédiatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth). Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years. Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted. © The Author(s) 2017. Published by Oxford University Press on behalf of

Antiviral activity of ovine interferon tau 4 against foot-and-mouth disease virus.

Science.gov (United States)

Usharani, Jayaramaiah; Park, Sun Young; Cho, Eun-Ju; Kim, Chungsu; Ko, Young-Joon; Tark, Dongseob; Kim, Su-Mi; Park, Jong-Hyeon; Lee, Kwang-Nyeong; Lee, Myoung-Heon; Lee, Hyang-Sim

2017-07-01

Foot-and-mouth disease (FMD) is an economically important disease in most parts of the world and new therapeutic agents are needed to protect the animals before vaccination can trigger the host immune response. Although several interferons have been used for their antiviral activities against Foot-and-mouth disease virus (FMDV), ovine interferon tau 4 (OvIFN-τ4), with a broad-spectrum of action, cross-species antiviral activity, and lower incidence of toxicity in comparison to other type І interferons, has not yet been evaluated for this indication. This is the first study to evaluate the antiviral activity of OvIFN-τ4 against various strains of FMDV. The effective anti-cytopathic concentration of OvIFN-τ4 and its effectiveness pre- and post-infection with FMDV were tested in vitro in LFBK cells. In vivo activity of OvIFN-τ4 was then confirmed in a mouse model of infection. OvIFN-τ4 at a concentration of 500 ng, protected mice until 5days post-FMDV challenge and provided 90% protection for 10 days following FMDV challenge. These results suggest that OvIFN-τ4 could be used as an alternative to other interferons or antiviral agents at the time of FMD outbreak. Copyright © 2017. Published by Elsevier B.V.

Enhancement by gamma-interferon of in vivo tumor radiolocalization by a monoclonal antibody against HLA-DR antigen

International Nuclear Information System (INIS)

Rowlinson, G.; Balkwill, F.; Snook, D.; Hooker, G.; Epenetos, A.A.

1986-01-01

Athymic nu/nu (nude) mice bearing s.c. human breast tumors were treated systemically with recombinant human gamma-interferon. These tumors were phenotypically negative for HLA-DR prior to therapy, but after 4 days of treatment, 80% of the cells expressed this antigen in vivo as assessed by immunoperoxidase (F. R. Balkwill et al., Eur. J. Cancer Clin. Oncol., in press, 1986). A radioiodine-labeled murine monoclonal antibody (TAL-1B5) against HLA-DR specifically localized to the tumors in recombinant human gamma-interferon-treated but not in control mice. An isotype-identical murine monoclonal antibody that did not react with control or recombinant human gamma-interferon-treated tumors did not show any specific localization. These results demonstrate that specific localization to tumors of radio-labeled monoclonal antibodies to HLA-DR can be facilitated by systemic therapy with gamma-interferon

Identification of viral genes associated with the interferon-inducing phenotype of a synthetic porcine reproductive and respiratory syndrome virus strain.

Science.gov (United States)

Sun, Haiyan; Pattnaik, Asit K; Osorio, Fernando A; Vu, Hiep L X

2016-12-01

We recently generated a fully synthetic porcine reproductive and respiratory syndrome virus strain (designated as PRRSV-CON), which confers unprecedented levels of heterologous protection. We report herein that the synthetic PRRSV-CON possesses a unique phenotype in that it induces type-I interferons (IFNs) instead of suppressing these cytokines as most of the naturally occurring PRRSV isolates do. Through gain- and loss- of-function studies, the IFN-inducing phenotype of PRRSV-CON was mapped to the 3.3kb genomic fragment encoding three viral nonstructural proteins: nsp1α, nsp1β and the N-terminal part of nsp2. Further studies indicated that a cooperation among these 3 proteins was required for effective induction of IFNs. Collectively, this study constitutes the first step toward understanding the mechanisms by which the synthetic PRRSV-CON confers heterologous protection. Copyright © 2016 Elsevier Inc. All rights reserved.

Meta-analysis of mutations in the NS5A gene and hepatitis C virus resistance to interferon therapy: uniting discordant conclusions

NARCIS (Netherlands)

Schinkel, Janke; Spaan, Willy J. M.; Kroes, Aloys C. M.

2004-01-01

Hepatitis C virus genotype 1B responds poorly to treatment with interferon, in contrast to the more interferon-sensitive genotypes 2 and 3. Studies on combination therapy regimens with PEG-interferon and ribavirin report sustained response rates that generally do not exceed 50%, in contrast to

Japanese encephalitis virus non-coding RNA inhibits activation of interferon by blocking nuclear translocation of interferon regulatory factor 3.

Science.gov (United States)

Chang, Ruey-Yi; Hsu, Ta-Wen; Chen, Yen-Lin; Liu, Shu-Fan; Tsai, Yi-Jer; Lin, Yun-Tong; Chen, Yi-Shiuan; Fan, Yi-Hsin

2013-09-27

Noncoding RNA (ncRNA) plays a critical role in modulating a broad range of diseases. All arthropod-borne flaviviruses produce short fragment ncRNA (sfRNA) collinear with highly conserved regions of the 3'-untranslated region (UTR) in the viral genome. We show that the molar ratio of sfRNA to genomic RNA in Japanese encephalitis virus (JEV) persistently infected cells is greater than that in acutely infected cells, indicating an sfRNA role in establishing persistent infection. Transfecting excess quantities of sfRNA into JEV-infected cells reduced interferon-β (IFN-β) promoter activity by 57% and IFN-β mRNA levels by 52%, compared to mock-transfected cells. Transfection of sfRNA into JEV-infected cells also reduced phosphorylation of interferon regulatory factor-3 (IRF-3), the IFN-β upstream regulator, and blocked roughly 30% of IRF-3 nuclear localization. Furthermore, JEV-infected sfRNA transfected cells produced 23% less IFN-β-stimulated apoptosis than mock-transfected groups did. Taken together, these results suggest that sfRNA plays a role against host-cell antiviral responses, prevents cells from undergoing apoptosis, and thus contributes to viral persistence. Copyright © 2013 Elsevier B.V. All rights reserved.

Modulation of gene expression in a human cell line caused by poliovirus, vaccinia virus and interferon

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Hoddevik Gunnar

2007-03-01

Full Text Available Abstract Background The project was initiated to describe the response of a human embryonic fibroblast cell line to the replication of two different viruses, and, more specifically, to look for candidate genes involved in viral defense. For this purpose, the cells were synchronously infected with poliovirus in the absence or presence of interferon-alpha, or with vaccinia virus, a virus that is not inhibited by interferon. By comparing the changes in transcriptosome due to these different challenges, it should be possible to suggest genes that might be involved in defense. Results The viral titers were sufficient to yield productive infection in a majority of the cells. The cells were harvested in triplicate at various time-points, and the transcriptosome compared with mock infected cells using oligo-based, global 35 k microarrays. While there was very limited similarities in the response to the different viruses, a large proportion of the genes up-regulated by interferon-alpha were also up-regulated by poliovirus. Interferon-alpha inhibited poliovirus replication, but there were no signs of any interferons being induced by poliovirus. The observations suggest that the cells do launch an antiviral response to poliovirus in the absence of interferon. Analyses of the data led to a list of candidate antiviral genes. Functional information was limited, or absent, for most of the candidate genes. Conclusion The data are relevant for our understanding of how the cells respond to poliovirus and vaccinia virus infection. More annotations, and more microarray studies with related viruses, are required in order to narrow the list of putative defence-related genes.

Clinico-pathogenetic substantiation and experience of the use of interferon alpha 2b in children with acute respiratory viral infections

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Marushko Yu.V.

2016-03-01

Full Text Available Objective. To evaluate the efficacy and safety of interferon preparations in children under three years with acute respiratory viral infections. Patients and methods. A total of 97 observed children with a diagnosis ARVI has been consulted by doctor at 152 days after the onset of the disease. In the main group in the complex treatment additionally was prescribed nasal interferon alpha 2b «Nazoferon» in the age dosages. Children of the control group had received conventional treatment only. Results. Due to the application of Nazoferon was observed a decrease in the duration as of the main symptoms of the disease (catarrhal phenomena and temperature reaction, so the effects of intoxication. On the fifth day of treatment the difference between clinical parameters was more pronounced. It is found that Nazoferon well tolerated, does not cause discomfort on the part of the respiratory system. Conclusions. The good clinical efficacy and lack of adverse reactions allow recommending Nazoferon for use in pediatric patients. Application of Nazoferon is important to start from the early 152 days of the disease. Allow it to use as a prophylactic measure.

DMPD: Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 12213596 Multiple signaling pathways leading to the activation of interferon regula...(.html) (.csml) Show Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3.... PubmedID 12213596 Title Multiple signaling pathways leading to the activation of

Interferon-γ gene polymorphisms at +874T/A loci associated with response to treatment with hepatitis C virus

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Hosein Norozian

2016-02-01

Full Text Available Background: Hepatitis C virus (HCV is a worldwide health problem, which associated with cirrhosis and hepatocellular carcinoma. Interferon-α and Ribavirin are only acceptable treatment regimen for these patients. These regimen are effective only on 50% of the patients. The aim of this study was to evaluate the response to treatment with interferon gamma gene polymorphism in patients with hepatitis C. Materials and Methods: In this study, a cross - sectional study, response or lack of response to treatment in 78 patients treated with interferon gamma gene polymorphism were studied at Shiraz Namazi Hospital from 2011-2012 . DNA samples extract by salt (salting out and interferon gamma gene polymorphism (+874T/A IFN–gamma was evaluate with ARMS-PCR technique. Data were analyzed using EPI Info2000 and SPSS 16 software (chi-square test. Results: Results showed that 39 patients (50% out of 78 studied patients had TT alleles, 11 patients (1.14% had AA alleles and 28 patients (9.39% had TA alleles. 49 patients (62.82% responded to treatment. TT genotype and allele frequencies between the studied groups showed significant differencey (P=0.002. Conclusion: Interferon gamma is a key cytokine in the immune response against hepatitis C. Polymorphism in the interferon-gamma gene is (+874T/AIFN–gamma One of the most important factors interferes with treatment response in hepatitis C patients.

Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling

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Craigon Marie

2009-08-01

Full Text Available Abstract Background Interferons (IFNs are potent antiviral cytokines capable of reprogramming the macrophage phenotype through the induction of interferon-stimulated genes (ISGs. Here we have used targeted RNA interference to suppress the expression of a number of key genes associated with IFN signalling in murine macrophages prior to stimulation with interferon-gamma. Genome-wide changes in transcript abundance caused by siRNA activity were measured using exon-level microarrays in the presence or absence of IFNγ. Results Transfection of murine bone-marrow derived macrophages (BMDMs with a non-targeting (control siRNA and 11 sequence-specific siRNAs was performed using a cationic lipid transfection reagent (Lipofectamine2000 prior to stimulation with IFNγ. Total RNA was harvested from cells and gene expression measured on Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. Network-based analysis of these data revealed six siRNAs to cause a marked shift in the macrophage transcriptome in the presence or absence IFNγ. These six siRNAs targeted the Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2 transcripts. The perturbation of the transcriptome by the six siRNAs was highly similar in each case and affected the expression of over 600 downstream transcripts. Regulated transcripts were clustered based on co-expression into five major groups corresponding to transcriptional networks associated with the type I and II IFN response, cell cycle regulation, and NF-KB signalling. In addition we have observed a significant non-specific immune stimulation of cells transfected with siRNA using Lipofectamine2000, suggesting use of this reagent in BMDMs, even at low concentrations, is enough to induce a type I IFN response. Conclusion Our results provide evidence that the type I IFN response in murine BMDMs is dependent on Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2, and that siRNAs targeted to these genes results in perturbation of key transcriptional networks associated

Radiotherapy plus cis-retinoic acid/interferon-α in cervical cancers: response and impact of cRA/IFN on tumor tissue oxygenation

International Nuclear Information System (INIS)

Haensgen, Gabriele; Koehler, Uwe; Dunst, Juergen

1997-01-01

Background: We have evaluated the impact of 13-cis-retinoic acid plus interferon in combination with radiotherapy on response and on tumor oxygenation in a phase II-study. Materials and methods: From June 1995 through April 1996, thirty-four patients with squamous cell carcinoma FIGO IIB (N=8) and IIIB (N=26) of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-α-2a (IFN-α-2a) as part of a phase-II-protocol at the Universities of Halle-Wittenberg (N=25), Leipzig (N=7) and Dresden (N=2). cRA/IFN-α-2a started 14 days prior to radiotherapy (1 mg per kilogramm body weight cRA orally daily plus 6x10 6 I.U. IFN-α-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 45Gy in 25 fractions of 1.8Gy plus HDR-brachytherapy with 5x7Gy). During radiotherapy, cRA/IFN-α-2a-treatment was continued with 50% of the daily doses. In 14 patients treated at the University of Halle-Wittenberg, tumor tissue pO 2 -measurements were performed prior to radiotherapy, at 20Gy, and at the end of radiotherapy with an Eppendorf-pO 2 -histograph. The oxygenation data of these patients were compared to 14 patients who had also pO 2 -measurements but had refused to participate in the cRA/IFN-α-2a-protocol and received radiotherapy alone during the same period. Results: All 8 patients with FIGO IIB tumors had a complete clinical remission 3 months after radiotherapy. In FIGO IIIB cancers, (19(26)) (73%) achieved a cCR, 5 (19%) had a PR and 2 died within six months after treatment due to intercurrent disease. The toxicity of cRA/IFN-α-2a was only mild to moderate (fever 43%, skin toxicity 36%, diarrhea 20%, elevation of liver enzymes 20%) with no grade (3(4)) toxicity. The 14 patients with cRA/IFN-α-2a-pretreatment prior to radiotherapy had significant higher median pO 2 -values in their tumors at the

Interferon α treatment of molluscum contagiosum in immunodeficiency

OpenAIRE

Hourihane, J.; Hodges, E.; Smith, J.; Keefe, M.; Jones, A.; Connett, G.

1999-01-01

A sister (aged 6 years) and brother (aged 8 years) presented four months apart with severe molluscum contagiosum. Both children demonstrated clinical and laboratory evidence of combined immunodeficiency. The extent of skin involvement by molluscum contagiosum precluded conventional treatment as well as intralesional interferon α (IFNα). Both subjects responded well to subcutaneous IFNα.



Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates

Science.gov (United States)

Schaap-Nutt, Anne; D’Angelo, Christopher; Amaro-Carambot, Emerito; Nolan, Sheila M.; Davis, Stephanie; Wise, Shenelle-Marie; Higgins, Caraline; Bradley, Konrad; Kim, Olivia; Mayor, Reina; Skiadopoulos, Mario H.; Collins, Peter L.; Murphy, Brian R.; Schmidt, Alexander C.

2010-01-01

The HPIV2 V protein inhibits type I interferon (IFN) induction and signaling. To manipulate the V protein, whose coding sequence overlaps that of the polymerase-associated phosphoprotein (P), without altering the P protein, we generated an HPIV2 virus in which P and V are expressed from separate genes (rHPIV2-P+V). rHPIV2-P+V replicated like HPIV2-WT in vitro and in non-human primates. HPIV2-P+V was modified by introducing two separate mutations into the V protein to create rHPIV2-L101E/L102E and rHPIV2-Δ122–127. In contrast to HPIV2-WT, both mutant viruses were unable to degrade STAT2, leaving virus-infected cells susceptible to IFN. Neither mutant, nor HPIV2-WT, induced significant amounts of IFN-β in infected cells. Surprisingly, neither rHPIV2-L101E/L102E nor rHPIV2-Δ122–127 was attenuated in two species of non-human primates. This indicates that loss of HPIV2's ability to inhibit IFN signaling is insufficient to attenuate virus replication in vivo as long as IFN induction is still inhibited. PMID:20667570

Barriers to treatment of failed or interferon ineligible patients in the era of DAA: single center study

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Kwang Il Seo

2017-03-01

Full Text Available Background/Aims Interferon-based treatment is not appropriate for a large number of patients with chronic hepatitis C for various medical and social reasons. Newly developed directly acting antivirals (DAAs have been used to treat chronic hepatitis C without severe adverse effects and have achieved a sustained viral response (SVR rate of 80-90% with short treatment duration. We were interested to determine whether all patients who failed to respond to or were ineligible for interferon-based therapy could be treated with DAAs. Methods Medical records of patients with positive serum anti-hepatitis C virus (HCV or HCV RNA between January 2009 and December 2013 were reviewed. Demographic, clinical, and treatment data were collected for analysis. Results A total of 876 patients were positive for both anti-HCV and HCV RNA. Of these, 244 patients were eligible for interferon, although this was associated with relapse in 39 (16% of patients. In total, 130 patients stopped interferon therapy (67% adverse effects, 28% non-adherent, 4% malignancy, 1% alcohol abuse and 502 patients were ineligible (66% medical contraindications, 25% non-adherent, 5% socioeconomic problems. Among 671 patients who were ineligible for or failed to respond to interferon therapy, more than 186 (27.7% could not be treated with DAA due to financial, social, or cancer-related conditions. Conclusions Newly developed DAAs are a promising treatment for patients with chronic hepatitis C who are ineligible for or failed to respond to interferon-based therapy. Nevertheless, not all chronic hepatitis C patients can be treated with DAAs due to various reasons.

Stimulation of Inducible Nitric Oxide Synthase Expression by Beta Interferon Increases Necrotic Death of Macrophages upon Listeria monocytogenes Infection▿

OpenAIRE

Zwaferink, Heather; Stockinger, Silvia; Reipert, Siegfried; Decker, Thomas

2008-01-01

Murine macrophage death upon infection with Listeria monocytogenes was previously shown to be increased by beta interferon, produced by the infected cells. We saw that interferon-upregulated caspase activation or other interferon-inducible, death-associated proteins, including TRAIL, protein kinase R, and p53, were not necessary for cell death. Macrophage death was reduced when inducible nitric oxide synthase (iNOS) was inhibited during infection, and iNOS-deficient macrophages were less susc...

Cost analysis of glatiramer acetate versus interferon-β for relapsing-remitting multiple sclerosis in patients with spasticity: the Escala study.

Science.gov (United States)

Sánchez-de la Rosa, Rainel; García-Bujalance, Laura; Meca-Lallana, José

2015-12-01

The Escala Study evidenced that the administration of glatiramer acetate for relapsing-remitting multiple sclerosis improved the spasticity of patients previously treated with interferon-β. However, whether such an improvement was translated into cost savings remained unclear. We therefore conducted a cost analysis of glatiramer acetate versus interferon-β in these patients with multiple sclerosis and spasticity. This cost analysis encompassed data from the observational Escala Study, which included patients with relapsing-remitting multiple sclerosis and spasticity whose treatment had been switched from interferon-β to glatiramer acetate. Costs prior to starting glatiramer acetate (interferon-β period) were compared to the subsequent six months on glatiramer acetate (glatiramer acetate period). The analysis was carried out following the recommendations for conducting pharmacoeconomic studies and from the Spanish National Health System perspective. Costs associated with multiple sclerosis treatment, spasticity treatment and relapse management were expressed in 2014 euros (€); a 7.5 % discount was applied-when needed-as stipulated in Spanish law. The management of relapsing-remitting multiple sclerosis, spasticity and relapses accounted for a 6-month cost per patient of 7,078.02€ when using interferon-β and 4,671.31€ when using glatiramer acetate. Switching from interferon-β to glatiramer acetate therefore represented a cost saving of 2,406.72€ per patient in favour of glatiramer acetate, which resulted from savings in treatment costs, relapse management and spasticity treatment of 1,890.02€, 430.48€ and 86.21€, respectively. The ratio of the costs during interferon-β was 1.5 times the costs during glatiramer acetate; thus, a fixed budget of 5,000,000€ would enable 1,070 patients to be treated with glatiramer acetate and only 706 patients with interferon-β. The treatment of relapsing-remitting multiple sclerosis with glatiramer acetate

A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment.

Science.gov (United States)

Devane, John G; Martin, Mary L; Matson, Mark A

2014-06-01

during week 1 treatment, indicating an early peak in FLS severity during the No Titration treatment and subsequent development of tolerance. In contrast, titration results in near baseline severity scores throughout the treatment period. Similar trends were seen for 4 and 12 hour FLS severity scores. Of the individual FLS, difference in fever severity was most marked. Safety profiles for both regimens were consistent with the approved prescribing information for interferon gamma-1b. Study limitations included the use of healthy subjects rather than disease subjects, the lack of a validated assessment tool for evaluating FLS and the relatively high discontinuation rate. A short 2 week, dose-titration regimen reduces FLS severity following interferon gamma-1b treatment initiation in normal subjects.

Combined adjuvant radiation and interferon-alpha 2B therapy in high-risk melanoma patients: the potential for increased radiation toxicity

International Nuclear Information System (INIS)

Hazard, Lisa J.; Sause, William T.; Noyes, R. Dirk

2002-01-01

Purpose: Surgically resected melanoma patients with high-risk features commonly receive adjuvant therapy with interferon-alpha 2b combined with radiation therapy; the purpose of our study was to evaluate the potential enhancement of radiation toxicity by interferon. Methods and Materials: Patients at LDS Hospital and the University of Utah Medical Center in Salt Lake City treated with interferon during radiotherapy or within 1 month of its completion were retrospectively identified, and their charts were reviewed. If possible, the patients were asked to return to the LDS Hospital radiation therapy department for follow-up. Results: Five of 10 patients receiving interferon-alpha 2b therapy during radiation therapy or within 1 month of its completion experienced severe subacute/late complications of therapy. Severe subacute/late complications included two patients with peripheral neuropathy, one patient with radiation necrosis in the brain, and two patients with radiation necrosis in the s.c. tissue. One patient with peripheral neuropathy and one patient with radiation necrosis also developed lymphedema. Conclusions: In vitro studies have identified a radiosensitizing effect by interferon-alpha on certain cell lines, which suggests the possibility that patients treated with interferon and radiation therapy may experience more severe radiation toxicities. We have observed severe subacute/late complications in five of 10 patients treated with interferon-alpha 2b during radiation therapy or within 1 month of its completion. Although an observational study of 10 patients lacks the statistic power to reach conclusions regarding the safety and complication rates of combined interferon and radiation therapy, it is sufficient to raise concerns and suggest the need for prospective studies

THE PERIPHERAL BLOOD LEUKOCYTES SUSCEPTIBILITY TO INTERFERON-α2 IN VITRO CHANGE AMONGST CHILDREN WITH INFECTIOUS MONONUCLEOSIS

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L. M. Kurtasova

2017-01-01

Full Text Available Objective: to measure cell susceptibility of peripheral blood leukocytes to interferon-α2 in vitro at children during the acute period in 1 and 6 months after infectious mononucleosis caused by the Epstein–Barr virus. 47 children aged 4–6 years with moderately severe form of the disease in the acute period of infectious mononucleosis caused by the Epstein–Barr virus (EBV were examined, as well as in 1 month (n = 17 and 6 months (n = 11 after the disease. The focus group consisted of 36 nearly healthy children. The cell susceptibility to interferon-α2 in vitro was determined by the method of Kurtasova L.M. et al. (2007. Chemiluminescence of blood leukocytes was studied by De Sole et al. (1983. The susceptibility change of peripheral blood leukocytes to interferon-α2 in vitro at children with infectious mononucleosis caused by Epstein–Barr virus in dynamics of the disease has been revealed. The expansion of the range of cell susceptibility to interferon-α2 in 6 months after the disease has been enclosed. The dependence of the susceptibility of peripheral blood leukocytes to interferon-α2 in vitro on the dose and the period of the disease has been fixed.

Induction of mammary gland tumor in female Sprague- Dawley rats ...

African Journals Online (AJOL)

STORAGESEVER

2010-07-12

Jul 12, 2010 ... The current methods for tumor induction in breast cancer research animal models are time-consuming, hazardous ... issue in animal has been a controversial and much disputed ..... to therapy and early detection of cancer.

Type I interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response

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Giovanna eSchiavoni

2013-12-01

Full Text Available Induction of potent tumor-specific cytotoxic T-cell responses is a fundamental objective in anticancer therapeutic strategies. This event requires that antigen-presenting cells (APC present tumor-associated antigens (Ag on their MHC class-I molecule, in a process termed cross-presentation. Dendritic cells (DC are particularly keen on this task and can induce the cross-priming of CD8+ T cells, when exposed to danger or inflammatory signals that stimulate their activation. Type I interferons (IFN-I, a family of long-known immunostimulatory cytokines, have been proven to produce optimal activation signal for DC-induced cross-priming. Recent in vitro and in vivo evidences have suggested that IFN-I -stimulated cross-priming by DC against tumor-associated Ag is a key mechanism for cancer immunosurveillance and may be usefully exploited to boost anti-tumor CD8+ T-cell responses. Here, we will review the cross-presentation properties of different DC subsets, with special focus on cell-associated and tumor Ag, and discuss how IFN-I can modify this function, with the aim of identifying more specific and effective strategies for improving anticancer responses.

Prediction of response to interferon therapy in multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, F; Søndergaard, Helle Bach; Koch-Henriksen, N

2014-01-01

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in the genes encoding interferon response factor (IRF)-5, IRF-8 and glypican-5 (GPC5) have been associated with disease activity in multiple sclerosis (MS) patients treated with interferon (IFN)-β. We analysed whether SNPs in the IRF5, IRF8 and GPC5...... genes are associated with clinical disease activity in MS patients beginning de novo treatment with IFN-β. METHODS: The SNPs rs2004640, rs3807306 and rs4728142 in IRF5, rs13333054 and rs17445836 in IRF8 and rs10492503 in GPC5 were genotyped in 575 patients with relapsing-remitting MS followed...... prospectively after the initiation of their first treatment with IFN-β. RESULTS: 62% of patients experienced relapses during the first 2 years of treatment, and 32% had disability progression during the first 5 years of treatment. Patients with a pretreatment annualized relapse rate >1 had an increased risk...

Identification and expression analysis of the interferon-induced protein with tetratricopeptide repeats 5 (IFIT5 gene in duck (Anas platyrhynchos domesticus.

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Bin Wang

Full Text Available The interferon-induced proteins with tetratricopeptide repeats (IFITs protein family mediates antiviral effects by inhibiting translation initiation, cell proliferation, and migration in the interferon (IFN dependent innate immune system. Several members of this family, including IFIT1, IFIT2, IFIT3 and IFIT5, have been heavily studied in mammals. Avian species contain only one family member, IFIT5, and little is known about the role of this protein in birds. In this study, duck IFIT5 (duIFIT5 full-length mRNA was cloned by reverse transcription polymerase chain reaction (RT-PCR and rapid amplification of the cDNA ends (RACE. Based on the sequence obtained, we performed a series of bioinformatics analyses, and found that duIFIT5 was most similar to homologs in other avian species. Also, duIFIT5 contained eight conserved TPR motifs and two conserved multi-domains (TPR_11 and TPR_12. Finally, we used duck hepatitis virus type 1 (DHV-1 and polyriboinosinicpolyribocytidylic acid (poly (I:C as a pathogen or a pathogen-associated molecular pattern induction to infect three-day-old domestic ducklings. The liver and spleen were collected to detect the change in duIFIT5 transcript level upon infection by quantitative real-time PCR (qRT-PCR. DuIFIT5 expression rapidly increased after DHV-1 infection and maintained a high level, while the transcripts of duIFIT5 peaked at 8h after poly (I:C infection and then returned to normal. Taken together, these results provide a greater understanding of avian IFIT5.

Identification and Expression Analysis of the Interferon-Induced Protein with Tetratricopeptide Repeats 5 (IFIT5) Gene in Duck (Anas platyrhynchos domesticus)

Science.gov (United States)

Mu, Chunyu; Su, Yanhui; Liu, Ran; Huang, Zhengyang; Li, Yang; Yu, Qingming; Chang, Guobin; Xu, Qi; Chen, Guohong

2015-01-01

The interferon-induced proteins with tetratricopeptide repeats (IFITs) protein family mediates antiviral effects by inhibiting translation initiation, cell proliferation, and migration in the interferon (IFN) dependent innate immune system. Several members of this family, including IFIT1, IFIT2, IFIT3 and IFIT5, have been heavily studied in mammals. Avian species contain only one family member, IFIT5, and little is known about the role of this protein in birds. In this study, duck IFIT5 (duIFIT5) full-length mRNA was cloned by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of the cDNA ends (RACE). Based on the sequence obtained, we performed a series of bioinformatics analyses, and found that duIFIT5 was most similar to homologs in other avian species. Also, duIFIT5 contained eight conserved TPR motifs and two conserved multi-domains (TPR_11 and TPR_12). Finally, we used duck hepatitis virus type 1 (DHV-1) and polyriboinosinicpolyribocytidylic acid (poly (I:C)) as a pathogen or a pathogen-associated molecular pattern induction to infect three-day-old domestic ducklings. The liver and spleen were collected to detect the change in duIFIT5 transcript level upon infection by quantitative real-time PCR (qRT-PCR). DuIFIT5 expression rapidly increased after DHV-1 infection and maintained a high level, while the transcripts of duIFIT5 peaked at 8h after poly (I:C) infection and then returned to normal. Taken together, these results provide a greater understanding of avian IFIT5. PMID:25816333

Potentiating day-old blood samples for detection of interferon-gamma responses following infection with Mycobacterium avium subsp. paratuberculosis

DEFF Research Database (Denmark)

Mikkelsen, Heidi; Nielsen, Søren Saxmose; Jungersen, Gregers

time interval from blood sampling to culture. The objective of the study was to assess options for use of day-old blood samples for early-stage diagnosis of MAP infections. Bovine interleukin 12 (IL-12) can induce, and IL-10 reduce, IFN-γ production. Therefore, addition of IL-12 and anti-IL-10 could...... result in production of IFN-γ in samples previously exposed to MAP antigens. Whole blood samples were collected from heifers in a Danish dairy herd known to be infected with MAP. The samples were collected on three sample dates, and on each date the blood samples were stimulated with PPDj and recombinant......The interferon gamma (IFN-γ) test measuring specific cell-mediated immune responses in whole blood can be used for diagnosis at an early stage of Mycobacterium avium subsp. paratuberculosis (MAP) infection. A major obstacle for the practical use of IFN-γ testing is the recommended maximum 8 hour...

Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion

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Ren Song

2016-02-01

Full Text Available Infection by alphaherpesviruses, including herpes simplex virus (HSV and pseudorabies virus (PRV, typically begins at epithelial surfaces and continues into the peripheral nervous system (PNS. Inflammatory responses are induced at the infected peripheral site prior to invasion of the PNS. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which includes the interferons (IFNs. The fundamental question is how do PNS cell bodies respond to these distant, potentially damaging events experienced by axons. Using compartmented cultures that physically separate neuron axons from cell bodies, we found that pretreating isolated axons with beta interferon (IFN-β or gamma interferon (IFN-γ significantly diminished the number of herpes simplex virus 1 (HSV-1 and PRV particles moving in axons toward the cell bodies in a receptor-dependent manner. Exposing axons to IFN-β induced STAT1 phosphorylation (p-STAT1 only in axons, while exposure of axons to IFN-γ induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated antiviral effects induced by IFN-γ, but not those induced by IFN-β. Proteomic analysis of IFN-β- or IFN-γ-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFN-γ, IFN-β induces a noncanonical, local antiviral response in axons. The activation of a local IFN response in axons represents a new paradigm for cytokine control of neuroinvasion.

Arthritis is inhibited in Borrelia-primed and infected interleukin-17A-deficient mice after administration of anti-gamma-interferon, anti-tumor necrosis factor alpha and anti-interleukin-6 antibodies.

Science.gov (United States)

Kuo, Joseph; Warner, Thomas F; Schell, Ronald F

2017-08-31

The role that cytokines play in the induction of Lyme arthritis is gradually being delineated. We showed previously that severe arthritis developed in a T-cell-driven murine model, even in mice lacking interleukin-17A (IL-17A) and administered anti-gamma-interferon (IFN-γ) antibody. Increased levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two pro-inflammatory cytokines, were detected in cultures of popliteal lymph node cells obtained from these mice. We hypothesized that concomitantly administered anti-IL-6, anti-TNF-α and anti-IFN-γ antibodies would inhibit the development of arthritis in IL-17A-deficient mice. Our results showed that swelling of the hind paws and histopathological changes consistent with arthritis were significantly reduced in IL-17A-deficient mice that administered the three anti-cytokine antibodies. These results suggest that treatment with multiple anti-cytokine antibodies can abrogate the induction of Lyme arthritis in mice. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A comparison of induction of anaesthesia using two different ...

African Journals Online (AJOL)

Background: Investigators have reported inter-patient variability with regard to propofol dosage for induction of anesthesia, since early dose finding studies. With the arrival of generic formulations of propofol, questions have arisen regarding further variability in dose requirements. Various studies have confirmed that generic ...

Morning versus evening induction of labour for improving outcomes.

Science.gov (United States)

Bakker, Jannet J H; van der Goes, Birgit Y; Pel, Maria; Mol, Ben Willem J; van der Post, Joris A M

2013-02-28

Induction of labour is a common intervention in obstetric practice. Traditionally, in most hospitals induction of labour with medication starts early in the morning, with the start of the working day for the day shift. In human and animal studies spontaneous onset of labour is proven to have a circadian rhythm with a preference for start of labour in the evening. Moreover, when spontaneous labour starts in the evening, the total duration of labour and delivery shortens and fewer obstetric interventions are needed. Based on these observations one might assume that starting induction of labour in the evening, in harmony with the circadian rhythm of natural birth, is more beneficial for both mother and child. To assess whether induction of labour starting in the evening, coinciding with the endogenous circadian rhythm, improves the outcome of labour compared with induction of labour starting in the early morning, organised to coincide with office hours. We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012). In addition, we searched MEDLINE (1966 to 16 February 2012) and EMBASE (1980 to 16 February 2012). We included all published and unpublished randomised controlled trials. We excluded trials that employed quasi-random methods of treatment allocation. Two review authors independently assessed trials for inclusion and risk of bias. Two review authors independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. The search resulted in 2693 articles that we screened on title and abstract for eligibility.Thirteen studies were selected for full text assessment. We included three randomised trials involving 1150 women. Two trials compared the administration of prostaglandins in the morning versus the evening in women with an unfavourable cervix, and one trial compared induction of labour in the morning versus the evening

Chemokine receptor CCR5 in interferon-treated multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, F; Kristiansen, Thomas Birk; Wittenhagen, P

2007-01-01

OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were...

[Autoimmunity in children with chronic hepatitis C treated with interferon alpha and ribavirin].

Science.gov (United States)

Gora-Gebka, Magdalena; Liberek, Anna; Bako, Wanda; Raczkowska-Kozak, Janina; Sikorska-Wisniewska, Grazyna; Korzon, Maria

2004-01-01

The role of interferon alpha or the virus itself in the pathogenesis and the risk of autoimmunological disorders in patients infected with HCV, still remain unknown, especially in children. The aim of the study was to evaluate the incidence of autoantibodies and the risk of autoimmunological disorders in children with chronic hepatitis C, treated with interferon alpha and ribavirin in the Department of Paediatrics, Paediatric Gastroenterology and Oncology in Gdansk. In the studied group of 12 patients, in 4 cases autoantibodies were present in low titers prior to the treatment and they had no prognostic value for the response to the therapy or the risk of autoimmunological disorders. Positive response for the treatment was achieved in 4 cases; in 3 cases indications for discontinuation of the therapy were established. During the therapy with interferon alpha and ribavirin, in 2 children elevation of serum titers of antibodies to liver-kidney microsome type 1 (anti-LKM1) (> 1:640) with normal gammaglobulin levels was noted. In none of the children autoimmunological disorders were observed.

Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems

DEFF Research Database (Denmark)

Rasmussen, Simon Brandtoft; Sørensen, Louise Nørgaard; Malmgaard, Lene

2007-01-01

Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes...... simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-alpha/beta) response is derived from several cell types and induced independently of TLR9...

Impairment of interferon regulatory factor-3 activation by hepatitis C virus core protein basic amino acid region 1.

Science.gov (United States)

Inoue, Kazuaki; Tsukiyama-Kohara, Kyoko; Matsuda, Chiho; Yoneyama, Mitsutoshi; Fujita, Takashi; Kuge, Shusuke; Yoshiba, Makoto; Kohara, Michinori

2012-11-30

Interferon regulatory factor-3 (IRF-3), a key transcriptional factor in the type I interferon system, is frequently impaired by hepatitis C virus (HCV), in order to establish persistent infection. However, the exact mechanism by which the virus establishes persistent infection has not been fully understood yet. The present study aimed to investigate the effects of various HCV proteins on IRF-3 activation, and elucidate the underlying mechanisms. To achieve this, full-length HCV and HCV subgenomic constructs corresponding to structural and each of the nonstructural proteins were transiently transfected into HepG2 cells. IFN-β induction, plaque formation, and IRF-3 dimerization were elicited by Newcastle disease virus (NDV) infection. The expressions of IRF-3 homodimer and its monomer, Ser386-phosphorylated IRF-3, and HCV core protein were detected by immunofluorescence and western blotting. IFN-β mRNA expression was quantified by real-time PCR (RT-PCR), and IRF-3 activity was measured by the levels of IRF-3 dimerization and phosphorylation, induced by NDV infection or polyriboinosinic:polyribocytidylic acid [poly(I:C)]. Switching of the expression of the complete HCV genome as well as the core proteins, E1, E2, and NS2, suppressed IFN-β mRNA levels and IRF-3 dimerization, induced by NDV infection. Our study revealed a crucial region of the HCV core protein, basic amino acid region 1 (BR1), to inhibit IRF-3 dimerization as well as its phosphorylation induced by NDV infection and poly (I:C), thus interfering with IRF-3 activation. Therefore, our study suggests that rescue of the IRF-3 pathway impairment may be an effective treatment for HCV infection. Copyright © 2012 Elsevier Inc. All rights reserved.

Tumor Necrosis Factors, Interferons and Matrix Metalloproteinase-9 in Sera of Non-Hodgkin's Lymphoma Patients

International Nuclear Information System (INIS)

Abdel Malak, C.A.; Karawya, E.M.; Hammouda, G.A.; Zakhary, N.I.

2003-01-01

In the present study, the serum levels of some cytokines and the matrix metalloproteinase-9 (MMP-9) were studied in an attempt to find suitable markers for early diagnosis of non- Hodgkin's lymphoma (NHL) and to assess their role in differentiating between disseminated and non disseminated cases. The present study was conducted on 60 patients with non disseminated NHL, 14 patients with disseminated NHL, in addition to 10 healthy controls. Their sera were used to determine tumor necrosis factor-α (TNF--α), tumor necrosis factor--β (TNF-β), interferon---α), (IFN--α), interferon-γ (IFN--γ) and Matrix Metalloproteinase-9 (MMP-9) using the ELISA technique. The results showed that the serum level of TNF---α), and IFN---α), can be used to differentiate between the control group and the group of NHL patients. However, they could not differentiate between non disseminated NHL (nd- NHL) and disseminated NHL (d- NHL). On the other hand, the serum level of TNF-β) can be used to differentiate between nd- NHL and d- NHL, but not between the control group and nd-NHL. Each of [FN--γ and MMP-9 were not useful in discrimination between the control group and the diseased ones. Our data revealed no correlation between serum level of the parameters investigated and the gender of the patients. The present results revealed that TNF-α) and INF-α), can be used as diagnostic tools for NHL. On the other hand, TNF-β) is useful in the differentiation between nd-NHL and d-NHL

Clinical Success With Imiquimod Alone and In Combination With Intralesional Interferon In Basal Cell Carcinoma

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Hayriye Sarıcaoğlu

2013-12-01

Full Text Available Background: Basal cell carcinoma (BCC is the most common type of skin cancer in humans. Surgery is still the gold standart for treatment of BCCs. However, there are also less-invasive, nonsurgical therapies such as imiquimod cream and intralesional interferon (IFN alpha-2b for the patients who are poor candidates for surgery and who care cosmetic outcomes. Objective: We report 11 BCC cases with various subtypes successfully treated with either imiquimod alone or in combination with interferon alfa-2b. Methods: Patients with various subtypes of histopathologically proven BCCs who were treated with imiquimod or combination of imiquimod and IFN alpha-2b between 2005-2010 years at our outpatient clinic are included in this report. Results: Of 11 patients we reported, only 4 patients (3 infiltrative, 1 solid types recieved intralesional interferon alpha-2b 3 million IU, 3 times a week combined with topical imiquimod. The rest 7 patients recieved only imiquimod 5% cream. All patients were cured with these regimens. Conclusion: Imiquimod is found to be effective not only in superficial, but also infiltrative, solid, and nodular types. Intralesional interferon alpha-2b is also known to be effective in BCCs and it has a synergistic effect when combined with imiquimod.

The interferon response circuit in antiviral host defense.

Science.gov (United States)

Haller, O; Weber, F

2009-01-01

Viruses have learned to multiply in the face of a powerful innate and adaptive immune response of the host. They have evolved multiple strategies to evade the interferon (IFN) system which would otherwise limit virus growth at an early stage of infection. IFNs induce the synthesis of a range of antiviral proteins which serve as cell-autonomous intrinsic restriction factors. For example, the dynamin-like MxA GTPase inhibits the multiplication of influenza and bunyaviruses (such as La Crosse virus, Hantaan virus, Rift Valley Fever virus, and Crimean-Congo hemorrhagic fever virus) by binding and sequestering the nucleocapsid protein into large perinuclear complexes. To overcome such intracellular restrictions, virulent viruses either inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Many viruses produce specialized proteins to disarm the danger signal or express virulence genes that target members of the IFN regulatory factor family (IRFs) or components of the JAK-STAT signaling pathway. An alternative evasion strategy is based on extreme viral replication speed which out-competes the IFN response. The identification of viral proteins with IFN antagonistic functions has great implications for disease prevention and therapy. Virus mutants lacking IFN antagonistic properties represent safe yet highly immunogenic candidate vaccines. Furthermore, novel drugs intercepting viral IFN-antagonists could be used to disarm the viral intruders.

Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver.

Science.gov (United States)

Tien, Yun-Chen; Liu, Ke; Pope, Chad; Wang, Pengcheng; Ma, Xiaochao; Zhong, Xiao-bo

2015-12-01

Drug treatment of neonates and infants and its long-term consequences on drug responses have emerged in recent years as a major challenge for health care professionals. In the current study, we use phenobarbital as a model drug and mouse as an in vivo model to demonstrate that the dose of phenobarbital and age of treatment are two key factors for the persistent induction of gene expression and consequential increases of enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult livers. We show that phenobarbital treatment at early life of day 5 after birth with a low dose (phenobarbital treatment with a high dose (>200 mg/kg) significantly increases expression and enzyme activities of these P450s in adult liver. We also demonstrate that phenobarbital treatment before day 10 after birth, but not at later ages, significantly increases mRNAs, proteins, and enzyme activities of the tested P450s. Such persistent induction of P450 gene expression and enzyme activities in adult livers by phenobarbital treatment only occurs within a sensitive age window early in life. The persistent induction in gene expression and enzyme activities is higher in female mice than in male mice for Cyp2b10 but not for Cyp2c29 and Cyp3a11. These results will stimulate studies to evaluate the long-term impacts of drug treatment with different doses at neonatal and infant ages on drug metabolism, therapeutic efficacy, and drug-induced toxicity throughout the rest of life. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Thyroid dysfunction in hepatitis C individuals treated with interferon-alpha and ribavirin: a review

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Luis Jesuíno de Oliveira Andrade

Full Text Available Hepatitis C (HCV is now the main cause of chronic hepatic disease, cirrhosis and hepatocellular carcinoma. Several extrahepatic diseases have been associated with chronic HCV infection, and in most cases appear to be directly related to the viral infection. Thyroid disorders are common in patients with chronic HCV. Some patients with chronic hepatitis C experience thyroid problems, and thyroid dysfunction may also be a side effect of interferon-based treatment. The principal risk factor for developing thyroid disease in the course of antiviral therapy is the previous positivity for anti-thyroid antibodies (anti-thyroid peroxidase especially in older women. Screening for autoantibodies and serum thyroid-stimulating hormone is recommended before, during and after interferon-alpha treatment, and patients should be informed of the risk of thyroid dysfunction. This review includes a summary of thyroid disease associated with chronic HCV infection, interferon-alpha and ribavirin for treatment of HCV and potential to induce thyroid dysfunction.

Loss of prion protein induces a primed state of type I interferon-responsive genes

DEFF Research Database (Denmark)

Malachin, Giulia; Reiten, Malin R.; Salvesen, Øyvind

2017-01-01

The cellular prion protein (PrPC) has been extensively studied because of its pivotal role in prion diseases; however, its functions remain incompletely understood. A unique line of goats has been identified that carries a nonsense mutation that abolishes synthesis of PrPC. In these animals, the Pr...... genotypes. About 70% of these were classified as interferon-responsive genes. In goats without PrPC, the majority of type I interferon-responsive genes were in a primed, modestly upregulated state, with fold changes ranging from 1.4 to 3.7. Among these were ISG15, DDX58 (RIG-1), MX1, MX2, OAS1, OAS2...... and DRAM1, all of which have important roles in pathogen defense, cell proliferation, apoptosis, immunomodulation and DNA damage response. Our data suggest that PrPC contributes to the fine-tuning of resting state PBMCs expression level of type I interferon-responsive genes. The molecular mechanism...

Response to standard interferon A2b and ribavirin combination therapy in chronic hepatitis C treatment naive patients

International Nuclear Information System (INIS)

Jadoon, S.M.K.; Muhammad, I.

2010-01-01

Background: Treatment of Chronic Hepatitis C is now well established with conventional interferon or pegylated interferon in combination with ribavirin. Peginterferon Alfa and Ribavirin for 6 to 12 months is currently approved initial therapy, which is expensive. Response of our patients to standard Interferon-alpha-2b and ribavirin for 24 weeks have been studied. The objective of this study was to asses Sustained Viral Response (SVR) with standard Interferon A2b and Ribavirin combination treatment in chronic Hepatitis C patients. Methods: This quasi-experimental study was conducted at Combined Military Hospital, Quetta from Jan 2006 to Jun 2007. One hundred and three patients, with 20-60 years of age suffering from chronic Hepatitis C were selected on the basis of raised ALT, positive anti-HCV antibodies, evidence of viraemia by quantitative PCR for HCV RNA and liver biopsy. All patients were started on same brand of Interferon alpha-2b, 3 MIU subcutaneously, thrice weekly and oral Ribavirin (1,000-1,200 mg/day) for 24 weeks. End treatment response (ETR) after completion of treatment and SVR six months after ETR were recorded. Results: The 103 patients, 85 males and 18 females with mean age of 21-48 years completed the treatment for 24 weeks. Mean ALT was 96.17 (SD +- 49.98). End treatment response (ETR) was 89.3% (p=0.032). Sustained Viral Response after 6 months of treatment was 86.4% (p=0.034). Conclusion: Standard Interferon and Ribavirin had excellent SVR. It is effective as well as economical treatment in Chronic Hepatitis C patients. (author)

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis.

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Kanda, Tatsuo; Yasui, Shin; Nakamura, Masato; Nakamoto, Shingo; Takahashi, Koji; Wu, Shuang; Sasaki, Reina; Haga, Yuki; Ogasawara, Sadahisa; Saito, Tomoko; Kobayashi, Kazufumi; Kiyono, Soichiro; Ooka, Yoshihiko; Suzuki, Eiichiro; Chiba, Tetsuhiro; Maruyama, Hitoshi; Imazeki, Fumio; Moriyama, Mitsuhiko; Kato, Naoya

2018-02-20

Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.

Interferon beta and vitamin D synergize to induce immunoregulatory receptors on peripheral blood monocytes of multiple sclerosis patients.

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Anne Waschbisch

Full Text Available Immunoglobulin-like transcript (ILT 3 and 4 are inhibitory receptors that modulate immune responses. Their expression has been reported to be affected by interferon, offering a possible mechanism by which this cytokine exerts its therapeutic effect in multiple sclerosis, a condition thought to involve excessive immune activity. To investigate this possibility, we measured expression of ILT3 and ILT4 on immune cells from multiple sclerosis patients, and in post-mortem brain tissue. We also studied the ability of interferon beta, alone or in combination with vitamin D, to induce upregulation of these receptors in vitro, and compared expression levels between interferon-treated and untreated multiple sclerosis patients. In vitro interferon beta treatment led to a robust upregulation of ILT3 and ILT4 on monocytes, and dihydroxyvitamin D3 increased expression of ILT3 but not ILT4. ILT3 was abundant in demyelinating lesions in postmortem brain, and expression on monocytes in the cerebrospinal fluid was higher than in peripheral blood, suggesting that the central nervous system milieu induces ILT3, or that ILT3 positive monocytes preferentially enter the brain. Our data are consistent with involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D.

Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons.

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Rauch, Isabella; Rosebrock, Felix; Hainzl, Eva; Heider, Susanne; Majoros, Andrea; Wienerroither, Sebastian; Strobl, Birgit; Stockinger, Silvia; Kenner, Lukas; Müller, Mathias; Decker, Thomas

2015-07-01

The interferon (IFN)-stimulated gene factor 3 (ISGF3) transcription factor with its Stat1, Stat2, and interferon regulatory factor 9 (IRF9) subunits is employed for transcriptional responses downstream of receptors for type I interferons (IFN-I) that include IFN-α and IFN-β and type III interferons (IFN-III), also called IFN-λ. Here, we show in a murine model of dextran sodium sulfate (DSS)-induced colitis that IRF9 deficiency protects animals, whereas the combined loss of IFN-I and IFN-III receptors worsens their condition. We explain the different phenotypes by demonstrating a function of IRF9 in a noncanonical transcriptional complex with Stat1, apart from IFN-I and IFN-III signaling. Together, Stat1 and IRF9 produce a proinflammatory activity that overrides the benefits of the IFN-III response on intestinal epithelial cells. Our results further suggest that the CXCL10 chemokine gene is an important mediator of this proinflammatory activity. We thus establish IFN-λ as a potentially anticolitogenic cytokine and propose an important role for IRF9 as a component of noncanonical Stat complexes in the development of colitis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Proposal of a model of mammalian neural induction

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Levine, Ariel J.; Brivanlou, Ali H.

2009-01-01

How does the vertebrate embryo make a nervous system? This complex question has been at the center of developmental biology for many years. The earliest step in this process – the induction of neural tissue – is intimately linked to patterning of the entire early embryo, and the molecular and embryological basis these processes are beginning to emerge. Here, we analyze classic and cutting-edge findings on neural induction in the mouse. We find that data from genetics, tissue explants, tissue grafting, and molecular marker expression support a coherent framework for mammalian neural induction. In this model, the gastrula organizer of the mouse embryo inhibits BMP signaling to allow neural tissue to form as a default fate – in the absence of instructive signals. The first neural tissue induced is anterior and subsequent neural tissue is posteriorized to form the midbrain, hindbrain, and spinal cord. The anterior visceral endoderm protects the pre-specified anterior neural fate from similar posteriorization, allowing formation of forebrain. This model is very similar to the default model of neural induction in the frog, thus bridging the evolutionary gap between amphibians and mammals. PMID:17585896

Severe depression following á-interferon usage in a patient with ...

African Journals Online (AJOL)

... following á-interferon usage in a patient with chronic myeloid leukemia. ... Chronic myeloid leukaemia (CML), with a median age of 40 years, is one of the ... as a side effect of á-IFN in the treatment of CML Method: Clinical and laboratory ...

Pulmonary Immune-Compartment-Specific Interferon Gamma Responses in HIV-Infected Individuals with Active Tuberculosis (TB in an Area of High TB Prevalence

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S. Buldeo

2012-01-01

Full Text Available There is a paucity of data on the pulmonary immune-compartment interferon gamma (IFNγ response to M. tuberculosis, particularly in settings of high tuberculosis (TB prevalence and in HIV-coinfected individuals. This data is necessary to understand the diagnostic potential of commercially available interferon gamma release assays (IGRAs in both the pulmonary immune-compartment and peripheral blood. We used intracellular cytokine staining by flow cytometry to assess the IFNγ response to purified protein derivative (PPD and early secretory antigen 6 (ESAT6 in induced sputa (ISp and blood samples from HIV-infected, smear-negative, TB suspects. We found that individuals with active TB disease produced significantly less IFNγ in response to PPD in their induced sputa samples than individuals with non-active TB (control group. This difference was not reflected in the peripheral blood, even within the CD27− CD4+ memory T lymphocyte population. These findings suggest that progression to active TB disease may be associated with the loss of IFNγ secretion at the site of primary infection. Our findings highlight the importance of studying pulmonary immune-compartment M. tuberculosis specific responses to elucidate IFNγ secretion across the spectrum of TB disease.

Inductive reasoning.

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Hayes, Brett K; Heit, Evan; Swendsen, Haruka

2010-03-01

Inductive reasoning entails using existing knowledge or observations to make predictions about novel cases. We review recent findings in research on category-based induction as well as theoretical models of these results, including similarity-based models, connectionist networks, an account based on relevance theory, Bayesian models, and other mathematical models. A number of touchstone empirical phenomena that involve taxonomic similarity are described. We also examine phenomena involving more complex background knowledge about premises and conclusions of inductive arguments and the properties referenced. Earlier models are shown to give a good account of similarity-based phenomena but not knowledge-based phenomena. Recent models that aim to account for both similarity-based and knowledge-based phenomena are reviewed and evaluated. Among the most important new directions in induction research are a focus on induction with uncertain premise categories, the modeling of the relationship between inductive and deductive reasoning, and examination of the neural substrates of induction. A common theme in both the well-established and emerging lines of induction research is the need to develop well-articulated and empirically testable formal models of induction. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website. Copyright © 2010 John Wiley & Sons, Ltd.

Induction of specific neuron types by overexpression of single transcription factors.

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Teratani-Ota, Yusuke; Yamamizu, Kohei; Piao, Yulan; Sharova, Lioudmila; Amano, Misa; Yu, Hong; Schlessinger, David; Ko, Minoru S H; Sharov, Alexei A

2016-10-01

Specific neuronal types derived from embryonic stem cells (ESCs) can facilitate mechanistic studies and potentially aid in regenerative medicine. Existing induction methods, however, mostly rely on the effects of the combined action of multiple added growth factors, which generally tend to result in mixed populations of neurons. Here, we report that overexpression of specific transcription factors (TFs) in ESCs can rather guide the differentiation of ESCs towards specific neuron lineages. Analysis of data on gene expression changes 2 d after induction of each of 185 TFs implicated candidate TFs for further ESC differentiation studies. Induction of 23 TFs (out of 49 TFs tested) for 6 d facilitated neural differentiation of ESCs as inferred from increased proportion of cells with neural progenitor marker PSA-NCAM. We identified early activation of the Notch signaling pathway as a common feature of most potent inducers of neural differentiation. The majority of neuron-like cells generated by induction of Ascl1, Smad7, Nr2f1, Dlx2, Dlx4, Nr2f2, Barhl2, and Lhx1 were GABA-positive and expressed other markers of GABAergic neurons. In the same way, we identified Lmx1a and Nr4a2 as inducers for neurons bearing dopaminergic markers and Isl1, Fezf2, and St18 for cholinergic motor neurons. A time-course experiment with induction of Ascl1 showed early upregulation of most neural-specific messenger RNA (mRNA) and microRNAs (miRNAs). Sets of Ascl1-induced mRNAs and miRNAs were enriched in Ascl1 targets. In further studies, enrichment of cells obtained with the induction of Ascl1, Smad7, and Nr2f1 using microbeads resulted in essentially pure population of neuron-like cells with expression profiles similar to neural tissues and expressed markers of GABAergic neurons. In summary, this study indicates that induction of transcription factors is a promising approach to generate cultures that show the transcription profiles characteristic of specific neural cell types.

Vitamin D in addition to peg-interferon-alpha/ribavirin in chronic hepatitis C virus infection: ANRS-HC25-VITAVIC study.

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Terrier, Benjamin; Lapidus, Nathanael; Pol, Stanislas; Serfaty, Lawrence; Ratziu, Vlad; Asselah, Tarik; Thibault, Vincent; Souberbielle, Jean-Claude; Carrat, Fabrice; Cacoub, Patrice

2015-05-14

To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin (PegIFN/RBV) therapy could improve the efficacy of PegIFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection. Genotype 1 or 4 HCV-infected patients with null response to previous PegIFN/RBV treatment and with hypovitaminosis D (vitamin D level was 15 ng/mL (range: 7-28). In modified intention-to-treat analysis, 29 patients who received at least one dose of PegIFN/RBV were included in the analysis. All patients except one normalized their vitamin D serum levels. The rate of early virologic response was 0/29 (0%). The rate of HCV RNA vitamin D to PegIFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1 or 4 HCV infection.

Prokaryotic expression of chicken interferon-γ fusion protein and its effect on expression of poultry heat shock protein 70 under heat stress.

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Sun, Jinhua; Chen, Yinglin; Qin, Feiyue; Guan, Xueting; Xu, Wei; Xu, Liangmei

2017-06-01

Interferons have attracted considerable attention due to their vital roles in the host immune response and low induction of antibiotic resistance. In this study, total RNA was extracted from spleen cells of chicken embryos inoculated with Newcastle disease vaccine, and the full-length chicken interferon-γ (ChIFN-γ) gene was amplified by RT-PCR. The full complementary DNA sequence of the ChIFN-γ gene was 495 bp long and was cloned into the prokaryotic expression vector pProEX™HT b . The plasmid was transformed into Escherichia coli DH5α and the expression of ChIFN-γ was induced by isopropyl β-D-1-thiogalactopyranoside. Sodium dodecyl sulfate - polyacrylamide gel electrophoresis and Western blot results showed the expressed fusion protein had a molecular weight of approximately 18 kDa and was recognized by an anti-His mAb. Moreover, ChIFN-γ was found to demonstrate anti-viral activity in vitro. To test the in vivo function of ChIFN-γ in broilers under heat stress, a total of 100 broilers were randomly assigned to either a control group or a treated group, in which they were hypodermically injected with recombinant ChIFN-γ. Results demonstrated ChIFN-γ affects the messenger RNA expression levels of heat shock protein 70 (HSP70) in the heart and lung tissues, and decreases the concentration of HSP70 in serum. Therefore, we conclude recombinant ChIFN-γ can reduce heat stress to some extent in vivo. © 2016 Japanese Society of Animal Science.

Homozygous deletion of the α- and β1-interferon genes in human leukemia and derived cell lines

International Nuclear Information System (INIS)

Diaz, M.O.; Ziemin, S.; Le Beau, M.M.; Pitha, P.; Smith, S.D.; Chilcote, R.R.; Rowley, J.D.

1988-01-01

The loss of bands p21-22 from one chromosome 9 homologue as a consequence of a deletion of the short arm [del(9p)], unbalanced translocation, or monosomy 9 is frequently observed in the malignant cells of patients with lymphoid neoplasias, including acute lymphoblastic leukemia and non-Hodgkin lymphoma. The α- and β 1 -interferon genes have been assigned to this chromosome region (9p21-22). The authors now present evidence of the homozygous deletion of the interferon genes in neoplastic hematopoietic cell lines and primary leukemia cells in the presence or absence of chromosomal deletions that are detectable at the level of the light microscope. In these cell lines, the deletion of the interferon genes is accompanied by a deficiency of 5'-methylthioadenosine phosphorylase, an enzyme of purine metabolism. These homozygous deletions may be associated with the loss of a tumor-suppressor gene that is involved in the development of these neoplasias. The relevant genes may be either the interferon genes themselves or a gene that has a tumor-suppressor function and is closely linked to them

SAFETY OF INTERFERON BETA 1A FOR A SUBCUTANEOUS ADMINISTRATION IN CHILDREN AND ADOLESCENTS WITH DISSEMINATED SCLEROSIS

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O.V. Bykova

2008-01-01

Full Text Available The onset of disseminated sclerosis occurs in childhood and juvenile age in 10% of patients. nevertheless, all immunomodulatory drugs for a treatment of this disease intended for adult population of patients, and there's an age limitation to the administration of these medications. There's only one interferon beta in group of «changing the clinical course of disseminated sclerosis medications», that was annotated to the administration in patients from 16 years. It's interferon betab1a (Rebif for subcutaneous administration in 22 ?g and 44 ?g dosage. This drug was well known as an effective and safe medication for a long term administration for a long time in adult neurological practice. But doctors have to use interferon betab1a «off label» yet in patients younger 16 years in Russia and in other countries, comparing risk of changing the regimen of age limitation and risk of deprivation of un derbaged patient of years of qualitative life.Key words: children, disseminated sclerosis, interferon beta 1a, treatment.

Antibody induction versus corticosteroid induction for liver transplant recipients

DEFF Research Database (Denmark)

Penninga, Luit; Wettergren, André; Wilson, Colin H

2014-01-01

BACKGROUND: Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell specific antibody induction compared with corticosteroid induction of immunosuppression after liver transplantation....... OBJECTIVES: To assess the benefits and harms of T-cell specific antibody induction versus corticosteroid induction for prevention of acute rejection in liver transplant recipients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register...... to identify additional trials. SELECTION CRITERIA: We included all randomised clinical trials assessing immunosuppression with T-cell specific antibody induction versus corticosteroid induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should...

Global analysis of host response to induction of a latent bacteriophage

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Keasling Jay D

2007-08-01

Full Text Available Abstract Background The transition from viral latency to lytic growth involves complex interactions among host and viral factors, and the extent to which host physiology is buffered from the virus during induction of lysis is not known. A reasonable hypothesis is that the virus should be evolutionarily selected to ensure host health throughout induction to minimize its chance of reproductive failure. To address this question, we collected transcriptional profiles of Escherichia coli and bacteriophage lambda throughout lysogenic induction by UV light. Results We observed a temporally coordinated program of phage gene expression, with distinct early, middle and late transcriptional classes. Our study confirmed known host-phage interactions of induction of the heat shock regulon, escape replication, and suppression of genes involved in cell division and initiation of replication. We identified 728 E. coli genes responsive to prophage induction, which included pleiotropic stress response pathways, the Arc and Cpx regulons, and global regulators crp and lrp. Several hundred genes involved in central metabolism, energy metabolism, translation and transport were down-regulated late in induction. Though statistically significant, most of the changes in these genes were mild, with only 140 genes showing greater than two-fold change. Conclusion Overall, we observe that prophage induction has a surprisingly low impact on host physiology. This study provides the first global dynamic picture of how host processes respond to lambda phage induction.

AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA.

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Nakaya, Yuki; Lilue, Jingtao; Stavrou, Spyridon; Moran, Eileen A; Ross, Susan R

2017-07-05

Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA. IMPORTANCE Autoimmune diseases like Aicardi-Goutières syndrome and lupus erythematosus arise when cells of the immune system become activated and attack host cells and tissues. We found that DNA generated by endogenous retroviruses and retroelements in inbred mice and mouse cells is recognized by several host proteins found in macrophages that are members of the ALR family and that these proteins both suppress and activate the pathways leading to the generation of cytokines and IFNs. We also show that there is great genetic diversity between different inbred mouse strains in the ALR genes, which might contribute to differential susceptibility to autoimmunity. Understanding how immune cells become activated is important to the control of disease. Copyright © 2017 Nakaya et al.

Guarding the frontiers: the biology of type III interferons

DEFF Research Database (Denmark)

Wack, Andreas; Terczynska-Dyla, Ewa; Hartmann, Rune

2015-01-01

Type III interferons (IFNs) or IFN-λs regulate a similar set of genes as type I IFNs, but whereas type I IFNs act globally, IFN-λs primarily target mucosal epithelial cells and protect them against the frequent viral attacks that are typical for barrier tissues. IFN-λs thereby help to maintain...

IL4/PGE2 induction of an enlarged early endosomal compartment in mouse macrophages is Rab5-dependent

International Nuclear Information System (INIS)

Wainszelbaum, Marisa J.; Proctor, Brandon M.; Pontow, Suzanne E.; Stahl, Philip D.; Barbieri, M. Alejandro

2006-01-01

The endosomal compartment and the plasma membrane form a complex partnership that controls signal transduction and trafficking of different molecules. The specificity and functionality of the early endocytic pathway are regulated by a growing number of Rab GTPases, particularly Rab5. In this study, we demonstrate that IL4 (a Th-2 cytokine) and prostaglandin E 2 (PGE 2 ) synergistically induce Rab5 and several Rab effector proteins, including Rin1 and EEA1, and promote the formation of an enlarged early endocytic (EEE) compartment. Endosome enlargement is linked to a substantial induction of the mannose receptor (MR), a well-characterized macrophage endocytic receptor. Both MR levels and MR-mediated endocytosis are enhanced approximately 7-fold. Fluid-phase endocytosis is also elevated in treated cells. Light microscopy and fractionation studies reveal that MR colocalizes predominantly with Rab5a and partially with Rab11, an endosomal recycling pathway marker. Using retroviral expression of Rab5a:S34N, a dominant negative mutant, and siRNA Rab5a silencing, we demonstrate that Rab5a is essential for the large endosome phenotype and for localization of MR in these structures. We speculate that the EEE is maintained by activated Rab5, and that the EEE phenotype is part of some macrophage developmental program such as cell fusion, a characteristic of IL4-stimulated cells

Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells.

Science.gov (United States)

Paglino, Justin C; Andres, Wells; van den Pol, Anthony N

2014-05-01

Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer

Early induction of NRF2 antioxidant pathway by RHBDF2 mediates rapid cutaneous wound healing.

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Hosur, Vishnu; Burzenski, Lisa M; Stearns, Timothy M; Farley, Michelle L; Sundberg, John P; Wiles, Michael V; Shultz, Leonard D

2017-04-01

Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2 cub/cub ) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2 cub/cub mice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2 cub/cub and Rhbdf2 +/+ mice at 0h, 15min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2 cub/cub mice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds. Copyright © 2017 Elsevier Inc. All rights reserved.

Induction linacs

International Nuclear Information System (INIS)

Keefe, D.

1986-07-01

The principle of linear induction acceleration is described, and examples are given of practical configurations for induction linacs. These examples include the Advanced Technology Accelerator, Long Pulse Induction Linac, Radial Line Accelerator (RADLAC), and Magnetically-Insulated Electron-Focussed Ion Linac. A related concept, the auto accelerator, is described in which the high-current electron-beam technology in the sub-10 MeV region is exploited to produce electron beams at energies perhaps as high as the 100 to 1000 MeV range. Induction linacs for ions are also discussed. The efficiency of induction linear acceleration is analyzed

Inductive foraging: improving the diagnostic yield of primary care consultations.

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Donner-Banzhoff, Norbert; Hertwig, Ralph

2014-03-01

Physicians attempting to make a diagnosis arrive at specific hypotheses early in their encounter with patients. Further data are collected in the light of these early hypotheses. While this hypothetico-deductive model has been accepted as both a description of physicians' data gathering and a norm, little attention has been paid to the preceding stage of the consultation. It is suggested that 'inductive foraging' is a relevant and appropriate mode of data acquisition for the first part of the patient encounter. Research evidence from cognitive psychology and medical reasoning research is discussed. With inductive foraging, 'pattern failure' rather than 'pattern recognition' is the mode of discovery. Largely, guidance should be left to the patient to lead the clinician into areas where departures from normality are to be found. This is in contrast to active and focused 'deductive inquiry,' which should be used only after most aetiologies, but a few have eliminated. Especially when the prevalence of serious disease is low, and a wide range of diagnoses must be evaluated, such as in General Practice, inductive foraging is a rational and efficient diagnostic strategy. Previously, too little attention has been paid to the initial stage of the consultation. Premature closure at this point may result in diagnostic error.

Early clearance of peripheral blasts measured by flow cytometry during the first week of AML induction therapy as a new independent prognostic factor: a GOELAMS study.

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Lacombe, F; Arnoulet, C; Maynadié, M; Lippert, E; Luquet, I; Pigneux, A; Vey, N; Casasnovas, O; Witz, F; Béné, M C

2009-02-01

An early appreciation of treatment efficacy could be very useful in acute myeloblastic leukemia (AML), and a prognostic value has been suggested for the morphological assessment of decrease in blasts during induction therapy. More sensitive, multiparametric flow cytometry (FCM) can detect far lower blast counts, allowing for a precise and reliable calculation of blast cell decrease rate (BDR). Such a multiparametric FCM four-colours/single-tube protocol, combining CD11b, CD45-ECD and CD16-PC5, was applied to peripheral blood samples from 130 AML patients, collected daily during induction chemotherapy. Normalized blast cell percentages were used to calculate the relevant decrease slopes. Slope thresholds (-15), or the time required to reach 90% depletion of the peripheral blast load (5 days), was strongly associated with the achievement of complete remission (P<0.0001). Log-rank test and Cox model showed that they also carried high statistical significance (P<0.0001) for disease-free survival. The prognostic value of cytogenetic features, confirmed in this series, was refined by BDR, which allowed to discriminate between good- and poor-risk patients among those with intermediate or normal karyotypes. This simple FCM protocol allows for an accurate prognostic sequential approach adapted to the determination of decrease in peripheral blast cells during induction chemotherapy.

Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients

DEFF Research Database (Denmark)

Penninga, Luit; Wettergren, André; Wilson, Colin H

2014-01-01

. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants....... Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 μmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small...... T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude...

The interferon response to intracellular DNA: why so many receptors?

Science.gov (United States)

Unterholzner, Leonie

2013-11-01

The detection of intracellular DNA has emerged to be a key event in the innate immune response to viruses and intracellular bacteria, and during conditions of sterile inflammation and autoimmunity. One of the consequences of the detection of DNA as a 'stranger' and a 'danger' signal is the production of type I interferons and pro-inflammatory cytokines. Much work has been dedicated to the elucidation of the signalling cascades that activate this DNA-induced gene expression programme. However, while many proteins have been proposed to act as sensors for intracellular DNA in recent years, none has been met with universal acceptance, and a theory linking all the recent observations is, as yet, lacking. This review presents the evidence for the various interferon-inducing DNA receptors proposed to date, and examines the hypotheses that might explain why so many different receptors appear to be involved in the innate immune recognition of intracellular DNA. Copyright © 2013 Elsevier GmbH. All rights reserved.

Interferon-Mediated Innate Immune Responses against Malaria Parasite Liver Stages

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Jessica L. Miller

2014-04-01

Full Text Available Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust innate immune response including type I interferon (IFN and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR, and interferon regulatory factor 3. Natural killer and CD49b+CD3+ natural killer T (NKT cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite.

The structure of the human interferon alpha/beta receptor gene.

Science.gov (United States)

Lutfalla, G; Gardiner, K; Proudhon, D; Vielh, E; Uzé, G

1992-02-05

Using the cDNA coding for the human interferon alpha/beta receptor (IFNAR), the IFNAR gene has been physically mapped relative to the other loci of the chromosome 21q22.1 region. 32,906 base pairs covering the IFNAR gene have been cloned and sequenced. Primer extension and solution hybridization-ribonuclease protection have been used to determine that the transcription of the gene is initiated in a broad region of 20 base pairs. Some aspects of the polymorphism of the gene, including noncoding sequences, have been analyzed; some are allelic differences in the coding sequence that induce amino acid variations in the resulting protein. The exon structure of the IFNAR gene and of that of the available genes for the receptors of the cytokine/growth hormone/prolactin/interferon receptor family have been compared with the predictions for the secondary structure of those receptors. From this analysis, we postulate a common origin and propose an hypothesis for the divergence from the immunoglobulin superfamily.

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo.

Science.gov (United States)

Douam, Florian; Soto Albrecht, Yentli E; Hrebikova, Gabriela; Sadimin, Evita; Davidson, Christian; Kotenko, Sergei V; Ploss, Alexander

2017-08-15

role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies. Copyright © 2017 Douam et al.

Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs in Interferon-Free Regimens.

Science.gov (United States)

Pawlotsky, Jean-Michel

2016-07-01

Treatment of hepatitis C virus (HCV) infection has progressed considerably with the approval of interferon-free, direct-acting antiviral (DAA)-based combination therapies. Although most treated patients achieve virological cure, HCV resistance to DAAs has an important role in the failure of interferon-free treatment regimens. The presence of viral variants resistant to NS5A inhibitors at baseline is associated with lower rates of virological cure in certain groups of patients, such as those with genotype 1a or 3 HCV, those with cirrhosis, and/or prior nonresponders to pegylated interferon-based regimens. DAA-resistant HCV is generally dominant at virological failure (most often relapse). Viruses resistant to NS3-4A protease inhibitors disappear from peripheral blood in a few weeks to months, whereas NS5A inhibitor-resistant viruses persist for years. Re-treatment options are available, but first-line treatment strategies should be optimized to efficiently prevent treatment failure due to HCV resistance. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

Science.gov (United States)

Bernardo, Ana R; Cosgaya, José M; Aranda, Ana; Jiménez-Lara, Ana M

2017-07-01

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

Two Distinct Interferon-γ in the Orange-Spotted Grouper (Epinephelus coioides: Molecular Cloning, Functional Characterization, and Regulation in Toll-Like Receptor Pathway by Induction of miR-146a

Directory of Open Access Journals (Sweden)

Wan Peng

2018-02-01

Full Text Available Interferon gamma (IFNγ is a Th1 cytokine that is critical for innate and adaptive immunity. Toll-like receptors (TLRs signaling pathways are critical in early host defense against invading pathogens. miR-146a has been reported to participate in the regulation of host immunity. The known mechanisms of integrations between the IFNγ and TLR signaling pathways are incompletely understood, especially in teleosts. In this study, orange-spotted grouper (Epinephelus coioides IFNγ1 and IFNγ2, their biological activities, especially their involvements in TLR pathway, were explored. We identified and cloned two IFNγ genes of E. coioides, namely EcIFNγ1 and EcIFNγ2. The produced recombinant E. coioides IFNγ1 (rEcIFNγ1 and IFNγ2 (rEcIFNγ2 proteins showed functions, which are similar to those of other bony fishes, such as enhancing nitric oxide responses and respiratory burst response. rEcIFNγ2 could regulate TLR pathway by enhancing the promoter activity of miR-146a upstream sequence and thus increasing the expression level of miR-146a, which possibly targets TNF receptor-associated factor 6 (TRAF6, a key adapter molecule in TLR signaling pathway. Taken together, these findings unravel a novel regulatory mechanism of anti-inflammatory response by IFNγ2, which could mediate TLR pathway through IFNγ2–miR-146a–TRAF6 negative regulation loop. It is suggested that IFNγ2 may provide a promising therapeutic, which may help to fine tune the immune response.

Protection of human cells against the effects of cadmium chloride by pretreatment with vitamins, interferon, and prior low-dose γ-irradiation

International Nuclear Information System (INIS)

Kusainova, K.A.; Vasil'eva, I.M.; Chekova, V.V.; Akhmatullina, N.B.; Zasukhina, G.D.

1992-01-01

Within the increasing environmental pollution there is a need to discover means to protect humans from the mutagenic effects of chemical pollutants. Natural antimutagens such as interferon and vitamins have some protective properties. Interferons simulate a variety of repair pathways in human cells and reduce the numbers of mutations induced by physical and chemical mutagens. This study compares the protective properties of interferon and vitamins with the known protective effects of small doses of ionizing radiation

The inhibitory effect of salmon calcitonin on tri-iodothyronine induction of early hypertrophy in articular cartilage.

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Pingping Chen-An

Full Text Available Salmon calcitonin has chondroprotective effect both in vitro and in vivo, and is therefore being tested as a candidate drug for cartilage degenerative diseases. Recent studies have indicated that different chondrocyte phenotypes may express the calcitonin receptor (CTR differentially. We tested for the presence of the CTR in chondrocytes from tri-iodothyronin (T3-induced bovine articular cartilage explants. Moreover, investigated the effects of human and salmon calcitonin on the explants.Early chondrocyte hypertrophy was induced in bovine articular cartilage explants by stimulation over four days with 20 ng/mL T3. The degree of hypertrophy was investigated by molecular markers of hypertrophy (ALP, IHH, COLX and MMP13, by biochemical markers of cartilage turnover (C2M, P2NP and AGNxII and histology. The expression of the CTR was detected by qPCR and immunohistochemistry. T3-induced explants were treated with salmon or human calcitonin. Calcitonin down-stream signaling was measured by levels of cAMP, and by the molecular markers.Compared with untreated control explants, T3 induction increased expression of the hypertrophic markers (p<0.05, of cartilage turnover (p<0.05, and of CTR (p<0.01. Salmon, but not human, calcitonin induced cAMP release (p<0.001. Salmon calcitonin also inhibited expression of markers of hypertrophy and cartilage turnover (p<0.05.T3 induced early hypertrophy of chondrocytes, which showed an elevated expression of the CTR and was thus a target for salmon calcitonin. Molecular marker levels indicated salmon, but not human, calcitonin protected the cartilage from hypertrophy. These results confirm that salmon calcitonin is able to modulate the CTR and thus have chondroprotective effects.

MECHANISMS OF CELL RESISTANCE TO CYTOMEGALOVIRUS ARE CONNECTED WITH CELL PROLIFERATION STATE AND TRANSCRIPTION ACTIVITY OF LEUKOCYTE AND IMMUNE INTERFERON GENES

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T. M. Sokolova

2007-01-01

Full Text Available Abstract. Cytomegalovirus (CMV infection in diploid human fibroblasts (HF and levels of cell resistance to this virus were shown to be in direct correlation with high α-interferon (IFNα gene activity and induction of IFNγ gene transcription. Regulation of IFNα mRNA transcription was revealed to be positively associated with cellular DNA synthesis. At the same time, activities of IFNβ and IFNγ genes were at the constantly low level and were not induced in DNA-synthetic phase (S-phase of the cells. Levels of IFNα mRNA synthesis are quite different for G0- vs S-phase-synchronized HF110044 cell cultures: appropriate values for dividing cells (S-phase proved to be 100-fold higher than in resting state (G0. The mode of CMV infection in resting HF-cell could be considered either as acute, or a productive one. On the contrary, proliferating cells exhibited lagging viral syntheses and delayed cell death. Arrest of CMV replication may be, to some extent, comparable with latent infectious state, being associated with high production of IFNα. Both basal and induced levels of IFNα mRNA in CMV-resistant adult human skin fibroblast cells (HSF-1608 were 10-fold higher than in human embryo lung cell line (HELF-977, which is highly sensitive to CMV. Moreover, a short-time induction of IFNγ genes was observed in resistant cells, whereas no such effect was noticed in highly sensitive cells. CMV reproduction in sensitive cell lines (HELF-977 and HELF-110044 partially inhibits IFNα mRNA transcription at the later stages of infection (24 to 48 hours. Thus, cellular resistance and control of CMV infection in diploid fibroblasts are associated predominantly with high transcription of IFNα gene, and with temporal induction of IFNγ gene. We did not reveal any participation of IFNβ genes in protection of human diploid fibroblasts from CMV.

Product related factors influencing the immunogenicity of interferon beta-1b

NARCIS (Netherlands)

Haji Abdolvahab, M.

2016-01-01

Therapeutic interferon beta is the first line treatment of relapsing remitting Multiple Sclerosis. However, despite their success in improving patient wellbeing, all IFNβ products encounter a significant problem: immunogenicity. In some patients, IFNβ products induce the formation of antidrug

SAMHD1 restricts HIV-1 replication and regulates interferon production in mouse myeloid cells.

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Ruonan Zhang

Full Text Available SAMHD1 restricts the replication of HIV-1 and other retroviruses in human myeloid and resting CD4(+ T cells and that is counteracted in SIV and HIV-2 by the Vpx accessory protein. The protein is a phosphohydrolase that lowers the concentration of deoxynucleoside triphosphates (dNTP, blocking reverse transcription of the viral RNA genome. Polymorphisms in the gene encoding SAMHD1 are associated with Aicardi-Goutières Syndrome, a neurological disorder characterized by increased type-I interferon production. SAMHD1 is conserved in mammals but its role in restricting virus replication and controlling interferon production in non-primate species is not well understood. We show that SAMHD1 is catalytically active and expressed at high levels in mouse spleen, lymph nodes, thymus and lung. siRNA knock-down of SAMHD1 in bone marrow-derived macrophages increased their susceptibility to HIV-1 infection. shRNA knock-down of SAMHD1 in the murine monocytic cell-line RAW264.7 increased its susceptibility to HIV-1 and murine leukemia virus and increased the levels of the dNTP pool. In addition, SAMHD1 knock-down in RAW264.7 cells induced the production of type-I interferon and several interferon-stimulated genes, modeling the situation in Aicardi-Goutières Syndrome. Our findings suggest that the role of SAMHD1 in restricting viruses is conserved in the mouse. The RAW264.7 cell-line serves as a useful tool to study the antiviral and innate immune response functions of SAMHD1.

[Change in the activity of natural killer cells in normal subjects and in virus diseases on exposure to interferon in vitro].

Science.gov (United States)

Petrov, R V; Saidov, M Z; Koval'chuk, L V; Sorokin, A M; Kaganov, B S

1984-04-01

The activity of natural killers was examined in peripheral blood of healthy subjects and patients with chronic hepatitis and disseminated sclerosis. An attempt was made to correct natural killer activity by human leukocyte interferon in vitro. To assess the activity of natural killers, use was made of the method of serial dilutions. An optimal effector/target ratio was employed in experiments. The patients with chronic hepatitis and disseminated sclerosis demonstrated a reduction in the activity of natural killers whatever the effector/target ratio. The action of interferon in vitro is specific immunomodulatory in nature. Administration of interferon in a dose of 250 Units/ml raises the magnitude of the cytotoxic index in healthy donors and in patients with chronic hepatitis and disseminated sclerosis, making the shape of the killer activity curve approach that of normal. Such an approach can be used for preliminary assessment of the sensitivity of natural killers to interferon in viral diseases of man. The potentialities and efficacy of interferon in clinical medicine are discussed.

HVR-1 heterogeneity during treatment with telaprevir with or without pegylated interferon alfa-2a.

Science.gov (United States)

Lange, Christian M; Susser, Simone; Herrmann, Eva; Karey, Ursula; Kieffer, Tara L; Kwong, Ann D; Schinkel, Janke; Reesink, Henk W; Zeuzem, Stefan; Sarrazin, Christoph

2011-11-01

The extensive heterogeneity of the hypervariable region-1 (HVR-1) of hepatitis C virus (HCV) evidences the high genetic flexibility of HCV and was shown to be associated with virologic response to interferon-α-based therapies. However, the evolution of HVR-1 heterogeneity during treatment with directly acting antivirals has not been studied. Clonal sequence analysis of HVR-1 quasispecies in the serum of patients who were treated with telaprevir (3 × 750 mg/day) alone, telaprevir plus pegylated interferon-α-2a (pegIFN-α-2a), or pegIFN-α-2a plus placebo for 14 days was performed. HVR-1 heterogeneity, expressed as Shannon complexity and Hamming distance, was analyzed with virologic response and with the emergence of variants associated with resistance to telaprevir. HVR-1 heterogeneity at baseline was not associated with response to telaprevir-based therapy (Shannon complexity 0.34 vs. 0.55, p = 0.38; Hamming distance 0.15 vs. 0.23, p = 0.51; for patients with or without viral breakthrough, respectively). No significant changes in HVR-1 complexity were observed from baseline to day 4 of therapy in patients in whom a continued decline in HCV RNA was observed (Shannon complexity = 0.55 vs. 0.51, p = 0.67; Hamming distance = 0.23 vs. 0.25, p = 0.81, respectively). This was similar in patients with viral breakthrough associated with telaprevir-resistant variants (Shannon complexity = 0.34 vs. 0.42, p = 0.68; Hamming distance = 0.15 vs. 0.2, p = 0.50, at baseline and day 4, respectively). Baseline and on-treatment HVR-1 heterogeneity are not associated with early viral response to telaprevir-based therapy.

In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction.

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Kenji Ohba

Full Text Available High prevalence of infection with high-risk human papilloma virus (HPV ranging from 25 to 100% (average 31% was observed in breast cancer (BC patients in Singapore using novel DNA chip technology. Early stage of BC demonstrated higher HPV positivity, and BC positive for estrogen receptor (ER showed significantly higher HPV infection rate. This unique association of HPV with BC in vivo prompted us to investigate a possible involvement of HPV in early stages of breast carcinogenesis. Using normal breast epithelial cells stably transfected with HPV-18, we showed apparent upregulation of mRNA for the cytidine deaminase, APOBEC3B (A3B which is reported to be a source of mutations in BC. HPV-induced A3B overexpression caused significant γH2AX focus formation, and DNA breaks which were cancelled by shRNA to HPV18 E6, E7 and A3B. These results strongly suggest an active involvement of HPV in the early stage of BC carcinogenesis via A3B induction.

Proliferative and antiproliferative effects of interferon-gamma and tumor necrosis factor-alpha on cell lines derived from cervical and ovarian malignancies

International Nuclear Information System (INIS)

Mutch, D.G.; Massad, L.S.; Kao, M.S.; Collins, J.L.

1990-01-01

Four human cell lines derived from cervical carcinomas (ME-180, SiHa, HT-3, and MS751) and three human cell lines derived from ovarian carcinomas (SK-OV-3, Caov-3, and NIH:OVCAR-3) were analyzed in vitro to determine the effect of recombinant interferon-gamma and recombinant human tumor necrosis factor-alpha on cell growth and survival. The effects of interferon-gamma, tumor necrosis factor-alpha, and both interferon-gamma and tumor necrosis factor-alpha on cell growth were measured after 24 and 72 hours of incubation by the incorporation of chromium 51. The results of this analysis showed that all seven cell lines were resistant to the antiproliferative action of tumor necrosis factor-alpha, that the growth of most cell lines was inhibited by interferon-gamma by 72 hours of incubation, and that after 72 hours of incubation all cell lines demonstrated a synergistic antiproliferative response to the combination of interferon-gamma and tumor necrosis factor-alpha. However, the effects of these cytokines on cell growth were found to differ among cell lines and varied with the concentration and the duration of incubation. The growth of one cell line (Caov-3) was stimulated by both tumor necrosis factor-alpha and interferon-gamma. These results suggest that the clinical effects of these cytokines on the growth of gynecologic cancers may be more complex than previously supposed

A leukocyte antigen, Leu-13, is involved in induction of resistance of human cells to x-ray cell killing by interferon-α

International Nuclear Information System (INIS)

Kita, Kazuko; Zhai, Ling; Sugaya, Shigeru; Suzuki, Nobuo

2003-01-01

We previously reported on human interferon (HuIFN)-induced resistance of human cells to X-ray and UV cell killing. In this study, we searched for the genes whose expression is responsible for the resistance, using a PCR-based mRNA differential display method and Northern blotting analysis. RSa cells were used for this analysis, because they show increased resistance to X-ray- and UV-caused cell killing by HuIFN-α treatment prior to irradiation. Messenger RNA expression levels for Leu-13, a leukocyte antigen, were markedly up-regulated in RSa cells after HuIFN-α treatment. Furthermore, pretreatment of RSa cells with antisense oligonucleotides for Leu-13 mRNA resulted in the suppression of the HuIFN-α-induced resistance of the cells to X-ray cell killing, but did not modulate HuIFN-α-induced resistance to UV cell killing. These results suggest that Leu-13 is involved in HuIFN-α-induced resistance of human cells to X-ray cell killing, but not to UV cell killing. (author)

Species difference in reactivity to lignin-like enzymatically polymerized polyphenols on interferon-γ synthesis and involvement of interleukin-2 production in mice.

Science.gov (United States)

Yamanaka, Daisuke; Ishibashi, Ken-Ichi; Adachi, Yoshiyuki; Ohno, Naohito

2016-09-01

Recent studies have revealed that lignin-like polymerized polyphenols can activate innate immune systems. In this study, we aimed to evaluate whether these polymerized polyphenols could activate leukocytes from different murine strains. Splenocytes from 12 mouse strains were investigated. Our results revealed species differences in reactivity to phenolic polymers on interferon-γ (IFN-γ) release. Mice that possessed the H2(a) or H2(k) haplotype antigens were the highly responsive strains. To clarify these different points in soluble factors, multiplex cytokine profiling analysis was carried out and we identified interleukin (IL)-2 as a key molecule for IFN-γ induction by polymerized polyphenols. Furthermore, inhibition of IL-2 and IL-2Rα by neutralizing antibodies significantly decreased cytokine production in the highly responsive mice strains. Our results indicate that species difference in reactivity to phenolic polymers is mediated by adequate release of IL-2 and its receptor, IL-2Rα. Copyright © 2016 Elsevier B.V. All rights reserved.

Interferon β induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.

Science.gov (United States)

Chort, Alice; Alves, Sandro; Marinello, Martina; Dufresnois, Béatrice; Dornbierer, Jean-Gabriel; Tesson, Christelle; Latouche, Morwena; Baker, Darren P; Barkats, Martine; El Hachimi, Khalid H; Ruberg, Merle; Janer, Alexandre; Stevanin, Giovanni; Brice, Alexis; Sittler, Annie

2013-06-01

We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.

Induction of the early response protein EGR-1 in human tumour cells after ionizing radiation is correlated with a reduction of repair of lethal lesions and an increase of repair of sublethal lesions

NARCIS (Netherlands)

Franken, Nicolaas A. P.; ten Cate, Rosemarie; van Bree, Chris; Haveman, Jaap

2004-01-01

The role of EGR-1 in potentially lethal damage repair (PLDR) was studied. Induction of the early response protein EGR-1 and survival after ionizing radiation of two human tumour cell lines after culturing for 48 h in serum-deprived medium was investigated. The glioblastoma cell line (Gli-6) and a

Osteopontin as a marker for response to pegylated interferon Alpha ...

African Journals Online (AJOL)

Osteopontin as a marker for response to pegylated interferon Alpha-2b treatment in Chronic HCV Saudi patients. Yousri Mostafa Hussein1,2, Ayman Alhazmi1, Saad Alzahrani3, Ahmad El-Askary1,4,. Abdulrahman Alghamdy5, Eman Bayomy4, Assmaa Selim6, Mohammed Alghamdy1. 1. Medical Laboratories Department ...

Interferon regulatory factor 5 gene polymorphism in Egyptian children with systemic lupus erythematosus.

Science.gov (United States)

Hammad, A; Mossad, Y M; Nasef, N; Eid, R

2017-07-01

Background Increased expression of interferon-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Interferon regulatory factor 5 (IRF5) is one of the transcription factors regulating interferon and was proved to be implicated in the pathogenesis of SLE in different populations. Objectives The objective of this study was to investigate the correlation between polymorphisms of the IRF5 gene and SLE susceptibility in a cohort of Egyptian children and to investigate their association with clinico-pathological features, especially lupus nephritis. Subjects and methods Typing of interferon regulatory factor 5 rs10954213, rs2004640 and rs2280714 polymorphisms were done using polymerase chain reaction-restriction fragment length polymorphism for 100 children with SLE and 100 matched healthy controls. Results Children with SLE had more frequent T allele and TT genotype of rs2004640 ( P c  = 0.003 and 0.024, respectively) compared to controls. Patients with nephritis had more frequent T allele of rs2004640 compared to controls ( P c  = 0.003). However the allele and genotype frequencies of the three studied polymorphisms did not show any difference in patients with nephritis in comparison to those without nephritis. Haplotype GTA of rs10954213, rs2004640 and rs2280714, respectively, was more frequent in lupus patients in comparison to controls ( p = 0.01) while the haplotype GGG was more frequent in controls than lupus patients ( p = 0.011). Conclusion The rs2004640 T allele and TT genotype and GTA haplotype of rs rs10954213, rs2004640, and rs2280714, respectively, can be considered as risk factors for the development of SLE. The presence of the rs2004640 T allele increases the risk of nephritis development in Egyptian children with SLE.

Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure.

Science.gov (United States)

Gram, Anna M; Sun, Chenglong; Landman, Sanne L; Oosenbrug, Timo; Koppejan, Hester J; Kwakkenbos, Mark J; Hoeben, Rob C; Paludan, Søren R; Ressing, Maaike E

2017-11-01

Most cells are believed to be capable of producing type I interferons (IFN I) as part of an innate immune response against, for instance, viral infections. In macrophages, IFN I is potently induced upon cytoplasmic exposure to foreign nucleic acids. Infection of these cells with herpesviruses leads to triggering of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP (cGAMP) synthase (cGAS). Thereby, the stimulator of interferon genes (STING) and the downstream molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are sequentially activated culminating in IFN I secretion. Human gamma-herpesviruses, such as Epstein-Barr virus (EBV), exploit B cells as a reservoir for persistent infection. In this study, we investigated whether human B cells, similar to macrophages, engage the cytoplasmic DNA sensing pathway to induce an innate immune response. We found that the B cells fail to secrete IFN I upon cytoplasmic DNA exposure, although they express the DNA sensors cGAS and IFI16 and the signaling components TBK1 and IRF3. In primary human B lymphocytes and EBV-negative B cell lines, this deficiency is explained by a lack of detectable levels of the central adaptor protein STING. In contrast, EBV-transformed B cell lines did express STING, yet both these lines as well as STING-reconstituted EBV-negative B cells did not produce IFN I upon dsDNA or cGAMP stimulation. Our combined data show that the cytoplasmic DNA sensing pathway is dysfunctional in human B cells. This exemplifies that certain cell types cannot induce IFN I in response to cytoplasmic DNA exposure providing a potential niche for viral persistence. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Evaluation of the persistence in the induction of Sister Chromatid Exchanges (SCE) by alkylating agents

International Nuclear Information System (INIS)

Rodriguez R, R.; Huerta V, C.; MOrales R, P.R.

2006-01-01

The persistence in the induction of sister chromatid exchanges (SCE) by the alkylating agents methyl and ethyl-methanesulfonates (MMS and EMS) was evaluated. For it, to groups of mice its were administered a dose of these agents and later its were analyzed the induced SCE's in two periods: early and late. Both agents caused high increments of SCE in the early period and small in the late one; however, the caused lately by EMS was significantly bigger. This late induction of SCE by EMS possibly is associated with an epigenetic change or with the presence of etiladucts in the phosphodiester bonds of the DNA. (Author)

Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.

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Dane Parker

2014-02-01

Full Text Available The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar⁻/⁻ mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia.

Induction of experimental autoimmune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1alpha or its CCR5 receptor

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Tran, E H; Kuziel, W A; Owens, T

2000-01-01

-type mice in Th1 cytokine gene expression, the kinetics and severity of disease, and infiltration of the central nervous system by lymphocytes, macrophages and granulocytes. RNase protection assays showed comparable accumulation of mRNA for the chemokines interferon-inducible protein-10, RANTES, macrophage...... and its CCR5 receptor in the induction of EAE by immunizing C57BL / 6 mice deficient in either MIP-1alpha or CCR5 with myelin oligodendrocyte glycoprotein (MOG). We found that MIP-1alpha-deficient mice were fully susceptible to MOG-induced EAE. These knockout animals were indistinguishable from wild...... chemoattractant protein-1, MIP-1beta, MIP-2, lymphotactin and T cell activation gene-3 during the course of the disease. CCR5-deficient mice were also susceptible to disease induction by MOG. The dispensability of MIP-1alpha and CCR5 for MOG-induced EAE in C57BL / 6 mice supports the idea that differential...

Human Cytomegalovirus Exploits Interferon-Induced Transmembrane Proteins To Facilitate Morphogenesis of the Virion Assembly Compartment

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Xie, Maorong; Xuan, Baoqin; Shan, Jiaoyu; Pan, Deng; Sun, Yamei; Shan, Zhao; Zhang, Jinping; Yu, Dong

2014-01-01

ABSTRACT Recently, interferon-induced transmembrane proteins (IFITMs) have been identified to be key effector molecules in the host type I interferon defense system. The invasion of host cells by a large range of RNA viruses is inhibited by IFITMs during the entry step. However, the roles of IFITMs in DNA virus infections have not been studied in detail. In this study, we report that human cytomegalovirus (HCMV), a large human DNA virus, exploits IFITMs to facilitate the formation of the virion assembly compartment (vAC) during infection of human fibroblasts. We found that IFITMs were expressed constitutively in human embryonic lung fibroblasts (MRC5 cells). HCMV infection inhibited IFITM protein accumulation in the later stages of infection. Overexpression of an IFITM protein in MRC5 cells slightly enhanced HCMV production and knockdown of IFITMs by RNA interference reduced the virus titer by about 100-fold on day 8 postinfection, according to the findings of a virus yield assay at a low multiplicity of infection. Virus gene expression and DNA synthesis were not affected, but the typical round structure of the vAC was not formed after the suppression of IFITMs, thereby resulting in defective virion assembly and the production of less infectious virion particles. Interestingly, the replication of herpes simplex virus, a human herpesvirus that is closely related to HCMV, was not affected by the suppression of IFITMs in MRC5 cells. These results indicate that IFITMs are involved in a specific pathway required for HCMV replication. IMPORTANCE HCMV is known to repurpose the interferon-stimulated genes (ISGs) viperin and tetherin to facilitate its replication. Our results expand the range of ISGs that can be exploited by HCMV for its replication. This is also the first report of a proviral function of IFITMs in DNA virus replication. In addition, whereas previous studies showed that IFITMs modulate virus entry, which is a very early stage in the virus life cycle, we

Therapeutic effectiveness of biosimilar standard interferon versus pegylated interferon for chronic hepatitis C genotypes 2 or 3

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Aline Gonzalez Vigani

Full Text Available BACKGROUND: Pegylated interferon (Peg-IFN and standard interferon (IFN play a significant role in the treatment of hepatitis C virus (HCV infection. Biosimilar standard IFN is widely available in Brazil for the treatment of HCV infection genotypes 2 or 3, but its efficacy compared to Peg-IFN is unknown. OBJECTIVE: To compare the sustained virological response (SVR rates following treatment with biosimilar standard IFN plus ribavirin (RBV versus Peg-IFN plus RBV in patients with HCV genotypes 2 or 3 infection. METHODS: A retrospective cohort study was conducted in patients with HCV genotypes 2 or 3 infection treated with biosimilar standard IFN plus RBV or with Peg-IFN plus RBV. SVR rates of the two treatments were compared. RESULTS: From January 2005 to December 2010, 172 patients with a mean age of 44 +/- 9.3 years were included. There were eight (4.7% patients with HCV genotype 2 infections. One hundred fourteen (66.3% were treated with biosimilar standard IFN plus RBV, whist 58 (33.7% patients were treated with Peg-IFN plus RBV. Between the two groups, there were no significant differences regarding age, gender, glucose level, platelet count, hepatic necroinflammatory grade, and hepatic fibrosis stage. Overall, 59.3% (102/172 patients had SVR. In patients treated with Peg-IFN plus RBV, 79.3% (46/58 had SVR compared to 49.1% (56/114 among those treated with biosimilar standard IFN plus RBV (p = 0.0001. CONCLUSION: In patients with HCV genotypes 2 or 3 infection, a higher SVR was observed in patients receiving Peg-IFN plus RBV related to patients treated with biosimilar standard IFN plus RBV.

Gender effects on treatment response to interferon-beta in multiple sclerosis

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Magyari, M; Koch-Henriksen, N; Laursen, B

2014-01-01

BACKGROUND: Gender appears to play a role in incidence and disease course of multiple sclerosis (MS). OBJECTIVE: The objective was to determine whether male and female patients with MS respond differently to interferon-beta treatment in terms of reduction in relapse rates. METHODS: We included all....... Patients served as their own controls, and relapse rates were compared between NAb-negative and NAb-positive periods. RESULTS: NAbs significantly abrogated the interferon-beta treatment efficacy in both genders. The all-over women:men relapse rate ratio irrespective of NAb status was 1.47 (95%CI; 1.......28-1.68). In a generalized linear Poisson models analysis with relapse counts as response variable, the main effects NAbs, sex, age at treatment start and number of relapses in 2 years before treatment start were strongly significant, but the effect of NAbs on relapse rates did not differ significantly between men and women...

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

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Sena, Armando; Bendtzen, Klaus; Cascais, Maria J

2010-01-01

for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta.......-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting...

Specific Interferon-¿ detection for the diagnosis of previous Q fever

NARCIS (Netherlands)

Schoffelen, T.; Joosten, L.A.; Herremans, T.; Haan, A.F.J.; Ammerdorffer, A.; Rumke, H.C.; Wijkmans, C.; Roest, H.I.J.; Netea, M.G.; Meer, van der J.W.; Sprong, T.; Deuren, van M.

2013-01-01

BACKGROUND: Current practice for diagnosis of Q fever, caused by the intracellular pathogen Coxiella burnetii, relies mainly on serology and, in prevaccination assessment, on skin tests (STs), which both have drawbacks. In this study, C. burnetii-specific interferon ¿ (IFN-¿) production was used as

Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry.

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Calès, P; Zarski, J P; Chapplain, J Marc; Bertrais, S; Sturm, N; Michelet, C; Babany, G; Chaigneau, J; Eddine Charaf, M

2012-02-01

We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) ≥ 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage. © 2011 Blackwell Publishing Ltd.

Evasion of interferon responses by Ebola and Marburg viruses.

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Basler, Christopher F; Amarasinghe, Gaya K

2009-09-01

The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), cause frequently lethal viral hemorrhagic fever. These infections induce potent cytokine production, yet these host responses fail to prevent systemic virus replication. Consistent with this, filoviruses have been found to encode proteins VP35 and VP24 that block host interferon (IFN)-alpha/beta production and inhibit signaling downstream of the IFN-alpha/beta and the IFN-gamma receptors, respectively. VP35, which is a component of the viral nucleocapsid complex and plays an essential role in viral RNA synthesis, acts as a pseudosubstrate for the cellular kinases IKK-epsilon and TBK-1, which phosphorylate and activate interferon regulatory factor 3 (IRF-3) and interferon regulatory factor 7 (IRF-7). VP35 also promotes SUMOylation of IRF-7, repressing IFN gene transcription. In addition, VP35 is a dsRNA-binding protein, and mutations that disrupt dsRNA binding impair VP35 IFN-antagonist activity while leaving its RNA replication functions intact. The phenotypes of recombinant EBOV bearing mutant VP35s unable to inhibit IFN-alpha/beta demonstrate that VP35 IFN-antagonist activity is critical for full virulence of these lethal pathogens. The structure of the VP35 dsRNA-binding domain, which has recently become available, is expected to provide insight into how VP35 IFN-antagonist and dsRNA-binding functions are related. The EBOV VP24 protein inhibits IFN signaling through an interaction with select host cell karyopherin-alpha proteins, preventing the nuclear import of otherwise activated STAT1. It remains to be determined to what extent VP24 may also modulate the nuclear import of other host cell factors and to what extent this may influence the outcome of infection. Notably, the Marburg virus VP24 protein does not detectably block STAT1 nuclear import, and, unlike EBOV, MARV infection inhibits STAT1 and STAT2 phosphorylation. Thus, despite their similarities, there are fundamental differences by which

DMPD: The role of the interferon regulatory factor (IRF) family in dendritic celldevelopment and function. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17702640 The role of the interferon regulatory factor (IRF) family in dendritic celldevelopment and function...in dendritic celldevelopment and function. PubmedID 17702640 Title The role of th...e interferon regulatory factor (IRF) family in dendritic celldevelopment and function. Authors Gabriele L, O

Association of a Network of Interferon-Stimulated Genes with a Locus Encoding a Negative Regulator of Non-conventional IKK Kinases and IFNB1

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Saloua Jeidane

2016-10-01

Full Text Available Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL linked in trans to the expression of 190 gene transcripts and in cis to the expression of only two genes, one of which was Ypel5. Most of the trans-expression QTL genes were interferon-stimulated genes (ISGs, and their expression in mouse macrophage cell lines was stimulated in an IFNB1-dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE. We thus found that the Ypel5 gene (contained in a locus linked to a network of ISGs in mice is a negative regulator of IFNB1 production and innate immune responses that interacts functionally and physically with TBK1/IKBKE kinases.

Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses.

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Majoros, Andrea; Platanitis, Ekaterini; Kernbauer-Hölzl, Elisabeth; Rosebrock, Felix; Müller, Mathias; Decker, Thomas

2017-01-01

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported. These include kinase-independent JAK functions as well as extra- and intranuclear activities of U-STATs without phosphotyrosines. Additionally, transcriptional control by STAT complexes resembling neither GAF nor ISGF3 contributes to transcriptome changes in IFN-treated cells. Our review summarizes the contribution of non-canonical JAK-STAT signaling to the innate antimicrobial immunity imparted by IFN. Moreover, we touch upon functions of IFN pathway proteins beyond the IFN response. These include metabolic functions of IRF9 as well as the regulation of natural killer cell activity by kinase-dead TYK2 and different phosphorylation isoforms of STAT1.

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon

International Nuclear Information System (INIS)

Dunst, Jeurgen; Heansgen, Gabriele; Lautenschleager, Christine; Feuchsel, Glenn; Becker, Axel

1999-01-01

Purpose: We have evaluated the tumor tissue pO 2 in cervical cancers during radiotherapy with special emphasis on the course of the pO 2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-α-2a. Methods and Materials: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitve radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO 2 with an Eppendorf pO 2 -histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-α-2a (IFN-α-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-α-2a in a dosage of 6 x 10 6 I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3 x 10 6 I.U. IFN-α-2a subcutaneously three times weekly until the end of the radiation treatment). pO 2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. Results: A poor oxygenation defined as a median pO 2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO 2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO 2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO 2 from 6.0 ± 3.1 mm Hg to 20.7 ± 21.2 mm Hg was found, p 2 was more pronounced in patients with radiotherapy plus additional cRA/IFN treatment as compared to patients treated

Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus

Science.gov (United States)

Rajan, Bhargavi; Zerrouki, Kamelia; Karnell, Jodi L; Sagar, Divya; Vainshtein, Inna; Farmer, Erika; Rosenthal, Kimberly; Morehouse, Chris; de los Reyes, Melissa; Schifferli, Kevin; Liang, Meina; Sanjuan, Miguel A; Sims, Gary P; Kolbeck, Roland

2018-01-01

Objective We investigated the mechanistic and pharmacological properties of anifrolumab, a fully human, effector-null, anti-type I interferon (IFN) alpha receptor 1 (IFNAR1) monoclonal antibody in development for SLE. Methods IFNAR1 surface expression and internalisation on human monocytes before and after exposure to anifrolumab were assessed using confocal microscopy and flow cytometry. The effects of anifrolumab on type I IFN pathway activation were assessed using signal transducer and activator of transcription 1 (STAT1) phosphorylation, IFN-stimulated response element–luciferase reporter cell assays and type I IFN gene signature induction. The ability of anifrolumab to inhibit plasmacytoid dendritic cell (pDC) function and plasma cell differentiation was assessed by flow cytometry and ELISA. Effector-null properties of anifrolumab were assessed in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays with B cells. Results Anifrolumab reduced cell surface IFNAR1 by eliciting IFNAR1 internalisation. Anifrolumab blocked type I IFN-dependent STAT1 phosphorylation and IFN-dependent signalling induced by recombinant and pDC-derived type I IFNs and serum of patients with SLE. Anifrolumab suppressed type I IFN production by blocking the type I IFN autoamplification loop and inhibited proinflammatory cytokine induction and the upregulation of costimulatory molecules on stimulated pDCs. Blockade of IFNAR1 suppressed plasma cell differentiation in pDC/B cell co-cultures. Anifrolumab did not exhibit CDC or ADCC activity. Conclusions Anifrolumab potently inhibits type I IFN-dependent signalling, including the type I IFN autoamplification loop, and is a promising therapeutic for patients with SLE and other diseases that exhibit chronic dysfunctional type I IFN signalling. PMID:29644082

Hepatitis B, interferon, and acne fulminans in a young girl

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Sandeep Arora

2016-01-01

Full Text Available Acne fulminans (AF is a very rare severe form of acne seen in young males, characterized by a sudden and explosive onset of hemorrhagic pustules and ulceration on the trunk, systemic features in the form of fever, polyarthropathy, malaise, erythema nodosum and painful osteolytic bone involvement with leukocytosis, and an elevated erythrocyte sedimentation rate. Conventional treatment of AF includes corticosteroids or immunosuppressive agents for the initial phase followed by isotretinoin. Active hepatitis B infection with a high viral load precludes the administration of any immunosuppressive drugs. We present the case of an 18-year-old girl with a history of occasional acne who presented with AF of sudden onset following administration of interferon-alpha-2a for her recently detected hepatitis B infection. Management of hepatitis B was withheld in view of her general condition. The patient was managed with low dose isotretinoin with subsidence of lesions. AF in a young female precipitated by interferon and its management with isotretinoin in the presence of active hepatitis B infection make the case unique.

Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation

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Sheng Li

2016-06-01

Full Text Available Background: Type I interferons (IFN-α/β have broad and potent immunoregulatory and antiproliferative activities. However, it is still known whether the dietary flavonoids exhibit their antiviral and anticancer properties by modulating the function of type I IFNs. Objective: This study aimed at determining the role of apigenin, a dietary plant flavonoid abundant in common fruits and vegetables, on the type I IFN-mediated inhibition of cancer cell viability. Design: Inhibitory effect of apigenin on human 26S proteasome, a known negative regulator of type I IFN signaling, was evaluated in vitro. Molecular docking was conducted to know the interaction between apigenin and subunits of 26S proteasome. Effects of apigenin on JAK/STAT pathway, 26S proteasome-mediated interferon receptor stability, and cancer cells viability were also investigated. Results: Apigenin was identified to be a potent inhibitor of human 26S proteasome in a cell-based assay. Apigenin inhibited the chymotrypsin-like, caspase-like, and trypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Results from computational modeling of the potential interactions of apigenin with the chymotrypsin site (β5 subunit, caspase site (β1 subunit, and trypsin site (β2 subunit of the proteasome were consistent with the observed proteasome inhibitory activity. Apigenin enhanced the phosphorylation of signal transducer and activator of transcription proteins (STAT1 and STAT2 and promoted the endogenous IFN-α-regulated gene expression. Apigenin inhibited the IFN-α-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1. Apigenin also sensitized the inhibitory effect of IFN-α on viability of cervical carcinoma HeLa cells. Conclusion: These results suggest that apigenin potentiates the inhibitory effect of IFN-α on cancer cell viability by activating JAK/STAT signaling pathway through inhibition of 26S

Regulatory T cells and other lymphocyte subpopulations in patients with melanoma developing interferon-induced thyroiditis during high-dose interferon-α2b treatment.

Science.gov (United States)

Soldevila, Berta; Alonso, Núria; Martínez-Arconada, Maria J; Granada, Maria L; Boada, Aram; Vallejos, Virginia; Fraile, Manuel; Fernández-Sanmartín, Marco A; Pujol-Borrell, Ricardo; Puig-Domingo, Manel; Sanmartí, Anna; Martínez-Cáceres, Eva M

2013-04-01

One of the side effects of interferon-alpha therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined. Our objective was to assess different peripheral blood lymphocyte subpopulations, mainly regulatory T cells (Tregs), in melanoma patients who developed IIT. From 30 melanoma patients receiving high-dose interferon (HDI)-alpha 2b (IFN-α2b) treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-MM) and healthy controls (Co-H). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment and at appearance of IIT (TT). Nine patients developed IIT (30%): four Hashimoto's thyroiditis and five destructive thyroiditis. An increase in Tregs was observed in both melanoma groups during HDI treatment. A decrease in CD3(+) , NKT lymphocyte subpopulations and Bcl2 expression on B cells was also observed in both groups. However, no changes were observed in the percentage of CD4(+) , CD8(+) , CD3(+) γδ(+) , CD19(+) , transitional B cells (CD24(high) CD38(high) CD19(+) CD27(-) ), natural killer (NK), invariant NKT (iNKT) lymphocytes and Th1/Th2 balance when BT was compared with ET. At TT, IIT patients had a higher Tregs percentage than Co-MM (P = 0·012) and Co-H (P = 0·004), a higher iNKT percentage than Co-MM (P = 0·011), a higher transitional B cells percentage than Co-H (P = 0·015), a lower CD3(+) percentage than Co-H (P = 0·001) and a lower Bcl2 expression on B cells than Co-H (P < 0·001). Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Tregs in melanoma patients who developed IIT. © 2012 Blackwell Publishing Ltd.

Alveolar macrophage–derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes

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Goritzka, Michelle; Makris, Spyridon; Kausar, Fahima; Durant, Lydia R.; Pereira, Catherine; Kumagai, Yutaro; Culley, Fiona J.; Mack, Matthias; Akira, Shizuo

2015-01-01

Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)–coupled retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN–dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN–mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation. PMID:25897172

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

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Burchert, A; Saussele, S; Eigendorff, E; Müller, M C; Sohlbach, K; Inselmann, S; Schütz, C; Metzelder, S K; Ziermann, J; Kostrewa, P; Hoffmann, J; Hehlmann, R; Neubauer, A; Hochhaus, A

2015-06-01

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

A Successful Induction of Lactation in Surrogate Pregnancy with Metoclopramide and Review of Lactation Induction

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Elahe Mirzaaga

2010-01-01

Full Text Available In surrogate pregnancies genetic parents have little opportunity for early bonding with their infants,either prenatally (in utero or during the immediate postnatal period. Procedures commonlyused to induce lactation include both pharmacologic and nonpharmacologic methods, often incombination. Studies reporting induced lactation are sparse, due to the rarity of augmentedlactation. Here we report a case of lactation induction following a surrogate pregnancy. Othermethods that can be used to augment lactation are described below. We used metoclopramide inthis case due to the success rates reported in previous studies and case reports. Additionally, itis a well tolerated and safe agent.

Role of reactive oxygen intermediates in the interferon-mediated depression of hepatic drug metabolism and protective effect of N-acetylcysteine in mice.

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Ghezzi, P; Bianchi, M; Gianera, L; Landolfo, S; Salmona, M

1985-08-01

Interferon (IFN) and IFN inducers are known to depress hepatic microsomal cytochrome P-450 levels, and the liver toxicity of IFN was reported to be lethal in newborn mice. We have observed that administration to mice of IFN and IFN inducers caused a marked increase in liver xanthine oxidase activity. Because this enzyme is well known to produce reactive oxygen intermediates and cytochrome P-450 was reported to be sensitive to the oxidative damage, we have tested the hypothesis that a free radical mechanism could mediate the depression of cytochrome P-450 levels by IFN. Administration to mice of the IFN inducer polyinosinic-polycytidylic acid (2 mg/kg i.p.) caused a 29 to 52% decrease in liver cytochrome P-450. Concomitant p.o. administration of the free radical scavenger, N-acetylcysteine (as a 2.5% solution in drinking water), or the xanthine oxidase inhibitor, allopurinol (100 mg/kg), protected against the IFN-mediated depression of P-450 kg), protected against the IFN-mediated depression of P-450 levels. The results suggest that an increased endogenous generation of free radicals, possibly due to the induction of xanthine oxidase, is implicated in the IFN-mediated depression of liver drug metabolism. The relevance of these data also extends to cases in which this side effect is observed in pathological situations (e.g., viral diseases and administration of vaccines) associated with an induction of IFN.

Induction machine handbook

CERN Document Server

Boldea, Ion

2002-01-01

Often called the workhorse of industry, the advent of power electronics and advances in digital control are transforming the induction motor into the racehorse of industrial motion control. Now, the classic texts on induction machines are nearly three decades old, while more recent books on electric motors lack the necessary depth and detail on induction machines.The Induction Machine Handbook fills industry's long-standing need for a comprehensive treatise embracing the many intricate facets of induction machine analysis and design. Moving gradually from simple to complex and from standard to

Concurrent autoimmune hepatitis and grave's disease in hepatitis C during pegylated interferon α-2a and ribavirin therapy.

Science.gov (United States)

Trikudanathan, Guru V; Ahmad, Imad; Israel, Jonathan L

2011-01-01

Classical interferon-α has been shown to be associated with the development of a variety of autoimmune disorders. A 34-year-old white woman with chronic hepatitis C virus infection who was treated with pegylated interferon α-2a and ribavirin, developed Grave's disease and autoimmune hepatitis (AIH) at 32 and 44 weeks, respectively, following initiation of the therapy. The diagnosis of AIH was made based on the new development of anti-smooth muscle antibodies, anti-mitochondrial antibodies, and liver biopsy findings. It was confirmed by positive response to steroid challenge and was assessed according to the international AIH scoring system. Based on the previous case reports, we review the existing literature. Clinicians should be aware of the possibility of multiple autoimmune disorders during interferon-based therapy for chronic hepatitis.

Sustained major molecular response on interferon alpha-2b in two patients with polycythemia vera

DEFF Research Database (Denmark)

Larsen, Thomas Stauffer; Bjerrum, O W; Pallisgaard, N

2008-01-01

Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia chromos...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response....

Potential for all-trans retinoic acid (tretinoin) to enhance interferon-alpha treatment response in chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma.

Science.gov (United States)

Kast, Richard E

2008-10-01

This note mechanistically accounts for recent unexplained findings that all-trans retinoic acid (ATRA, also termed tretinoin) exerts an anti-viral effect against hepatitis C virus (HCV) in chronically infected patients, in whom ATRA also showed synergy with interferon-alpha. How HCV replication was suppressed was unclear. Both effects of ATRA can be accounted for by ATRA's upregulation of RIG protein, an 18 kDa product of retinoic induced gene-1. Increased RIG then couples ATRA to increased Type 1 interferons' production. Details of this mechanism predict that ATRA will similarly augment interferon-a activity in treating chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma and that the addition of ribavirin and/or bexarotene will each incrementally enhance interferon-a responses in these cancers.

Pulmonary berylliosis. Experimental induction. Early detection

International Nuclear Information System (INIS)

Andre, Stephane

1984-01-01

This research thesis reports the study of the biological reactivity of industrial and environmental aerosols, notably beryllium powder aerosols. In order to study beryllium toxicity under its metal form, and the dose-effect relationship and the suspected carcinogen effect, a pulmonary berylliosis has been experimentally induced in rat and monkey. In order to develop means of rapid detection of exposure and sensitisation to beryllium, the author studied early pathological cellular mechanisms occurring during a pulmonary granulomatosis. Quantitative and qualitative modifications have been searched for, more particularly at the level of endo-alveolar cellular populations of macrophages and lymphocytes. The study has also been extended to the sensitisation of lymphocytes with respect to beryllium. After some generalities about beryllium (properties, sources, uses, exposure sources), and an overview of its toxicity (epidemiology, pathologies, experiments, biological mechanisms, detoxification), the author reports the introduction of a chronic pulmonary berylliosis into animals, discusses the various noticed pathologies and their analysis, and reports in situ and in vitro studies [fr

IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP

NARCIS (Netherlands)

Jønsson, K L; Laustsen, A; Krapp, C; Skipper, K A; Thavachelvam, K; Hotter, D; Egedal, J H; Kjolby, M; Mohammadi, P; Prabakaran, T; Sørensen, L K; Sun, C; Jensen, S B; Holm, C K; Lebbink, R J; Johannsen, M; Nyegaard, M; Mikkelsen, J G; Kirchhoff, F; Paludan, S R; Jakobsen, M R

2017-01-01

Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other

Enterovirus 2Apro targets MDA5 and MAVS in infected cells

NARCIS (Netherlands)

Feng, Q.; Langereis, M.A.; Lork, M.; Nguyen, M.H.; Hato, S.V.; Lanke, K.H.W.; Emdad, L.; Bhoopathi, P.; Fisher, P.B.; Lloyd, R.E.; Kuppeveld, F.J.M. van

2014-01-01

RIG-I-like receptors (RLRs) MDA5 and RIG-I are key players in the innate antiviral response. Upon recognition of viral RNA, they interact with MAVS, eventually inducing type I interferon production. The interferon induction pathway is commonly targeted by viruses. How enteroviruses suppress

Enterovirus 2Apro targets MDA5 and MAVS in infected cells

NARCIS (Netherlands)

Feng, Qian; Langereis, Martijn A; Lork, Marie; Nguyen, Mai; Hato, Stanleyson V; Lanke, Kjerstin; Emdad, Luni; Bhoopathi, Praveen; Fisher, Paul B; Lloyd, Richard E; van Kuppeveld, Frank J M

2014-01-01

UNLABELLED: RIG-I-like receptors (RLRs) MDA5 and RIG-I are key players in the innate antiviral response. Upon recognition of viral RNA, they interact with MAVS, eventually inducing type I interferon production. The interferon induction pathway is commonly targeted by viruses. How enteroviruses

INTERFERON BETA IN TREATMENT OF DISSEMINATED SCLEROSIS IN ADOLESCENTS — INFLUENCE ON NEUROPSYCHOLOGICAL STATUS AND PAROXYSMAL STATES

Directory of Open Access Journals (Sweden)

A.N. Platonova

2010-01-01

Full Text Available Disseminated sclerosis is chronic progressive disease of central nervous system, which is characterized by demyelination, degeneration of nerve fibers and polymorphous clinical symptoms. According to literature data, 2–10% of patients have onset of a disease in childhood and adolescence. Frequent clinical symptoms of disseminated sclerosis, especially in adolescents, are paroxysmal states and neuropsychological disorders. Drugs containing interferon beta which are used for immunomodulating treatment, can increase the rate of paroxysmal neuropsychological disorders in patients with disseminated sclerosis. Present study with participation of 78 adolescents analyzed frequency and spectrum of neuropsychological disorders and paroxysmal states in patients 12–17 years old and relation of revealed disorders with a treatment with interferon beta.Key words: adolescents, disseminated sclerosis, interferon beta, treatment, depression, paroxysmal states, anxiety, neuropsychological testing.(Voprosy sovremennoi pediatrii — Current Pediatrics. – 2010;9(4:34-39

The efficacy of intravitreal interferon alpha-2b for the treatment of experimental endotoxin-induced uveitis.

Science.gov (United States)

Afarid, Mehrdad; Lashkarizadeh, Hamid; Ashraf, Mohammad J; Nowroozzadeh, Mohammad Hossein; Shafiee, Sayed M

2016-05-01

To study the efficacy of intravitreal interferon alpha-2b for endotoxin-induced uveitis. A total of 36 rabbits were randomly allocated to one of the three groups: (1) received interferon plus balanced-salt solution; (2) received lipopolysaccharide (LPS) plus interferon; and (3) received LPS plus balanced-salt solution. Intraocular inflammation was evaluated by slit-lamp biomicroscopy (standardization of uveitis nomenclature grading), binocular indirect ophthalmoscopy (BIO) score, and histopathology. Group 2 showed significantly lower mean (±standard deviation) anterior chamber reaction than Group 3 (3.1 ± 0.9 vs. 3.8 ± 0.4) on day 1 postinjection, lower vitreous cells on days 1 through 7 (day 1: 3.1 ± 0.9 vs. 3.8 ± 0.4; day 3: 2.1 ± 1.6 vs. 3.8 ± 0.4; day 7: 1.9 ± 1.3 vs. 3.6 ± 0.7), and lower BIO score on days 1-7 (day 1: 3.3 ± 1.2 vs. 4.4 ± 0.7; day 3: 3.0 ± 1.4 vs. 4.3 ± 0.9; day 7: 2.4 ± 1.4 vs. 3.7 ± 1.2). The protein content of anterior and vitreous aspirates was lower in Group 2 than 3 (1618.5 ± 411.4 vs. 2567.3 ± 330.8 and 2157.0 ± 283.3 vs. 3204.6 ± 259.5, respectively). Intravitreal interferon alpha-2b was effective in controlling endotoxin-induced uveitis.

Re-emergence of interferon-α in the treatment of chronic myeloid leukemia

Science.gov (United States)

Talpaz, M; Hehlmann, R; Quintás-Cardama, A; Mercer, J; Cortes, J

2013-01-01

Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML. PMID:23238589

Deregulation of Interferon Signaling in Malignant Cells

Directory of Open Access Journals (Sweden)

Leonidas C. Platanias

2010-02-01

Full Text Available Interferons (IFNs are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs have been used extensively over the years, alone or in combination with other drugs, for the treatment of various malignancies. This review summarizes the current knowledge on IFN signaling components and pathways that are deregulated in human malignancies. The relevance of deregulation of IFN signaling pathways in defective innate immune surveillance and tumorigenesis are discussed.

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer.

Science.gov (United States)

Walter, Katherine R; Goodman, Merit L; Singhal, Hari; Hall, Jade A; Li, Tianbao; Holloran, Sean M; Trinca, Gloria M; Gibson, Katelin A; Jin, Victor X; Greene, Geoffrey L; Hagan, Christy R

2017-10-01

The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, Interferon (IFN)-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to IFN treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR's ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for IFN-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. IFN activation is a critical early step in nascent tumor recognition and destruction through immunosurveillance. As the large majority of breast tumors are PR positive at the time of diagnosis, PR-dependent downregulation of IFN signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors. Implications: This study highlights a novel transcriptional mechanism through which PR drives breast cancer development and potentially evades the immune system. Mol Cancer Res; 15(10); 1331-40. ©2017 AACR . ©2017 American Association for Cancer Research.

Induction of PLSCR1 in a STING/IRF3-dependent manner upon vector transfection in ovarian epithelial cells.

Directory of Open Access Journals (Sweden)

Karthik M Kodigepalli

Full Text Available Toll-like receptors (TLRs are the primary sensors of the innate immune system that recognize pathogenic nucleic acids including double-stranded plasmid DNA (dsDNA. TLR signaling activates multiple pathways including IRF3 which is involved in transcriptional induction of inflammatory cytokines (i.e. interferons (IFNs. Phospholipid scramblase 1, PLSCR1, is a highly inducible IFN-regulated gene mediating anti-viral properties of IFNs. Herein, we report a novel finding that dsDNA transfection in T80 immortalized normal ovarian surface epithelial cell line leads to a marked increase in PLSCR1 mRNA and protein. We also noted a comparable response in primary mammary epithelial cells (HMECs. Similar to IFN-2α treated cells, de novo synthesized PLSCR1 was localized predominantly to the plasma membrane. dsDNA transfection, in T80 and HMEC cells, led to activation of MAPK and IRF3. Although inhibition of MAPK (using U0126 did not modulate PLSCR1 mRNA and protein, IRF3 knockdown (using siRNA significantly ablated the PLSCR1 induction. In prior studies, the activation of IRF3 was shown to be mediated by cGAS-STING pathway. To investigate the contribution of STING to PLSCR1 induction, we utilized siRNA to reduce STING expression and observed that PLSCR1 protein was markedly reduced. In contrast to normal T80/HMECs, the phosphorylation of IRF3 as well as induction of STING and PLSCR1 were absent in ovarian cancer cells (serous, clear cell, and endometrioid suggesting that the STING/IRF3 pathway may be dysregulated in these cancer cells. However, we also noted induction of different TLR and IFN mRNAs between the T80 and HEY (serous epithelial ovarian carcinoma cell lines upon dsDNA transfection. Collectively, these results indicate that the STING/IRF3 pathway, activated following dsDNA transfection, contributes to upregulation of PLSCR1 in ovarian epithelial cells.

Increased expression of beta 2-microglobulin and histocompatibility antigens on human lymphoid cells induced by interferon

DEFF Research Database (Denmark)

Hokland, M; Heron, I; Berg, K

1982-01-01

Normal human peripheral blood lymphocytes were incubated in the presence of different concentrations of interferon for various incubation periods. Subsequently, the amount of beta 2-Microglobulin and HLA-A, B and C surface antigens was estimated by means of quantitative immunofluorescence (flow...... cytofluorometry) and by a radioimmunoassay for beta 2-Microglobulin. It was found that the amounts of these MHC antigens increased in a dose and time-dependent way after interferon treatment. Furthermore, the influence of different temperatures on this IFN-induced increase in beta 2-Microglobulin was gradually...

Interferon Action on Parental Semliki Forest Virus Ribonucleic Acid

Science.gov (United States)

Friedman, Robert M.; Fantes, Karl H.; Levy, Hilton B.; Carter, William B.

1967-01-01

Actinomycin D-treated chick fibroblasts were infected with purified 32P-labeled Semliki forest virus, and ribonucleic acid (RNA) was extracted after 1 or 2 hr. Within 1 hr, viral RNA forms sedimenting in sucrose gradients at 42S, 30S, and 16S were present. The 42S form corresponded to the RNA of the virion. The 16S form appeared to be a double-stranded template for the formation of new viral RNA, since nascent RNA was associated with it and the molecule could be heat-denatured and subsequently reannealed by slow cooling. Interferon treatment before infection, or puromycin (50 μg/ml) or cycloheximide (200 μg/ml) added at the time of virus infection, had no effect on the formation of the 30S RNA but inhibited the production of the 16S form. Several findings made it unlikely that these results were due to breakdown of parental RNA and reincorporation of 32P into progeny structures. The results suggested that the mechanism of interferon action involves inhibition of protein synthesis by parental viral RNA, since a specific viral RNA polymerase had previously been demonstrated to be necessary for production of 16S RNA. No protein synthesis appears necessary for formation of 30S RNA from parental virus RNA. PMID:5621488

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3.

Science.gov (United States)

Rabbani, M A G; Ribaudo, Michael; Guo, Ju-Tao; Barik, Sailen

2016-12-15

A major arm of cellular innate immunity is type I interferon (IFN), represented by IFN-α and IFN-β. Type I IFN transcriptionally induces a large number of cellular genes, collectively known as IFN-stimulated gene (ISG) proteins, which act as antivirals. The IFIT (interferon-induced proteins with tetratricopeptide repeats) family proteins constitute a major subclass of ISG proteins and are characterized by multiple tetratricopeptide repeats (TPRs). In this study, we have interrogated IFIT proteins for the ability to inhibit the growth of human parainfluenza virus type 3 (PIV3), a nonsegmented negative-strand RNA virus of the Paramyxoviridae family and a major cause of respiratory disease in children. We found that IFIT1 significantly inhibited PIV3, whereas IFIT2, IFIT3, and IFIT5 were less effective or not at all. In further screening a set of ISG proteins we discovered that several other such proteins also inhibited PIV3, including IFITM1, IDO (indoleamine 2,3-dioxygenase), PKR (protein kinase, RNA activated), and viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)/Cig5. The antiviral effect of IDO, the enzyme that catalyzes the first step of tryptophan degradation, could be counteracted by tryptophan. These results advance our knowledge of diverse ISG proteins functioning as antivirals and may provide novel approaches against PIV3. The innate immunity of the host, typified by interferon (IFN), is a major antiviral defense. IFN inhibits virus growth by inducing a large number of IFN-stimulated gene (ISG) proteins, several of which have been shown to have specific antiviral functions. Parainfluenza virus type 3 (PIV3) is major pathogen of children, and no reliable vaccine or specific antiviral against it currently exists. In this article, we report several ISG proteins that strongly inhibit PIV3 growth, the use of which may allow a better antiviral regimen targeting PIV3. Copyright © 2016, American Society for Microbiology

Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in Hepatitis C virus replicon

Directory of Open Access Journals (Sweden)

Luftig Ronald

2007-09-01

Full Text Available Abstract Background Alpha interferon in combination with ribavirin is the standard therapy for hepatitis C virus infection. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The mechanisms of IFN-resistance are unclear. The aim of this study was to determine the contribution of host cell factors to the mechanisms of interferon resistance using replicon cell lines. Results HCV replicons with high and low activation of the IFN-promoter were cultured for a prolonged period of time in the presence of interferon-alpha (IFN-alpha2b. Stable replicon cell lines with resistant phenotype were isolated and characterized by their ability to continue viral replication in the presence of IFN-alpha. Interferon resistant cell colonies developed only in replicons having lower activation of the IFN promoter and no resistant colonies arose from replicons that exhibit higher activation of the IFN promoter. Individual cell clones were isolated and nine IFN resistant cell lines were established. HCV RNA and protein levels in these cells were not altered by IFN- alpha2b. Reduced signaling and IFN-resistant phenotype was found in all Huh-7 cell lines even after eliminating HCV, suggesting that cellular factors are involved. Resistant phenotype in the replicons is not due to lack of interferon receptor expression. All the cell lines show defect in the JAK-STAT signaling and phosphorylation of STAT 1 and STAT 2 proteins were strongly inhibited due to reduced expression of Tyk2 and Jak-1 protein. Conclusion This in vitro study provides evidence that altered expression of the Jak-Stat signaling proteins can cause IFN resistance using HCV replicon cell clones.