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 ...

Role of interferon in resistance and immunity to protozoa

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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.

Diabetes is associated with lower tuberculosis antigen-specific interferon gamma release in Tanzanian tuberculosis patients and non-tuberculosis controls

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Faurholt-Jepsen, Daniel; Aabye, Martine Grosos; Jensen, Andreas Vestergaard

2014-01-01

in diabetes patients and therefore the validity of interferon gamma release assays (IGRA) may be compromised. The aim of the present study was to assess the association between diabetes and Mycobacterium tuberculosis (Mtb) antigen-specific interferon gamma (IFN-γ) release in a TB endemic area among culture......-confirmed TB patients and non-TB controls. Methods: Culture-confirmed pulmonary TB patients (n = 187) and healthy non-TB neighbourhood controls (n = 190) from Mwanza, Tanzania were tested for the presence of circulating T cells recognizing Mtb antigens using an IGRA. The diabetes status of all participants...

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.

Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses.

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Holm, Christian K; Rahbek, Stine H; Gad, Hans Henrik; Bak, Rasmus O; Jakobsen, Martin R; Jiang, Zhaozaho; Hansen, Anne Louise; Jensen, Simon K; Sun, Chenglong; Thomsen, Martin K; Laustsen, Anders; Nielsen, Camilla G; Severinsen, Kasper; Xiong, Yingluo; Burdette, Dara L; Hornung, Veit; Lebbink, Robert Jan; Duch, Mogens; Fitzgerald, Katherine A; Bahrami, Shervin; Mikkelsen, Jakob Giehm; Hartmann, Rune; Paludan, Søren R

2016-02-19

Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

The use of recombinant omega interferon therapy in canine atopic dermatitis: a double-blind controlled study.

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Carlotti, Didier Noël; Boulet, Marc; Ducret, Joël; Machicote, Gustavo; Jasmin, Pierre; Rème, Christophe A; Albouy, Maxime

2009-10-01

This double-blind controlled study assessed whether reduced doses of omega interferon (rFeIFN-omega) (Virbagen Omega) could improve the clinical signs of canine atopic dermatitis (CAD) over a 6-month period, in comparison with cyclosporin. Thirty-one dogs diagnosed with CAD were entered in the study. Complicating infections were treated prior to entry. Dogs received 10 injections of rFeIFN-omega (1-5 million units according to bodyweight) or placebo over 6 months, and placebo capsules or cyclosporin (5 mg/kg) once daily for 2 months and then twice weekly for 4 months in groups 1 and 2 respectively. Flea control, non-medicated shampooing and ear cleansing were performed regularly. If a bacterial infection or Malassezia overgrowth developed, it was treated with oral cephalexin or with 3% chlorhexidine shampoo respectively. Oral prednisolone was used before day 90 to relieve pruritus when required for humane reasons (1 mg/kg once daily for 7 days). The CADESI-03 and a pruritus index were evaluated on day (D) 0, D14, D35, D56, D90, D120 and D180. No significant difference was detected between the groups for the time courses of lesions or pruritus over 6 months. On D90, the proportions of dogs with > or =50% improvement of pruritus and lesion scores were 56% and 72% respectively with interferon, 75% and 75% respectively with cyclosporin. Five dogs from group 1 and two dogs from group 2 were withdrawn from the study for treatment failure. Both products were well tolerated. Treatment with rfeIFN-omega at low doses may help for the long-term management of CAD.

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)

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

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.

Bropirimine inhibits osteoclast differentiation through production of interferon-β

International Nuclear Information System (INIS)

Suzuki, Hiroaki; Mochizuki, Ayako; Yoshimura, Kentaro; Miyamoto, Yoichi; Kaneko, Kotaro; Inoue, Tomio; Chikazu, Daichi; Takami, Masamichi; Kamijo, Ryutaro

2015-01-01

Bropirimine is a synthetic agonist for toll-like receptor 7 (TLR7). In this study, we investigated the effects of bropirimine on differentiation and bone-resorbing activity of osteoclasts in vitro. Bropirimine inhibited osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) induced by receptor activator of nuclear factor κB ligand (RANKL) in a concentration-dependent manner. Furthermore, it suppressed the mRNA expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), a master transcription factor for osteoclast differentiation, without affecting BMM viability. Bropirimine also inhibited osteoclast differentiation induced in co-cultures of mouse bone marrow cells (BMCs) and mouse osteoblastic UAMS-32 cells in the presence of activated vitamin D_3. Bropirimine partially suppressed the expression of RANKL mRNA in UAMS-32 cells induced by activated vitamin D_3. Finally, the anti-interferon-β (IFN-β) antibody restored RANKL-dependent differentiation of BMMs into osteoclasts suppressed by bropirimine. These results suggest that bropirimine inhibits differentiation of osteoclast precursor cells into osteoclasts via TLR7-mediated production of IFN-β.

Bropirimine inhibits osteoclast differentiation through production of interferon-β

Energy Technology Data Exchange (ETDEWEB)

Suzuki, Hiroaki [Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555 (Japan); Mochizuki, Ayako [Department of Oral Physiology, Showa University School of Dentistry, Tokyo 142-8555 (Japan); Yoshimura, Kentaro; Miyamoto, Yoichi [Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555 (Japan); Kaneko, Kotaro [Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555 (Japan); Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo 160-0023 (Japan); Inoue, Tomio [Department of Oral Physiology, Showa University School of Dentistry, Tokyo 142-8555 (Japan); Chikazu, Daichi [Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo 160-0023 (Japan); Takami, Masamichi [Department of Pharmacology, Showa University School of Dentistry, Tokyo 142-8555 (Japan); Kamijo, Ryutaro, E-mail: kamijor@dent.showa-u.ac.jp [Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555 (Japan)

2015-11-06

Bropirimine is a synthetic agonist for toll-like receptor 7 (TLR7). In this study, we investigated the effects of bropirimine on differentiation and bone-resorbing activity of osteoclasts in vitro. Bropirimine inhibited osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) induced by receptor activator of nuclear factor κB ligand (RANKL) in a concentration-dependent manner. Furthermore, it suppressed the mRNA expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), a master transcription factor for osteoclast differentiation, without affecting BMM viability. Bropirimine also inhibited osteoclast differentiation induced in co-cultures of mouse bone marrow cells (BMCs) and mouse osteoblastic UAMS-32 cells in the presence of activated vitamin D{sub 3}. Bropirimine partially suppressed the expression of RANKL mRNA in UAMS-32 cells induced by activated vitamin D{sub 3}. Finally, the anti-interferon-β (IFN-β) antibody restored RANKL-dependent differentiation of BMMs into osteoclasts suppressed by bropirimine. These results suggest that bropirimine inhibits differentiation of osteoclast precursor cells into osteoclasts via TLR7-mediated production of IFN-β.

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.

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.

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.

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.

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.

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.

The immunomodulatory effects of interferon-gamma on mature B-lymphocyte responses.

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Jurado, A; Carballido, J; Griffel, H; Hochkeppel, H K; Wetzel, G D

1989-06-15

Interferon-gamma (IFN-gamma) exerts a broad spectrum of activities which affect the responses of mature B-cells. It strongly inhibits B-cell activation, acts as a B-cell growth factor (BCGF), and also induces final differentiation to immunoglobulin (Ig) production. IFN-gamma is deeply involved in the differential control of isotype expression, as it enhances IgG2a production and suppresses both IgG1 and IgE production. Although it is now possible to draw a general scheme of the effects of IFN-gamma on B-cells, a number of paradoxical results still exist in the field. In this manuscript, different experimental systems are analyzed in an attempt to explain these apparent paradoxes.

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.

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

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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...

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

Ribavirin plus interferon versus interferon for chronic hepatitis C

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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....

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

Interleukin-4 and interferon-¿ production by Leishmania stimulated peripheral blood mononuclear cells from nonexposed individuals

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Kurtzhals, J A; Kemp, M; Poulsen, L K

1995-01-01

of antigen stimulation suggesting a response due to antigen recognition. Both IL-4 and IFN-gamma production was abrogated by depletion of CD2+ or CD4+ but not CD8+ cells. CD2+ or CD4+ but not CD8+ enriched cultures produced cytokines as unseparated PBMC. Thus, in non-exposed individuals circulating...... call for studies of the importance of cytokine production by cross-reactive T cells for the outcome of L. donovani infections in humans and show that the method for IL-4 detection is useful for this purpose.......Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) production by Leishmania reactive peripheral blood mononuclear cells (PBMC) from non-exposed individuals was investigated. IFN-gamma was measured in culture supernatants after antigen stimulation. For the measurement of IL-4, antigen stimulated...

Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

International Nuclear Information System (INIS)

Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

2008-01-01

Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1

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.

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...

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.

Science.gov (United States)

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.

DMPD: Type I interferon [corrected] gene induction by the interferon regulatory factorfamily of transcription factors. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 16979567 Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...ng) (.svg) (.html) (.csml) Show Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...orrected] gene induction by the interferon regulatory factorfamily of transcription factors. Authors Honda K

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

DEFF Research Database (Denmark)

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...

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

Interferons: between structure and function

Directory of Open Access Journals (Sweden)

Katarzyna Bandurska

2014-05-01

Full Text Available Interferons are a family of proteins that are released by a variety of cells in response to infections caused by viruses. Currently, we distinguish three types of interferons. They are classified based on the nucleotide sequence, interaction with specific receptors, chromosomal location, structure and physicochemical properties. The following interferons are classified as type I: α, β, ω, κ, ε, ζ, τ, δ, ν. They are recognized and bound by a receptor formed by two peptides, IFN-αR1 and IFN-αR2. Representative of type II interferons is interferon-γ. It binds to a receptor composed of chains IFNGR-1 and IFNGR-2. The recently classified type III interferons comprise IFN-λ1, IFN-λ2, and IFN-λ3. They act on receptors formed by λR1 IFN-and IL-10R2 subunits. A high level of antiviral protection is achieved by IFN-α, IFN-β and IFN-λ. Antiviral activity of interferons is based on the induction and regulation of innate and acquired immune mechanisms. By binding to transmembrane receptors, IFN interacts with target cells mainly by activating the JAK/STAT, but also other signaling pathways. This leads to induction and activation of many antiviral agents, such as protein kinase RNA-activated (PKR, ribonuclease 2-5A pathway, and Mx proteins, as well as numerous apoptotic pathways. As a result of the protective effect of interferons, the virus binding to cells and viral particles penetration into cells is stopped, and the release of the nucleocapsid from an envelope is suppressed. Disruption of transcription and translation processes of the structural proteins prevents the formation of virions or budding of viruses, and as a result degradation of the viral mRNA; the started processes inhibit the chain synthesis of viral proteins and therefore further stimulate the immune system cells.

Human gamma interferon production by cytotoxic T lymphocytes sensitized during hepatitis A virus infection

International Nuclear Information System (INIS)

Maier, K.; Gabriel, P.; Koscielniak, E.; Stierhof, Y.D.; Wiedmann, K.H.; Flehmig, B.; Vallbracht, A.

1988-01-01

The production of interferon (IFN) during a chromium-51 release assay with hepatitis A virus (HAV)-infected fibroblasts and autologous peripheral blood lymphocytes from patients with acute HAV infection was studied to determine whether IFN plays a role in immunopathogenesis of hepatitis A infection in humans. Skin fibroblasts of eight patients after acute HAV infection and from two control persons without history of current of past HAV infection were infected with HAV. Peripheral blood lymphocytes were collected at different times after the onset of icterus and tested in a chromium-51 release assay against autologous HAV-infected skin fibroblasts for their cytolytic and IFN-producing activity. The IFN produced during the assay was characterized and found to have the properties of human gamma IFN. Cytotoxicity and gamma IFN release were virus specific. The cell types responsible for both functions were characterized and found to be in the HLA-dependent T8 + lymphocyte subset. Considering that gamma IFN has an antiviral effect on persistent HAV infection in vitro and that it probably accounts for stimulation of HLA class I antigen expression on hepatocytes, these experimental results presented here demonstrate that human gamma IFN produced by HAV-specific T cells may participate in pathogenesis of hepatitis A infection in humans

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

Energy Technology Data Exchange (ETDEWEB)

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.

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....

Porcine deltacoronavirus nsp5 inhibits interferon-β production through the cleavage of NEMO.

Science.gov (United States)

Zhu, Xinyu; Fang, Liurong; Wang, Dang; Yang, Yuting; Chen, Jiyao; Ye, Xu; Foda, Mohamed Frahat; Xiao, Shaobo

2017-02-01

Porcine deltacoronavirus (PDCoV) causes acute enteric disease and mortality in seronegative neonatal piglets. Previously we have demonstrated that PDCoV infection suppresses the production of interferon-beta (IFN-β), while the detailed mechanisms are poorly understood. Here, we demonstrate that nonstructural protein 5 (nsp5) of PDCoV, the 3C-like protease, significantly inhibits Sendai virus (SEV)-induced IFN-β production by targeting the NF-κB essential modulator (NEMO), confirmed by the diminished function of NEMO cleaved by PDCoV. The PDCoV nsp5 cleavage site in the NEMO protein was identified as glutamine 231, and was identical to the porcine epidemic diarrhea virus nsp5 cleavage site, revealing the likelihood of a common target in NEMO for coronaviruses. Furthermore, this cleavage impaired the ability of NEMO to activate the IFN response and downstream signaling. Taken together, our findings reveal PDCoV nsp5 to be a newly identified IFN antagonist and enhance the understanding of immune evasion by deltacoronaviruses. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

No Love Lost Between Viruses and Interferons.

Science.gov (United States)

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.

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

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

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.

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.

Zika virus inhibits type‐I interferon production and downstream signaling

OpenAIRE

Kumar, Anil; Hou, Shangmei; Airo, Adriana M; Limonta, Daniel; Mancinelli, Valeria; Branton, William; Power, Christopher; Hobman, Tom C

2016-01-01

Zika virus is an emerging mosquito‐borne pathogen that is associated with Guillain–Barré syndrome in adults and microcephaly and other neurological defects in newborns. Despite being declared an international emergency by the World Health Organization, comparatively little is known about its biology. Here, we investigate the strategies employed by the virus to suppress the host antiviral response. We observe that once established, Zika virus infection is impervious to interferon treatment sug...

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.

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)

Interferon-¿ and interleukin-4 production by human T cells recognizing Leishmania donovani antigens separated by SDS-PAGE

DEFF Research Database (Denmark)

Bahrenscheer, J; Kemp, M; Kurtzhals, J A

1995-01-01

of proliferation and interferon-gamma (IFN-gamma) production in cultures of peripheral blood mononuclear cells (PBMC) from individuals who had recovered from visceral leishmaniasis caused by L. donovani. The release of interleukin-4 (IL-4) by PBMC stimulated with the isolated L. donovani antigen fractions...... was measured after treatment with phorbol-myristate-acetate and ionomycin. The cells proliferated in response to all protein fractions with molecular weights in the range production...... was infrequently observed. The results show that T cells from individuals who have been cured of visceral leishmaniasis recognize and respond to a wide range of leishmanial antigens. There was no evidence of particular fractions constantly giving either IFN-gamma or IL-4-producing responses....

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...

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)

Type 1 Diabetes and Interferon Therapy

OpenAIRE

Nakamura, Kan; Kawasaki, Eiji; Imagawa, Akihisa; Awata, Takuya; Ikegami, Hiroshi; Uchigata, Yasuko; Kobayashi, Tetsuro; Shimada, Akira; Nakanishi, Koji; Makino, Hideichi; Maruyama, Taro; Hanafusa, Toshiaki

2011-01-01

OBJECTIVE Interferon therapy can trigger induction of several autoimmune diseases, including type 1 diabetes. To assess the clinical, immunologic, and genetic characteristics of type 1 diabetes induced by interferon therapy, we conducted a nationwide cross-sectional survey. RESEARCH DESIGN AND METHODS Clinical characteristics, anti-islet autoantibodies, and HLA-DR typing were examined in 91 patients for whom type 1 diabetes developed during or shortly after interferon therapy. RESULTS Median ...

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.

Treatment profile of hepatitis C patients - a comparison of interferon alpha 2a and 2b treatment regimes

International Nuclear Information System (INIS)

Aziz, S.; Rajper, J.; Nafay, S.; Imran, K.; Khan, M.H.

2010-01-01

To compare the side effects, cost, end treatment response (ETR) and Sustained viral response (SVR) with combination therapy of either interferon alpha 2a or 2b in combination with Ribavarin. Study Design: Randomized Control Clinical Trial (RCCT). Place and Duration of Study: The study was conducted at Sarwar Zuberi Liver Centre (SZLC), Civil Hospital Karachi (CHK), from May 2004 to July 2009. Methodology: Patients positive for qualitative HCV ribonucleic acid (RNA) by Polymerase chain reaction (PCR) and genotype 3 were included. Patients with decompensated cirrhosis, severe depressive illness, autoimmune hepatitis, hyperthyroidism, pregnancy, heart failure, uncontrolled diabetes, obstructive pulmonary disease, children less than three years and patients who had previously received treatment were excluded. Single blind randomization using computerized randomization list was done and patients divided into groups A and B, those requiring treatment were given injection Interferon 3 million units (MU) subcutaneously (SC) three times/week and Ribavarin 1000 mg per day (weight greater or equal to 75kg) and 1200 mg/day (weight > 75kg) orally with either interferon alpha 2a (group A; FDA approved products) or alpha 2b (group B; non FDA approved product). Demographics, side effects, ETR and SVR were noted. ETR was defined as absence of virus at the end of treatment and SVR was taken as absence of HCV RNA at 6 months after completion of treatment. Results: There were a total 310 patients with mean age of 34.07 +- 9.38 years including 52.4% males, (n=162). Majority of the patients were from North Pakistan. There were 155 patients each in group A and group B respectively. The cost of treatment for interferon alpha for a single patient for 6 months was Rs 60,000, while for Interferon alpha 2b was Rs 30,000. Side effects (fever initially, followed by fatigue, headache, musculoskeletal pain, depression, alopecia, insomnia, and anorexia) were more prominent in group B when compared

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

Diminished interferon-gamma production and responsiveness after endotoxin administration to healthy humans

NARCIS (Netherlands)

Weijer, Sebastiaan; Lauw, Fanny N.; Branger, Judith; van den Blink, Bernt; van der Poll, Tom

2002-01-01

To obtain insight in the capacity of the lipopolysaccharide (LPS)-tolerant host to produce interferon (IFN)-gamma and to respond to this cytokine, whole blood was obtained from healthy humans before and 4 h after intravenous injection of LPS (4 ng/kg) and stimulated ex vivo. LPS exposure in vivo

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

Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-alpha therapy.

Science.gov (United States)

Fekkes, Durk; Van Gool, Arthur R; Bannink, Marjolein; Sleijfer, Stefan; Kruit, Wim H J; van der Holt, Bronno; Eggermont, Alexander M M; Hengeveld, Michiel W; Stoter, Gerrit

2009-10-01

Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-alpha (IFN-alpha). Animal studies showed that IFN-alpha administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H(2)O(2) generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-alpha. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-alpha, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-alpha are unlikely to contribute to definite psychiatric disturbance.

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

Science.gov (United States)

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.

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.

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-alpha suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.

LENUS (Irish Health Repository)

Tajuddin, Tariq

2012-02-01

BACKGROUND AND AIM: Neutropenia, a major side-effect of interferon-alpha (IFN-alpha) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G-CSF), an important growth factor for neutrophils. We hypothesized that IFN-alpha might suppress G-CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll-like receptor (TLR) agonist might overcome this suppression. METHODS: Fifty-five patients who were receiving IFN-alpha\\/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G-CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme-linked immunosorbent assay following 18 h of culture in the absence or presence of IFN- alpha or the TLR7\\/8 agonist, CL097. RESULTS: Therapeutic IFN-alpha caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G-CSF. The reduction in ANC over the course of IFN-alpha treatment was paralleled by a decrease in the ability of PBMCs to produce G-CSF. In vitro G-CSF production by PBMCs was suppressed in the presence of IFN-alpha; however, co-incubation with a TLR7\\/8 agonist significantly enhanced G-CSF secretion by cells obtained both from HCV patients and healthy controls. CONCLUSIONS: Suppressed G-CSF production in the presence of IFN-alpha may contribute to IFN-alpha-induced neutropenia. However, a TLR7\\/8 agonist elicits G-CSF secretion even in the presence of IFN-alpha, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-alpha-induced neutropenia.

Interferon alpha for the adjuvant treatment of cutaneous melanoma.

Science.gov (United States)

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

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.

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

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...

Production of interferon-¿ and interleukin-4 by human T cells recognizing Leishmania lipophosphoglycan-associated protein

DEFF Research Database (Denmark)

Kemp, M; Kurtzhals, J A; Christensen, C B

1993-01-01

The Leishmania protein LPGAP which is co-isolated with lipophosphoglycan is a specific activator of T cells from individuals who have recovered from American leishmaniasis. We have tested the effect of LPGAP on peripheral blood mononuclear cells (PBMC) from Kenyan donors cured from L. donovani in....... The results show that both IFN-gamma producing (Th1-like) and IL-4 producing (Th2-like) T cells recognizing LPGAP are expanded after infection with L. donovani in humans....... infections. LPGAP induced vigorous proliferation and production of interferon-gamma (IFN-gamma) by the cells. In addition PBMC incubated with LPGAP released interleukin-4 (IL-4) after pulsing with ionomycin and phorbol myristate acetate. Single cells were isolated from LPGAP-stimulated cell lines...

Diagnosis of Coxiella burnetii infection: comparison of a whole blood interferon-gamma production assay and a Coxiella ELISPOT.

Directory of Open Access Journals (Sweden)

Teske Schoffelen

Full Text Available Diagnosis of ongoing or past infection with Coxiella burnetii, the causative agent of Q fever, relies heavily on serology: the measurement of C. burnetii-specific antibodies, reflecting the host's humoral immune response. However, cell-mediated immune responses play an important, probably even more relevant, role in infections caused by the intracellular C. burnetii bacterium. Recent studies have investigated interferon-gamma (IFN-γ based assays, including a whole-blood IFN-γ production assay and a Coxiella enzyme-linked immunospot (Coxiella ELISPOT, as potential diagnostic tools for Q fever diagnosis. Both are in-house developed assays using stimulating antigens of different origin. The main objective of this study was to compare the test performance of the IFN-γ production assay and the Coxiella ELISPOT for detecting a cellular immune response to C. burnetii in Q fever patients, and to assess the correlation between both assays. To that end, both tests were performed in a well-defined patient group of chronic Q fever patients (n = 16 and a group of healthy seronegative individuals (n = 17. Among patients, both the Coxiella ELISPOT and the IFN-γ production assay detected positive response in 14/16. Among controls, none were positive in the Coxiella ELISPOT, whereas the IFN-γ production assay detected positive results in 1/17 and 3/17, when using Henzerling and Nine Mile as stimulating antigens, respectively. These results suggest the Coxiella ELISPOT has a somewhat higher specificity than the IFN-γ production assay when Nine Mile is used as antigen stimulus. The assays showed moderate correlation: the Spearman correlation coefficient r ranged between 0.37-0.60, depending on the antigens used. Further investigation of the diagnostic potential for C. burnetii infection of both assays is warranted.

Interferon-alpha in the treatment of multiple myeloma

DEFF Research Database (Denmark)

Khoo, T.L.; Joshua, D.; Gibson, J.

2011-01-01

Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the hematological malignancy multiple myeloma. Interferon has been used......-induction agent with other chemotherapy regimens, and as maintenance therapy after conventional chemotherapy or complete remission after autologous or allogeneic transplantation. Interferon as a single induction agent or co-induction agent with other chemotherapy agents appears only to have minimal benefit...... in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs" - thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment...

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

Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR -/- ) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR -/- ) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR -/- λR -/- mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the

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.

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

Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-a therapy

NARCIS (Netherlands)

D. Fekkes (Durk); A.R. van Gool (Arthur); M. Bannink (Marjolein); S. Sleijfer (Stefan); W.H.J. Kruit (Wim); B. van der Holt (Bronno); A.M.M. Eggermont (Alexander); M.W. Hengeveld (Michiel); G. Stoter (Gerrit)

2009-01-01

textabstractAbstract Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-alpha (IFN-alpha). Animal studies showed that IFN-alpha administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases

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)

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.

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

Directory of Open Access Journals (Sweden)

Florian Douam

2017-08-01

Full Text Available Yellow fever virus (YFV is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β signaling and type II interferon (IFN-γ signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ integrates into this antiviral system. Here, we report that while wild-type (WT and IFN-λ receptor knockout (λR−/− mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR−/− mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB. α/βR−/− λR−/− mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity.

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

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 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.

beta. -endorphin augments the cytolytic activity and interferon production of natural killer cells

Energy Technology Data Exchange (ETDEWEB)

Mandler, R.N.; Biddison, W.E.; Mandler, R.; Serrate, S.A.

1986-02-01

The in vitro effects of the neurohormone ..beta..-endorphin (b-end) on natural killer (NK) activity and interferon (IFN) production mediated by large granular lymphocytes (LGL) were investigated. LGL-enriched fractions from peripheral blood mononuclear cells (PBMC) from normal human volunteers were obtained by fractionation over discontinuous Percoll gradients. LGL were preincubated with or without various concentrations of b-end or the closely related peptides ..cap alpha..-endorphin (a-end), ..gamma..-endorphin (g-end), or D-ALA/sub 2/-..beta..-endorphin (D-ALA/sub 2/-b-end), a synthetic b-end analogue. NK activity was assayed on /sup 51/Cr-labeled K562 target cells. Preincubation of LGL effectors (but not K562 targets) for 2 to 18 hr with concentrations of b-end between 10/sup -7/ M and 10/sup -10/ M produced significant augmentation of NK cytolytic activity (mean percentage increase: 63%). The classic opiate antagonist naloxone blocked the enhancing effect when used at a 100-fold molar excess relative to b-end. These findings demonstrate that b-end enhances NK activity and IFN production of purified LGL, and suggests that b-end might bind to an opioid receptor on LGL that can be blocked by naloxone. These results lend support to the concepts of regulation of the immune response by neurohormones and the functional relationship between the nervous and immune systems.

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 �

Design of an efficient medium for heterologous protein production in Yarrowia lipolytica: case of human interferon alpha 2b.

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Gasmi, Najla; Ayed, Atef; Nicaud, Jean-Marc; Kallel, Héla

2011-05-20

The non conventional yeast Yarrowia lipolytica has aroused a strong industrial interest for heterologous protein production. However most of the studies describing recombinant protein production by this yeast rely on the use of complex media, such media are not convenient for large scale production particularly for products intended for pharmaceutical applications. In addition medium composition can also affect the production yield. Hence it is necessary to design an efficient medium for therapeutic protein expression by this host. Five different media, including four minimal media and a complex medium, were assessed in shake flasks for the production of human interferon alpha 2b (hIFN α2b) by Y. lipolytica under the control of POX2 promoter inducible with oleic acid. The chemically defined medium SM4 formulated by Invitrogen for Pichia pastoris growth was the most suitable. Using statistical experimental design this medium was further optimized. The selected minimal medium consisting in SM4 supplemented with 10 mg/l FeCl₃, 1 g/l glutamate, 5 ml/l PTM1 (Pichia Trace Metals) solution and a vitamin solution composed of myo-inositol, thiamin and biotin was called GNY medium. Compared to shake flask, bioreactor culture in GNY medium resulted in 416-fold increase of hIFN α2b production and 2-fold increase of the biological activity. Furthermore, SM4 enrichment with 5 ml/l PTM1 solution contributed to protect hIFN α2b against the degradation by the 28 kDa protease identified by zymography gel in culture supernatant. The screening of the inhibitory effect of the trace elements present in PTM1 solution on the activity of this protease was achieved using a Box-Behnken design. Statistical data analysis showed that FeCl₃ and MnSO₄ had the most inhibitory effect. We have designed an efficient medium for large scale production of heterologous proteins by Y. lipolytica. The optimized medium GNY is suitable for the production of hIFN α2b with the advantage that no

The effect of beta-interferon therapy on myelin basic protein-elicited CD4+ T cell proliferation and cytokine production in multiple sclerosis

DEFF Research Database (Denmark)

Hedegaard, Chris J; Krakauer, Martin; Bendtzen, Klaus

2008-01-01

Interferon (IFN)-beta therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein...... (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-beta therapy. The MBP-elicited IFN-gamma-, TNF-alpha- and IL-10 production decreased during therapy (p...

[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

Eosinophils Regulate Interferon Alpha Production in Plasmacytoid Dendritic Cells Stimulated with Components of Neutrophil Extracellular Traps.

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Skrzeczynska-Moncznik, Joanna; Zabieglo, Katarzyna; Bossowski, Jozef P; Osiecka, Oktawia; Wlodarczyk, Agnieszka; Kapinska-Mrowiecka, Monika; Kwitniewski, Mateusz; Majewski, Pawel; Dubin, Adam; Cichy, Joanna

2017-03-01

Eosinophils constitute an important component of helminth immunity and are not only associated with various allergies but are also linked to autoinflammatory disorders, including the skin disease psoriasis. Here we demonstrate the functional relationship between eosinophils and plasmacytoid dendritic cells (pDCs) as related to skin diseases. We previously showed that pDCs colocalize with neutrophil extracellular traps (NETs) in psoriatic skin. Here we demonstrate that eosinophils are found in psoriatic skin near neutrophils and NETs, suggesting that pDC responses can be regulated by eosinophils. Eosinophils inhibited pDC function in vitro through a mechanism that did not involve cell contact but depended on soluble factors. In pDCs stimulated by specific NET components, eosinophil-conditioned media attenuated the production of interferon α (IFNα) but did not affect the maturation of pDCs as evidenced by the unaltered expression of the costimulatory molecules CD80 and CD86. As pDCs and IFNα play a key role in autoimmune skin inflammation, these data suggest that eosinophils may influence autoinflammatory responses through their impact on the production of IFNα by pDCs.

Peripheral Blood Cells from Patients with Autoimmune Addison's Disease Poorly Respond to Interferons In Vitro, Despite Elevated Serum Levels of Interferon-Inducible Chemokines

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Bjånesøy, Trine; Hellesen, Alexander; Breivik, Lars; Bakke, Marit; Husebye, Eystein S.; Bratland, Eirik

2015-01-01

Autoimmune Addison's disease (AAD) is a disorder caused by an immunological attack on the adrenal cortex. The interferon (IFN)-inducible chemokine CXCL10 is elevated in serum of AAD patients, suggesting a peripheral IFN signature. However, CXCL10 can also be induced in adrenocortical cells stimulated with IFNs, cytokines, or microbial components. We therefore investigated whether peripheral blood mononuclear cells (PBMCs) from AAD patients display an enhanced propensity to produce CXCL10 and the related chemokine CXCL9, after stimulation with type I or II IFNs or the IFN inducer poly (I:C). Although serum levels of CXCL10 and CXCL9 were significantly elevated in patients compared with controls, IFN stimulated patient PBMC produced significantly less CXCL10/CXCL9 than control PBMC. Low CXCL10 production was not significantly associated with medication, disease duration, or comorbidities, but the low production of poly (I:C)-induced CXCL10 among patients was associated with an AAD risk allele in the phosphatase nonreceptor type 22 (PTPN22) gene. PBMC levels of total STAT1 and -2, and IFN-induced phosphorylated STAT1 and -2, were not significantly different between patients and controls. We conclude that PBMC from patients with AAD are deficient in their response to IFNs, and that the adrenal cortex itself may be responsible for the increased serum levels of CXCL10. PMID:25978633

Peripheral Blood Cells from Patients with Autoimmune Addison's Disease Poorly Respond to Interferons In Vitro, Despite Elevated Serum Levels of Interferon-Inducible Chemokines.

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Edvardsen, Kine; Bjånesøy, Trine; Hellesen, Alexander; Breivik, Lars; Bakke, Marit; Husebye, Eystein S; Bratland, Eirik

2015-10-01

Autoimmune Addison's disease (AAD) is a disorder caused by an immunological attack on the adrenal cortex. The interferon (IFN)-inducible chemokine CXCL10 is elevated in serum of AAD patients, suggesting a peripheral IFN signature. However, CXCL10 can also be induced in adrenocortical cells stimulated with IFNs, cytokines, or microbial components. We therefore investigated whether peripheral blood mononuclear cells (PBMCs) from AAD patients display an enhanced propensity to produce CXCL10 and the related chemokine CXCL9, after stimulation with type I or II IFNs or the IFN inducer poly (I:C). Although serum levels of CXCL10 and CXCL9 were significantly elevated in patients compared with controls, IFN stimulated patient PBMC produced significantly less CXCL10/CXCL9 than control PBMC. Low CXCL10 production was not significantly associated with medication, disease duration, or comorbidities, but the low production of poly (I:C)-induced CXCL10 among patients was associated with an AAD risk allele in the phosphatase nonreceptor type 22 (PTPN22) gene. PBMC levels of total STAT1 and -2, and IFN-induced phosphorylated STAT1 and -2, were not significantly different between patients and controls. We conclude that PBMC from patients with AAD are deficient in their response to IFNs, and that the adrenal cortex itself may be responsible for the increased serum levels of CXCL10.

Specificity, cross-talk and adaptation in Interferon signaling

Science.gov (United States)

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.

Production of human interferon alfa 2b in plants of Nicotiana excelsior by Agrobacterium-mediated transient expression.

Science.gov (United States)

Sindarovska, Y R; Gerasymenko, I M; Sheludko, Y V; Olevinskaya, Z M; Spivak, N Y; Kuchuk, N V

2010-01-01

Human interferon alpha2b gene was transiently expressed in Nicotiana excelsior plants. Fusion with N. plumbaginifolia calreticulin signal peptide for improved apoplast targeting and carrying out the expression under optimized conditions resulted in maximal interferon activity of 3.2 x 10(3) IU/g fresh weight (FW) with an average of 2.1 +/- 0.8 x 10(3) IU/g FW. It proves that N. excelsior is a suitable host for Agrobacterium-mediated transient expression of genes encoding physiologically active human proteins. The transient expression conditions optimized for GFP marker protein were confirmed to be preferable for hIFN alpha2b.

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-γ and interleukin-17 production from PPD-stimulated PBMCss of patients with pulmonary tuberculosis.

Science.gov (United States)

Nunnari, Giuseppe; Pinzone, Marilia R; Vancheri, Carlo; Palermo, Filippo; Cacopardo, Bruno

2013-04-01

The purpose of this study was to evaluate Interferon (IFN)-γ and Interleukin(IL)-17 profiles in patients with different clinical presentations of pulmonary tuberculosis (TB) and to compare them with those of tuberculin-negative and tuberculin-reactive healthy controls Peripheral blood mononuclear cells (PBMCss), isolated from patients (n=52) and controls (n=30), were stimulated ex vivo with purified protein derivative (PPD) and IFN-γ and IL-17 levels in the supernatant were measured. At baseline, PBMCss from patients with TB released a significantly lower amount of IL-17 (p=0.043) than PBMCss from healthy controls, whereas IFN-γ levels were similar in the two groups. After PPD stimulation, a significant rise in IL-17 levels was found only among healthy controls (p=0.02). This rise in IL-17 levels was similar between tuberculin-reactive and tuberculin-negative subjects. After PPD stimulation, patients with infiltrative TB secreted higher levels of IL-17 and IFN-γ than those affected with chronic, miliary and cavitary TB (p PPD stimulation (p PPD stimulation of PBMCs from patients with pulmonary TB does not significantly stimulate IL-17 release; however, higher IL-17 and IFN-γ levels are found in patients with infiltrative disease, in comparison with those affected with miliary, cavitary and chronic TB.

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.

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....

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.

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

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

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.

Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1

Energy Technology Data Exchange (ETDEWEB)

Zhang, Qingzhan; Shi, Kaichuang; Yoo, Dongwan, E-mail: dyoo@illinois.edu

2016-02-15

Type I interferons (IFN-α/β) are the major components of the innate immune response of hosts, and in turn many viruses have evolved to modulate the host response during infection. We found that the IFN-β production was significantly suppressed during PEDV infection in cells. To identify viral IFN antagonists and to study their suppressive function, viral coding sequences for the entire structural and nonstructural proteins were cloned and expressed. Of 16 PEDV nonstructural proteins (nsps), nsp1, nsp3, nsp7, nsp14, nsp15 and nsp16 were found to inhibit the IFN-β and IRF3 promoter activities. The sole accessory protein ORF3, structure protein envelope (E), membrane (M), and nucleocapsid (N) protein were also shown to inhibit such activities. PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP) by degrading CBP. A further study showed that the CBP degradation by nsp1 was proteasome-dependent. Our data demonstrate that PEDV modulates the host innate immune responses by degrading CBP and suppressing ISGs expression. - Highlights: • PEDV modulates the host innate immune system by suppressing the type I interferon production and ISGs expression. • Ten viral proteins were identified as IFN antagonists, and nsp1 was the most potent viral IFN antagonist. • PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP). • PEDV nsp1 caused the CBP degradation in the nucleus, which may be the key mechanism for PEDV-mediated IFN downregulation.

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

In vitro inhibition of monkeypox virus production and spread by Interferon-β

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Johnston Sara C

2012-01-01

Full Text Available Abstract Background The Orthopoxvirus genus contains numerous virus species that are capable of causing disease in humans, including variola virus (the etiological agent of smallpox, monkeypox virus, cowpox virus, and vaccinia virus (the prototypical member of the genus. Monkeypox is a zoonotic disease that is endemic in the Democratic Republic of the Congo and is characterized by systemic lesion development and prominent lymphadenopathy. Like variola virus, monkeypox virus is a high priority pathogen for therapeutic development due to its potential to cause serious disease with significant health impacts after zoonotic, accidental, or deliberate introduction into a naïve population. Results The purpose of this study was to investigate the prophylactic and therapeutic potential of interferon-β (IFN-β for use against monkeypox virus. We found that treatment with human IFN-β results in a significant decrease in monkeypox virus production and spread in vitro. IFN-β substantially inhibited monkeypox virus when introduced 6-8 h post infection, revealing its potential for use as a therapeutic. IFN-β induced the expression of the antiviral protein MxA in infected cells, and constitutive expression of MxA was shown to inhibit monkeypox virus infection. Conclusions Our results demonstrate the successful inhibition of monkeypox virus using human IFN-β and suggest that IFN-β could potentially serve as a novel safe therapeutic for human monkeypox disease.

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.

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

STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control.

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Karoly Toth

2015-08-01

Full Text Available Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as

Interleukin 12 in part regulates gamma interferon release in human whole blood stimulated with Leptospira interrogans

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de Fost, Maaike; Hartskeerl, Rudy A.; Groenendijk, Martijn R.; van der Poll, Tom

2003-01-01

Heat-killed pathogenic Leptospira interrogans serovar rachmati induced the production of gamma interferon (IFN-gamma) and the IFN-gamma-inducing cytokines interleukin-12p40 (IL-12p40) and tumor necrosis factor alpha in human whole blood in vitro. The production of IFN-gamma was largely dependent on

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.

Activation of the human beta interferon gene by the adenovirus type 12 E1B gene

International Nuclear Information System (INIS)

Shiroki, K.; Toth, M.

1988-01-01

The transcription of endogenous beta interferon mRNA was activated in human embryo kidney (HEK) cells infected with adenovirus 12 (Ad12) but was activated only inefficiently or not at all in HEK cells infected with Ad5 and rc-1 (Ad5 dl312 containing the Ad12 E1A region). The analysis with Ad12 mutants showed that Ad12 E1B products, especially the 19K protein, were important for the expression of the endogenous beta interferon gene and Ad12 E1A products were not involved in the expression. The expression of exogeneously transfected pIFN-CAT (a hybrid plasmid having the human beta interferon promoter fused with the CAT gene) was activated in HEK and chicken embryo fibroblast (CEF) cells infected with either Ad12 or Ad5. The analysis of cotransfection of CEF cells with pIFN-CAT and plasmids containing fragments of Ad12 or Ad5 DNA showed that Ad12 or Ad5 E1B (possibly the 19K protein) was and E1A was not involved in the expression of the exogenous pIFN-CAT

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.

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.

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

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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

The interferon response to intracellular DNA: why so many receptors?

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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 alpha inhibits viral replication of a live-attenuated porcine reproductive and respiratory syndrome virus vaccine preventing development of an adaptive immune response in swine

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Type I interferons, such as interferon alpha (IFNa), contribute to innate antiviral immunity by promoting production of antiviral mediators and are also involved in promoting an adaptive immune response. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating and c...

Human umbilical cord-derived mesenchymal stem cells utilise Activin-A to suppress Interferon-gamma production by natural killer cells.

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Debanjana eChaterjee

2014-12-01

Full Text Available Following allogeneic hematopoietic stem cell transplantation (HSCT, interferon (IFN-gamma levels in the recipient’s body can strongly influence the clinical outcome. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs are lucrative as biological tolerance-inducers in HSCT settings. Hence, we studied the molecular mechanism of how UC-MSCs influence natural killer (NK cell-mediated IFN-gamma production. Allogeneic NK cells were cultured in direct contact with UC-MSCs or cell free supernatants from MSC cultures (MSC conditioned media. We found that soluble factors secreted by UC-MSCs strongly suppressed IL-12/IL-18-induced IFN-gamma production by NK cells by reducing phosphorylation of STAT4, NF-kB as well as T-bet activity. UC-MSCs secreted considerable amounts of Activin-A, which could suppress IFN-gamma production by NK cells. Neutralisation of Activin-A in MSC-conditioned media significantly abrogated their suppressive abilities. Till date, multiple groups have reported that prostaglandin (PG-E2 produced by MSCs can suppress NK cell functions. Indeed, we found that inhibition of PGE2 production by MSCs could also significantly restore IFN-gamma production. However, the effects of Activin-A and PGE2 were not cumulative. To the best of our knowledge, we are first to report the role of Activin-A in MSC-mediated suppression of IFN-gamma production by NK cells.

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

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.

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....

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.

Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus.

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Nogueira, Marcelle Almeida de Sousa; Gavioli, Camila Fátima Biancardi; Pereira, Nátalli Zanete; de Carvalho, Gabriel Costa; Domingues, Rosana; Aoki, Valéria; Sato, Maria Notomi

2015-04-01

Lichen planus (LP) is a common inflammatory skin disease of unknown etiology. Reports of a common transactivation of quiescent human endogenous retroviruses (HERVs) support the connection of viruses to the disease. HERVs are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancer and autoimmune diseases. We explored the transcriptional activity of HERV sequences as well as the antiviral restriction factor and interferon-inducible genes in the skin from LP patients and healthy control (HC) donors. The study included 13 skin biopsies from patients with LP and 12 controls. Real-time PCR assay identified significant decrease in the HERV-K gag and env mRNA expression levels in LP subjects, when compared to control group. The expressions of HERV-K18 and HERV-W env were also inhibited in the skin of LP patients. We observed a strong correlation between HERV-K gag with other HERV sequences, regardless the down-modulation of transcripts levels in LP group. In contrast, a significant up-regulation of the cytidine deaminase APOBEC 3G (apolipoprotein B mRNA-editing), and the GTPase MxA (Myxovirus resistance A) mRNA expression level was identified in the LP skin specimens. Other transcript expressions, such as the master regulator of type I interferon-dependent immune responses, STING (stimulator of interferon genes) and IRF-7 (interferon regulatory factor 7), IFN-β and the inflammassome NALP3, had increased levels in LP, when compared to HC group. Our study suggests that interferon-inducible factors, in addition to their role in innate immunity against exogenous pathogens, contribute to the immune control of HERVs. Evaluation of the balance between HERV and interferon-inducible factor expression could possibly contribute to surveillance of inflammatory/malignant status of skin diseases.

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

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

DEFF Research Database (Denmark)

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...

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

OpenAIRE

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 bee...

Porphyromonas gingivalis Promotes Unrestrained Type I Interferon Production by Dysregulating TAM Signaling via MYD88 Degradation.

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Mizraji, Gabriel; Nassar, Maria; Segev, Hadas; Sharawi, Hafiz; Eli-Berchoer, Luba; Capucha, Tal; Nir, Tsipora; Tabib, Yaara; Maimon, Avraham; Dishon, Shira; Shapira, Lior; Nussbaum, Gabriel; Wilensky, Asaf; Hovav, Avi-Hai

2017-01-10

Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial-induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I. Further examination revealed that the expression of certain TAM components was reduced as a result of prolonged degradation of MYD88 by the infection. As a result of such prolonged IFN-I production, innate immunological functions of the gingiva were disrupted, and CD4 + T cells were constitutively primed by dendritic cells, leading to elevated RANKL expression and, subsequently, alveolar bone loss (ABL). Blocking IFN-I signaling restored proper immunological function and prevented ABL. Importantly, a loss of negative regulation on IFN-I expression by TAM signaling was also evident in periodontitis patients. These findings thus suggest a role for IFN-I in the pathogenesis of periodontitis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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)....

Biochemical and Structural Insights into the Preference of Nairoviral DeISGylases for Interferon-Stimulated Gene Product 15 Originating from Certain Species

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Deaton, M. K.; Dzimianski, J. V.; Daczkowski, C. M.; Whitney, G. K.; Mank, N. J.; Parham, M. M.; Bergeron, E.; Pegan, S. D.; Perlman, S.

2016-07-13

The regulation of the interferon type I (IFN-I) response has been shown to rely on posttranslational modification by ubiquitin (Ub) and Ub-like interferon-stimulated gene product 15 (ISG15) to stabilize, or activate, a variety of IFN-I signaling and downstream effector proteins. Unlike Ub, which is almost perfectly conserved among eukaryotes, ISG15 is highly divergent, even among mammals. Since zoonotic viruses rely on viral proteins to recognize, or cleave, ISG15 conjugates in order to evade, or suppress, innate immunity, the impact of ISG15 biodiversity on deISGylating proteases of the ovarian tumor family (vOTU) from nairoviruses was evaluated. The enzymatic activities of vOTUs originating from the Crimean-Congo hemorrhagic fever virus, Erve virus, and Nairobi sheep disease virus were tested against ISG15s from humans, mice, shrews, sheep, bats, and camels, which are mammalian species known to be infected by nairoviruses. This along with investigation of binding by isothermal titration calorimetry illustrated significant differences in the abilities of nairovirus deISGylases to accommodate certain species of ISG15. To investigate the molecular underpinnings of species preferences of these vOTUs, a structure was determined to 2.5 Å for a complex of Erve virus vOTU protease and a mouse ISG15 domain. This structure revealed the molecular basis of Erve virus vOTU's preference for ISG15 over Ub and the first structural insight into a nonhuman ISG15. This structure also revealed key interactions, or lack thereof, surrounding three amino acids that may drive a viral deISgylase to prefer an ISG15 from one species over that of another.

IMPORTANCEViral ovarian tumor domain proteases (vOTUs) are one of the two principal classes of viral proteases observed to reverse posttranslational modification of host proteins by ubiquitin and interferon-stimulated gene product 15 (ISG15), subsequently facilitating downregulation of

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....

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-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.

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)

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.

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.

Gender effects on treatment response to interferon-beta in multiple sclerosis

DEFF Research Database (Denmark)

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...

Thymoquinone Suppresses IRF-3-Mediated Expression of Type I Interferons via Suppression of TBK1

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Nur Aziz

2018-05-01

Full Text Available Interferon regulatory factor (IRF-3 is known to have a critical role in viral and bacterial innate immune responses by regulating the production of type I interferon (IFN. Thymoquinone (TQ is a compound derived from black cumin (Nigella sativa L. and is known to regulate immune responses by affecting transcription factors associated with inflammation, including nuclear factor-κB (NF-κB and activator protein-1 (AP-1. However, the role of TQ in the IRF-3 signaling pathway has not been elucidated. In this study, we explored the molecular mechanism of TQ-dependent regulation of enzymes in IRF-3 signaling pathways using the lipopolysaccharide (LPS-stimulated murine macrophage-like RAW264.7 cell line. TQ decreased mRNA expression of the interferon genes IFN-α and IFN-β in these cells. This inhibition was due to its suppression of the transcriptional activation of IRF-3, as shown by inhibition of IRF-3 PRD (III-I luciferase activity as well as the phosphorylation pattern of IRF-3 in the immunoblotting experiment. Moreover, TQ targeted the autophosphorylation of TANK-binding kinase 1 (TBK1, an upstream key enzyme responsible for IRF-3 activation. Taken together, these findings suggest that TQ can downregulate IRF-3 activation via inhibition of TBK1, which would subsequently decrease the production of type I IFN. TQ also regulated IRF-3, one of the inflammatory transcription factors, providing a novel insight into its anti-inflammatory activities.

Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma

Energy Technology Data Exchange (ETDEWEB)

Basu, Partha, E-mail: BasuP@iarc.fr [Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, Lyon (France); Jenson, Alfred Bennett [James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (United States); Majhi, Tapas; Choudhury, Prabir [Department of Radiation Oncology, Chittaranjan National Cancer Institute, Kolkata (India); Mandal, Ranajit; Banerjee, Dipanwita [Department of Gynecological Oncology, Chittaranjan National Cancer Institute, Kolkata (India); Biswas, Jaydip [Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata (India); Pan, Jianmin; Rai, Shesh Nath; Ghim, Shin je; Miller, Donald [James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (United States)

2016-01-01

Purpose: Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer. Methods and Materials: Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10{sup 6} IU subcutaneously) 3 times a week for 4 weeks and daily RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m{sup 2}) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years. Results: Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy–related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths. Conclusions: Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The

Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery.

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Tsung-Hsien Chang

2009-06-01

Full Text Available Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs, suppressing production of type I interferons (IFNs while inducing the release of large quantities of proinflammatory cytokines. Although the viral VP35 protein has been shown to inhibit IFN responses, the mechanism by which it blocks IFN production has not been fully elucidated. We expressed VP35 from a mouse-adapted variant of Ebola Zaire virus in murine DCs by retroviral gene transfer, and tested for IFN transcription upon Newcastle Disease virus (NDV infection and toll-like receptor signaling. We found that VP35 inhibited IFN transcription in DCs following these stimuli by disabling the activity of IRF7, a transcription factor required for IFN transcription. By yeast two-hybrid screens and coimmunoprecipitation assays, we found that VP35 interacted with IRF7, Ubc9 and PIAS1. The latter two are the host SUMO E2 enzyme and E3 ligase, respectively. VP35, while not itself a SUMO ligase, increased PIAS1-mediated SUMOylation of IRF7, and repressed Ifn transcription. In contrast, VP35 did not interfere with the activation of NF-kappaB, which is required for induction of many proinflammatory cytokines. Our findings indicate that Ebola Zaire virus exploits the cellular SUMOylation machinery for its advantage and help to explain how the virus overcomes host innate defenses, causing rapidly overwhelming infection to produce a syndrome resembling fulminant septic shock.

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...

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...

Interferon-γ and proliferation responses to Salmonella enterica Serotype Typhi proteins in patients with S. Typhi Bacteremia in Dhaka, Bangladesh.

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Alaullah Sheikh

2011-06-01

Full Text Available Salmonella enterica serotype Typhi is a human-restricted intracellular pathogen and the cause of typhoid fever. Cellular immune responses are required to control and clear Salmonella infection. Despite this, there are limited data on cellular immune responses in humans infected with wild type S. Typhi.For this work, we used an automated approach to purify a subset of S. Typhi proteins identified in previous antibody-based immuno-affinity screens and antigens known to be expressed in vivo, including StaF-putative fimbrial protein-STY0202, StbB-fimbrial chaperone-STY0372, CsgF-involved in curli production-STY1177, CsgD- putative regulatory protein-STY1179, OppA-periplasmic oligopeptide binding protein precursor-STY1304, PagC-outer membrane invasion protein-STY1878, and conserved hypothetical protein-STY2195; we also generated and analyzed a crude membrane preparation of S. Typhi (MP. In comparison to samples collected from uninfected Bangladeshi and North American participants, we detected significant interferon-γ responses in PBMCs stimulated with MP, StaF, StbB, CsgF, CsgD, OppA, STY2195, and PagC in patients bacteremic with S. Typhi in Bangladesh. The majority of interferon-γ expressing T cells were CD4 cells, although CD8 responses also occurred. We also assessed cellular proliferation responses in bacteremic patients, and confirmed increased responses in infected individuals to MP, StaF, STY2195, and PagC in convalescent compared to acute phase samples and compared to controls. StaF is a fimbrial protein homologous to E. coli YadK, and contains a Pfam motif thought to be involved in cellular adhesion. PagC is expressed in vivo under the control of the virulence-associated PhoP-regulon required for intra-macrophage survival of Salmonella. STY2195 is a conserved hypothetical protein of unknown function.This is the first analysis of cellular immune responses to purified S. Typhi antigens in patients with typhoid fever. These results indicate

Strain differences in the somnogenic effects of interferon inducers in mice.

Science.gov (United States)

Toth, L A

1996-12-01

Increased slow-wave sleep accompanies influenza infection in C57BL/6 mice but not BALB/c mice. These strains of mice possess different alleles of the genetic lucus If-1, which codes for high (If-1h; C57BL/6) and low (If-1(1); BALB/c) production of interferon (IFN), a putative sleep-inducing cytokine. To evaluate the contribution of the If-1 gene to differences in murine sleep propensity, sleep patterns were evaluated in mice treated with the IFN inducers polyinosinic:polycytidilic acid (pIC) or Newcastle disease virus (NDV), with influenza virus, or with murine interferon (IFN-alpha) or IFN-alpha/beta. As compared with baseline values, C57BL/6 mice exhibited increased slow-wave sleep after all three challenges, but BALB/c mice did not. Congenic B6.C-H28c mice, which bear the BALB/c allele for low IFN production on the C57BL/6 genetic background, showed enhanced slow-wave sleep after influenza infection but not after NDV. Exogenous IFN did not enhance slow-wave sleep in either C57BL/6 or BALB/c mice. These data suggest that the If-1 allele may influence the somnogenic responsiveness of mice under some conditions but that additional mechanisms may contribute to sleep enhancement during infectious disease.

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.

Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling.

Science.gov (United States)

Melki, Isabelle; Rose, Yoann; Uggenti, Carolina; Van Eyck, Lien; Frémond, Marie-Louise; Kitabayashi, Naoki; Rice, Gillian I; Jenkinson, Emma M; Boulai, Anaïs; Jeremiah, Nadia; Gattorno, Marco; Volpi, Sefano; Sacco, Olivero; Terheggen-Lagro, Suzanne W J; Tiddens, Harm A W M; Meyts, Isabelle; Morren, Marie-Anne; De Haes, Petra; Wouters, Carine; Legius, Eric; Corveleyn, Anniek; Rieux-Laucat, Frederic; Bodemer, Christine; Callebaut, Isabelle; Rodero, Mathieu P; Crow, Yanick J

2017-08-01

Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI). We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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.

Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses.

Science.gov (United States)

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.

Is TB Testing Associated With Increased Blood Interferon-Gamma Levels?

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Aideen E. Kennedy

2017-10-01

Full Text Available The Republic of Ireland reports a relatively low prevalence of Johne’s disease (JD compared to international counterparts. Postulated reasons for this include a lower average herd size and a grass-based production system. Ireland also engages in high levels of bovine tuberculosis (bTB testing. As interferon-gamma (IFN-γ is believed to play a key role in protecting against JD, it is our hypothesis that administration of purified protein derivative (PPD, as part of the bTB test, is associated with a systemic increase in IFN-γ production, which may potentially limit clinical progression of the disease. We studied 265 cows (202 Friesian and 63 “Non-Friesian,” e.g., JerseyX, Norwegian Red to assess IFN-γ levels and Mycobacterium avium subspecies paratuberculosis (MAP antibody response before and after the bTB test. As part of the compulsory annual bTB test, avian and bovine PPD were administered at two separate cervical sites. To assess IFN-γ production, blood samples were taken before and 72 h after PPD administration. MAP antibody response was assessed before and 10 days post-PPD administration. A significant increase in MAP antibody response was identified post-bTB compared to pre-bTB response (p < 0.001. Additionally, IFN-γ production significantly increased at the post-bTB time point (p < 0.001 compared to the pre-bTB test readings. This may indicate a beneficial effect of bTB testing in controlling JD.

Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon

Science.gov (United States)

Akiyama, Hisashi; Ramirez, Nora-Guadalupe Pina; Gibson, Gregory; Kline, Christopher; Watkins, Simon; Ambrose, Zandrea

2017-01-01

ABSTRACT A hallmark of human immunodeficiency virus type 1 (HIV-1) infection in vivo is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicate in vivo via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4+ T cells in trans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in cis and CD4+ T cells in trans and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation in vivo, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27gag and CD169, suggesting productive infection of CD169+ myeloid cells in vivo. While cell-free HIV-1 infection of IFN-α-treated CD4+ T cells was robustly decreased, initiation of infection in trans via coculture with CD169+ IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in cis and in trans to attenuate a type I IFN-induced antiviral state. IMPORTANCE HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN

Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D2 Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species

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Ji-Yun Kim

2017-12-01

Full Text Available Prostaglandin D2 (PGD2 is a potent lipid mediator that controls inflammation, and its dysregulation has been implicated in diverse inflammatory disorders. Despite significant progress made in understanding the role of PGD2 as a key regulator of immune responses, the molecular mechanism underlying PGD2 production remains unclear, particularly upon challenge with different and multiple inflammatory stimuli. Interferons (IFNs potentiate macrophage activation and act in concert with exogenous inflammatory mediators such as toll-like receptor (TLR ligands to amplify inflammatory responses. A recent study found that IFN-γ enhanced lipopolysaccharide-induced PGD2 production, indicating a role of IFNs in PGD2 regulation. Here, we demonstrate that TLR-induced PGD2 production by macrophages was significantly potentiated by signaling common to IFN-β and IFN-γ in a signal transducer and activators of transcription (STAT1-dependent mechanism. Such potentiation by IFNs was also observed for PGE2 production, despite the differential regulation of PGD synthase and PGE synthase isoforms mediating PGD2 and PGE2 production under inflammatory conditions. Mechanistic analysis revealed that the generation of intracellular reactive oxygen species (ROS was remarkably potentiated by IFNs and required for PGD2 production, but was nullified by STAT1 deficiency. Conversely, the regulation of STAT1 level and activity by IFNs was largely dependent on ROS levels. Using a model of zymosan-induced peritonitis, the relevance of this finding in vivo was supported by marked inhibition of PGD2 and ROS produced in peritoneal exudate cells by STAT1 deficiency. Collectively, our findings suggest that IFNs, although not activating on their own, are potent amplifiers of TLR-induced PGD2 production via positive-feedback regulation between STAT1 and ROS.

The Poly-γ-D-Glutamic Acid Capsule of Bacillus licheniformis, a Surrogate of Bacillus anthracis Capsule Induces Interferon-Gamma Production in NK Cells through Interactions with Macrophages.

Science.gov (United States)

Lee, Hae-Ri; Jeon, Jun Ho; Rhie, Gi-Eun

2017-05-28

The poly-γ- D -glutamic acid (PGA) capsule, a major virulence factor of Bacillus anthracis , provides protection of the bacterium from phagocytosis and allows its unimpeded growth in the host. We investigated crosstalk between murine natural killer (NK) cells and macrophages stimulated with the PGA capsule of Bacillus licheniformis , a surrogate of the B. anthracis capsule. PGA induced interferon-gamma production from NK cells cultured with macrophages. This effect was dependent on macrophage-derived IL-12 and cell-cell contact interaction with macrophages through NK cell receptor NKG2D and its ligand RAE-1. The results showed that PGA could enhance NK cell activation by inducing IL-12 production in macrophages and a contact-dependent crosstalk with macrophages.

Transcriptional expression of type I interferon response genes and stability of housekeeping genes in the human endometrium and endometriosis

DEFF Research Database (Denmark)

Vestergaard, Anna L; Knudsen, Ulla B; Munk, Torben

2011-01-01

Endometriosis is a painful chronic female disease defined by the presence of endometrial tissue implants in ectopic locations. The pathogenesis is much debated, and type I interferons could be involved. The expression of genes of the type I interferon response were profiled by a specific PCR Array...... of RNA obtained from ectopic and eutopic endometrium collected from 9 endometriosis patients and 9 healthy control women. Transcriptional expression levels of selected interferon-regulated and housekeeping genes were investigated by real-time quantitative reverse transcriptase PCR (qRT-PCR). Stably...... expressed housekeeping genes for valid normalization of transcriptional studies of endometrium and endometriosis have not yet been published. Here, seven housekeeping genes were evaluated for stability using the GeNorm and NormFinder software. A normalization factor based on HMBS, TBP, and YWHAZ expression...

Interferon-induced changes in pharmacokinetics and tumor uptake of 111In-labeled antimelanoma antibody 96.5 in melanoma patients

International Nuclear Information System (INIS)

Rosenblum, M.G.; Lamki, L.M.; Murray, J.L.; Carlo, D.J.; Gutterman, J.U.

1988-01-01

The type I interferons [both partially purified human leukocyte interferon (HuIFN-alpha) and recombinant alpha interferon] and the type II interferons have been shown to increase the expression of tumor-associated antigens in vitro. To determine whether HuIFN-alpha could increase tumor acquisition of the antimelanoma antibody 96.5 in vivo, five patients with metastatic malignant melanoma were treated with HuIFN-alpha at a dose of 3 X 10(6) units daily by im administration. Twenty-four hours after the first dose of HuIFN-alpha, 1 mg of antibody 96.5 labeled with 5 mCi of 111 In was coadministered with 19 mg of unlabeled 96.5. Five patients matched for metastatic site and lesion size who had not received HuIFN-alpha were also given a dose of 5 mCi of radiolabeled 96.5 at the same total antibody dose (20 mg). In patients treated with HuIFN-alpha, there was a statistically significant increase in the plasma half-life of the 111 In label (39.7 +/- 3.3 hr) compared to the untreated control group (29.8 +/- 3.2 hr). In addition, there was an increase in the apparent volume of distribution of the antibody in the HuIFN-alpha group (5.56 +/- 0.67 L) compared to controls (3.15 +/- 0.5 L) suggesting both an increased immediate extravascular distribution of radiolabeled antibody and a decrease in the subsequent rate of clearance of antibody from plasma. These two phenomena result in a 28% decrease in the area under the concentration curve in the HuIFN-alpha-treated group compared to controls. Computer analysis of whole-body scans from patients showed a threefold increase in radiolabeled antibody distributed to tumor relative to blood pool but no change in organ:blood ratios for liver, spleen, bone, or kidney compared to controls

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.

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

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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.

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 ...

Simvastatin as add-on therapy to interferon β-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial

DEFF Research Database (Denmark)

Sorensen, Per Soelberg; Lycke, Jan; Erälinna, Juha-Pekka

2011-01-01

Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective. We aimed to establish whether add-on of simvastatin, a statin with anti-inflammatory properties, improves this efficacy.......Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective. We aimed to establish whether add-on of simvastatin, a statin with anti-inflammatory properties, improves this efficacy....

Interferon Induction by RNA Viruses and Antagonism by Viral Pathogens

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Yuchen Nan

2014-12-01

Full Text Available Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR. Host PRR for RNA viruses include Toll-like receptors (TLR and retinoic acid-inducible gene I (RIG-I like receptors (RLR. Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

Sphingosine kinase inhibitor suppresses IL-18-induced interferon-gamma production through inhibition of p38 MAPK activation in human NK cells

International Nuclear Information System (INIS)

Cheon, Soyoung; Song, Seok Bean; Jung, Minkyung; Park, Yoorim; Bang, Jung-Wook; Kim, Tae Sung; Park, Hyunjeong; Kim, Cherl-hyun; Yang, Yool-hee; Bang, Sa Ik; Cho, Daeho

2008-01-01

Natural killer (NK) cells play an important role in the innate immune response. Interleukin-18 (IL-18) is a well-known interferon-gamma (IFN-γ inducing factor, which stimulates immune response in NK and T cells. Sphingosine kinase (SPHK) catalyzes the formation of sphingosine 1-phosphate (S1P), which acts as a second messenger to function as an anti-apoptotic factor and proliferation stimulator of immune cells. In this study, to elucidate whether SPHK is involved in IL-18-induced IFN-γ production, we measured IL-18-induced IFN-γ production after pre-treatment with SPHK inhibitor (SKI) in NK-92MI cells. We found that IL-18-induced IFN-γ expression was blocked by SKI pre-treatment in both mRNA and protein levels. In addition, the increased IFN-γ production by stimulation with IL-18 is mediated through both SPHK and p38 MAPK. To determine the upstream signals of SKI and p38 MAPK in IL-18-induced IFN-γ production, phosphorylation levels of p38 MAPK was measured after SKI pre-treatment. As a result, inhibition of SPHK by SKI blocked phosphorylation of p38 MAPK, showing that SPHK activation by IL-18 is an upstream signal of p38 MAPK activation. Inhibition of SPHK by SKI also inhibited IL-18-induced IFN-γ production in human primary NK cells. In conclusion, SPHK activation is an essential factor for IL-18-induced IFN-γ production via p38 MAPK

[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.

Retinoic Acid Modulates Interferon-γ Production by Hepatic Natural Killer T Cells via Phosphatase 2A and the Extracellular Signal-Regulated Kinase Pathway

Science.gov (United States)

Chang, Heng-Kwei

2015-01-01

Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune function, such as defending against infections and immune regulation. Although RA affects various types of immune cells, including antigen-presenting cells, B lymphocytes, and T lymphocytes, whether it affects natural killer T (NKT) cells remain unknown. In this study, we found that RA decreased interferon (IFN)-γ production by activated NKT cells through T-cell receptor (TCR) and CD28. We also found that RA reduced extracellular signal-regulated kinase (ERK) phosphorylation, but increased phosphatase 2A (PP2A) activity in TCR/CD28-stimulated NKT cells. The increased PP2A activity, at least partly, contributed to the reduction of ERK phosphorylation. Since inhibition of ERK activation decreases IFN-γ production by TCR/CD28-stimulated NKT cells, RA may downregulate IFN-γ production by TCR/CD28-stimulated NKT cells through the PP2A-ERK pathway. Our results demonstrated a novel function of RA in modulating the IFN-γ expression by activated NKT cells. PMID:25343668

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 effect of alpha-interferon on bone marrow megakaryocytes and platelet production rate in essential thrombocythemia

International Nuclear Information System (INIS)

Wadenvik, H.; Kutti, J.; Ridell, B.; Revesz, P.; Jacobsson, S.; Magnusson, B.; Westin, J.; Vilen, L.

1991-01-01

In 10 patients with previously untreated essential thrombocythemia (ET), by using 111 In-labeled platelets and megakaryocyte morphometry, the relation between platelet production rate and bone marrow megakaryocytes was evaluated before and during alpha-2b-interferon (IFN) therapy. A highly significant decrease in platelet count occurred during IFN therapy; the platelet counts, at baseline and after 2 and 6 months of IFN therapy, were 1,102 +/- 345 x 10(9)/L, 524 +/- 169 x 10(9)/L (P less than .0001), and 476 +/- 139 x 10(9)/L (P less than .0001), respectively. The decrement in platelet count was mainly a result of diminished platelet production rate, which at baseline and after 2 and 6 months of IFN therapy was 89 +/- 30 x 10(10) platelets/d, 53 +/- 18 x 10(10) platelets/d (P = .0033), and 45 +/- 20 x 10(10) platelets/d (P less than .0001), respectively. Also, a slight shortening of platelet mean life-span (MLS) was observed in response to IFN treatment; platelet MLS was 7.96 +/- 0.69 days at baseline and 6.68 +/- 1.30 days (P = .012) after 6 months of IFN therapy. IFN induced a significant decrease in bone marrow megakaryocyte volume; both megakaryocyte nuclear and cytoplasmatic volumes were affected. The mean megakaryocyte volume was 372 +/- 126 x 10(2) pL/microL at baseline and 278 +/- 147 x 10(2) pL/microL (P = .049) after 6 months of IFN therapy. However, the number of megakaryocytes did not show any significant change in response to IFN. It is concluded that alpha-IFN reduces platelet production rate and the peripheral platelet count in ET mainly through an anti-proliferative action on the megakaryocytes and to a considerably lesser degree by a shortening of platelet MLS

Field production and functional evaluation of chloroplast-derived interferon-alpha2b.

Science.gov (United States)

Arlen, Philip A; Falconer, Regina; Cherukumilli, Sri; Cole, Amy; Cole, Alexander M; Oishi, Karen K; Daniell, Henry

2007-07-01

Type I interferons (IFNs) inhibit viral replication and cell growth and enhance the immune response, and therefore have many clinical applications. IFN-alpha2b ranks third in world market use for a biopharmaceutical, behind only insulin and erythropoietin. The average annual cost of IFN-alpha2b for the treatment of hepatitis C infection is $26,000, and is therefore unavailable to the majority of patients in developing countries. Therefore, we expressed IFN-alpha2b in tobacco chloroplasts, and transgenic lines were grown in the field after obtaining United States Department of Agriculture Animal and Plant Health Inspection Service (USDA-APHIS) approval. Stable, site-specific integration of transgenes into chloroplast genomes and homoplasmy through several generations were confirmed. IFN-alpha2b levels reached up to 20% of total soluble protein, or 3 mg per gram of leaf (fresh weight). Transgenic IFN-alpha2b had similar in vitro biological activity to commercially produced PEG-Introntrade mark when tested for its ability to protect cells against cytopathic viral replication in the vesicular stomatitis virus cytopathic effect (VSV CPE) assay and to inhibit early-stage human immunodeficiency virus (HIV) infection. The antitumour and immunomodulating properties of IFN-alpha2b were also seen in vivo. Chloroplast-derived IFN-alpha2b increased the expression of major histocompatibility complex class I (MHC I) on splenocytes and the total number of natural killer (NK) cells. Finally, IFN-alpha2b purified from chloroplast transgenic lines (cpIFN-alpha2b) protected mice from a highly metastatic tumour line. This demonstration of high levels of expression of IFN-alpha2b, transgene containment and biological activity akin to that of commercial preparations of IFN-alpha2b facilitated the first field production of a plant-derived human blood protein, a critical step towards human clinical trials and commercialization.

Field production and functional evaluation of chloroplast-derived interferon-α2b

Science.gov (United States)

Arlen, Philip A.; Falconer, Regina; Cherukumilli, Sri; Cole, Amy; Cole, Alexander M.; Oishi, Karen K.; Daniell, Henry

2008-01-01

Summary Type I interferons (IFNs) inhibit viral replication and cell growth and enhance the immune response, and therefore have many clinical applications. IFN-α2b ranks third in world market use for a biopharmaceutical, behind only insulin and erythropoietin. The average annual cost of IFN-α2b for the treatment of hepatitis C infection is $26 000, and is therefore unavailable to the majority of patients in developing countries. Therefore, we expressed IFN-α2b in tobacco chloroplasts, and transgenic lines were grown in the field after obtaining United States Department of Agriculture Animal and Plant Health Inspection Service (USDA-APHIS) approval. Stable, site-specific integration of transgenes into chloroplast genomes and homoplasmy through several generations were confirmed. IFN-α2b levels reached up to 20% of total soluble protein, or 3 mg per gram of leaf (fresh weight). Transgenic IFN-α2b had similar in vitro biological activity to commercially produced PEG-Intron™ when tested for its ability to protect cells against cytopathic viral replication in the vesicular stomatitis virus cytopathic effect (VSV CPE) assay and to inhibit early-stage human immunodeficiency virus (HIV) infection. The antitumour and immunomodulating properties of IFN-α2b were also seen in vivo . Chloroplast-derived IFN-α2b increased the expression of major histocompatibility complex class I (MHC I) on splenocytes and the total number of natural killer (NK) cells. Finally, IFN-α2b purified from chloroplast transgenic lines (cpIFN-α2b) protected mice from a highly metastatic tumour line. This demonstration of high levels of expression of IFN-α2b, transgene containment and biological activity akin to that of commercial preparations of IFN-α2b facilitated the first field production of a plant-derived human blood protein, a critical step towards human clinical trials and commercialization. PMID:17490449

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

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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.

Parainfluenza virus 3 blocks antiviral mediators downstream of the interferon lambda receptor by modulating stat1 phosphorylation

Science.gov (United States)

Paramyxoviruses are known to inhibit type I interferon (IFN) production, however there is a lack of information regarding the type III IFN response during infection. Type III IFNs signal through a unique heterodimeric receptor, the IFN-'R1/IL-10R2, which is primarily expressed by epithelial cells. ...

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.

A synthetic NCAM-derived mimetic peptide, FGL, exerts anti-inflammatory properties via IGF-1 and interferon-gamma modulation

DEFF Research Database (Denmark)

Downer, Eric J; Cowley, Thelma R; Cox, Fionnuala

2009-01-01

activation and subsequent pro-inflammatory cytokine production. The aim of the current study was to determine if FGL corrects the age-related imbalance in hippocampal levels of insulin-like growth factor-1 (IGF-1) and pro-inflammatory interferon-gamma (IFNgamma), and subsequently attenuates the glial...

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

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...

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

Science.gov (United States)

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.

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.

Science.gov (United States)

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.

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.

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...

Canonical and Non-Canonical Aspects of JAK–STAT Signaling: Lessons from Interferons for Cytokine Responses

Science.gov (United States)

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. PMID:28184222

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

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...

Increased level and interferon-γ production of circulating natural killer cells in patients with scrub typhus.

Science.gov (United States)

Kang, Seung-Ji; Jin, Hye-Mi; Cho, Young-Nan; Kim, Seong Eun; Kim, Uh Jin; Park, Kyung-Hwa; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung; Park, Yong-Wook

2017-07-01

Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus. This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs). The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN)-γ after stimulation with interleukin (IL)-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase. This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients.

Increased level and interferon-γ production of circulating natural killer cells in patients with scrub typhus.

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Seung-Ji Kang

2017-07-01

Full Text Available Natural killer (NK cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus.This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs. The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN-γ after stimulation with interleukin (IL-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase.This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients.

The Role of Interferon Antagonist, Non-Structural Proteins in the Pathogenesis and Emergence of Arboviruses

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Samantha S. Soldan

2011-06-01

Full Text Available A myriad of factors favor the emergence and re-emergence of arthropod-borne viruses (arboviruses, including migration, climate change, intensified livestock production, an increasing volume of international trade and transportation, and changes to ecosystems (e.g., deforestation and loss of biodiversity. Consequently, arboviruses are distributed worldwide and represent over 30% of all emerging infectious diseases identified in the past decade. Although some arboviral infections go undetected or are associated with mild, flu-like symptoms, many are important human and veterinary pathogens causing serious illnesses such as arthritis, gastroenteritis, encephalitis and hemorrhagic fever and devastating economic loss as a consequence of lost productivity and high mortality rates among livestock. One of the most consistent molecular features of emerging arboviruses, in addition to their near exclusive use of RNA genomes, is the inclusion of viral, non-structural proteins that act as interferon antagonists. In this review, we describe these interferon antagonists and common strategies that arboviruses use to counter the host innate immune response. In addition, we discuss the complex interplay between host factors and viral determinants that are associated with virus emergence and re-emergence, and identify potential targets for vaccine and anti-viral therapies.

Negative Role of RIG-I Serine 8 Phosphorylation in the Regulatin of Interferon-beta Production

Energy Technology Data Exchange (ETDEWEB)

E Nistal-Villan; M Gack; G Martinez-Delgado; N Maharaj; K Inn; H Yang; R Wang; A Aggarwal; J Jung; A Garcia-Sastre

2011-12-31

RIG-I (retinoic acid-inducible gene I) and TRIM25 (tripartite motif protein 25) have emerged as key regulatory factors to induce interferon (IFN)-mediated innate immune responses to limit viral replication. Upon recognition of viral RNA, TRIM25 E3 ligase binds the first caspase recruitment domain (CARD) of RIG-I and subsequently induces lysine 172 ubiquitination of the second CARD of RIG-I, which is essential for the interaction with downstream MAVS/IPS-1/CARDIF/VISA and, thereby, IFN-beta mRNA production. Although ubiquitination has emerged as a major factor involved in RIG-I activation, the potential contribution of other post-translational modifications, such as phosphorylation, to the regulation of RIG-I activity has not been addressed. Here, we report the identification of serine 8 phosphorylation at the first CARD of RIG-I as a negative regulatory mechanism of RIG-I-mediated IFN-beta production. Immunoblot analysis with a phosphospecific antibody showed that RIG-I serine 8 phosphorylation steady-state levels were decreased upon stimulation of cells with IFN-beta or virus infection. Substitution of serine 8 in the CARD RIG-I functional domain with phosphomimetic aspartate or glutamate results in decreased TRIM25 binding, RIG-I ubiquitination, MAVS binding, and downstream signaling. Finally, sequence comparison reveals that only primate species carry serine 8, whereas other animal species carry an asparagine, indicating that serine 8 phosphorylation may represent a primate-specific regulation of RIG-I activation. Collectively, these data suggest that the phosphorylation of RIG-I serine 8 operates as a negative switch of RIG-I activation by suppressing TRIM25 interaction, further underscoring the importance of RIG-I and TRIM25 connection in type I IFN signal transduction.

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.

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.

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.

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.

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...

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

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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

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.

Adjuvant interferon gamma in patients with pulmonary atypical Mycobacteriosis: A randomized, double-blind, placebo-controlled study

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Sánchez-de la Osa Reinaldo B

2008-02-01

Full Text Available Abstract Background High antibiotic resistance is described in atypical Mycobacteriosis, mainly by Mycobacterium avium complex (MAC. Methods A randomized, double-blind, placebo-controlled clinical trial was carried out in two hospitals to evaluate the effect of interferon (IFN gamma as immunoadjuvant to chemotherapy on patients with atypical mycobacteria lung disease. Patients received placebo or 1 × 106 IU recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to daily oral azithromycin, ciprofloxacin, ethambutol and rifampin. Sputum samples collection for direct smear observation and culture as well as clinical and thorax radiography assessments were done during treatment and one year after. Cytokines and oxidative stress determinations were carried out in peripheral blood before and after treatment. Results Eighteen patients were included in the IFN group and 14 received placebo. Groups were homogeneous at entry; average age was 60 years, 75% men, 84% white; MAC infection prevailed (94%. At the end of treatment, 72% of patients treated with IFN gamma were evaluated as complete responders, but only 36% in the placebo group. The difference was maintained during follow-up. A more rapid complete response was obtained in the IFN group (5 months before, with a significantly earlier improvement in respiratory symptoms and pulmonary lesions reduction. Disease-related deaths were 35.7% of the patients in the placebo group and only 11.1% in the IFN group. Three patients in the IFN group normalized their globular sedimentation rate values. Although differences in bacteriology were not significant during the treatment period, some patients in the placebo group converted again to positive during follow-up. Significant increments in serum TGF-beta and advanced oxidation protein products were observed in the placebo group but not among IFN receiving patients. Treatments were well tolerated

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

Delayed growth of EL4 lymphoma in SR-A-deficient mice is due to upregulation of nitric oxide and interferon-gamma production by tumor-associated macrophages.

Science.gov (United States)

Komohara, Yoshihiro; Takemura, Kenichi; Lei, Xiao Feng; Sakashita, Naomi; Harada, Mamoru; Suzuki, Hiroshi; Kodama, Tatsuhiko; Takeya, Motohiro

2009-11-01

Class A scavenger receptors (SR-A, CD204) are highly expressed in tumor-associated macrophages (TAM). To investigate the function of SR-A in TAM, wild-type and SR-A-deficient (SR-A(-/-)) mice were injected with EL4 cells. Although these groups of mice did not differ in the numbers of infiltrating macrophages and lymphocytes and in neovascularization, SR-A(-/-) mice had delayed growth of EL4 tumors. Expression of inducible nitric oxide (NO) synthase and interferon (IFN)-gamma mRNA increased significantly in tumor tissues from SR-A(-/-) mice. Engulfment of necrotic EL4 cells induced upregulation of NO and IFN-gamma production by cultured macrophages, and production of NO and IFN-gamma increased in SR-A(-/-) macrophages in vitro. IFN-beta production by cultured macrophages was also elevated in SR-A(-/-) macrophages in vitro. These results suggested that the antitumor activity of macrophages increased in SR-A(-/-) mice because of upregulation of NO and IFN-gamma production. These data indicate an important role of SR-A in regulating TAM function by inhibiting toll-like receptor (TLR)4-IFN-beta signaling.

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

Identification of two auto-cleavage products of nonstructural protein 1 (nsp1) in porcine reproductive and respiratory syndrome virus infected cells: nsp1 function as interferon antagonist

International Nuclear Information System (INIS)

Chen, Z.; Lawson, S.; Sun, Z.; Zhou, X.; Guan, X.; Christopher-Hennings, J.; Nelson, E.A.; Fang, Y.

2010-01-01

The porcine reproductive and respiratory syndrome virus nsp1 is predicted to be auto-cleaved from the replicase polyprotein into nsp1α and nsp1β subunits. In infected cells, we detected the actual existence of nsp1α and nsp1β. Cleavage sites between nsp1α/nsp1β and nsp1β/nsp2 were identified by protein microsequencing analysis. Time course study showed that nsp1α and nsp1β mainly localize into the cell nucleus after 10 h post infection. Further analysis revealed that both proteins dramatically inhibited IFN-β expression. The nsp1β was observed to significantly inhibit expression from an interferon-stimulated response element promoter after Sendai virus infection or interferon treatment. It was further determined to inhibit nuclear translocation of STAT1 in the JAK-STAT signaling pathway. These results demonstrated that nsp1β has ability to inhibit both interferon synthesis and signaling, while nsp1α alone strongly inhibits interferon synthesis. These findings provide important insights into mechanisms of nsp1 in PRRSV pathogenesis and its impact in vaccine development.

Prenatal Dexamethasone and Postnatal High-Fat Diet Decrease Interferon Gamma Production through an Age-Dependent Histone Modification in Male Sprague-Dawley Rats

Science.gov (United States)

Yu, Hong-Ren; Tain, You-Lin; Sheen, Jiunn-Ming; Tiao, Mao-Meng; Chen, Chih-Cheng; Kuo, Ho-Chang; Hung, Pi-Lien; Hsieh, Kai-Sheng; Huang, Li-Tung

2016-01-01

Overexposure to prenatal glucocorticoid (GC) disturbs hypothalamic-pituitary-adrenocortical axis-associated neuroendocrine metabolism and susceptibility to metabolic syndrome. A high-fat (HF) diet is a major environmental factor that can cause metabolic syndrome. We aimed to investigate whether prenatal GC plus a postnatal HF diet could alter immune programming in rat offspring. Pregnant Sprague-Dawley rats were given intraperitoneal injections of dexamethasone or saline at 14–21 days of gestation. Male offspring were then divided into four groups: vehicle, prenatal dexamethasone exposure, postnatal HF diet (VHF), and prenatal dexamethasone exposure plus a postnatal HF diet (DHF). The rats were sacrificed and adaptive immune function was evaluated. Compared to the vehicle, the DHF group had lower interferon gamma (IFN-γ) production by splenocytes at postnatal day 120. Decreases in H3K9 acetylation and H3K36me3 levels at the IFN-γ promoter correlated with decreased IFN-γ production. The impaired IFN-γ production and aberrant site-specific histone modification at the IFN-γ promoter by prenatal dexamethasone treatment plus a postnatal HF diet resulted in resilience at postnatal day 180. Prenatal dexamethasone and a postnatal HF diet decreased IFN-γ production through a site-specific and an age-dependent histone modification. These findings suggest a mechanism by which prenatal exposure to GC and a postnatal environment exert effects on fetal immunity programming. PMID:27669212

Prenatal Dexamethasone and Postnatal High-Fat Diet Decrease Interferon Gamma Production through an Age-Dependent Histone Modification in Male Sprague-Dawley Rats

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Hong-Ren Yu

2016-09-01

Full Text Available Overexposure to prenatal glucocorticoid (GC disturbs hypothalamic-pituitary-adrenocortical axis-associated neuroendocrine metabolism and susceptibility to metabolic syndrome. A high-fat (HF diet is a major environmental factor that can cause metabolic syndrome. We aimed to investigate whether prenatal GC plus a postnatal HF diet could alter immune programming in rat offspring. Pregnant Sprague-Dawley rats were given intraperitoneal injections of dexamethasone or saline at 14–21 days of gestation. Male offspring were then divided into four groups: vehicle, prenatal dexamethasone exposure, postnatal HF diet (VHF, and prenatal dexamethasone exposure plus a postnatal HF diet (DHF. The rats were sacrificed and adaptive immune function was evaluated. Compared to the vehicle, the DHF group had lower interferon gamma (IFN-γ production by splenocytes at postnatal day 120. Decreases in H3K9 acetylation and H3K36me3 levels at the IFN-γ promoter correlated with decreased IFN-γ production. The impaired IFN-γ production and aberrant site-specific histone modification at the IFN-γ promoter by prenatal dexamethasone treatment plus a postnatal HF diet resulted in resilience at postnatal day 180. Prenatal dexamethasone and a postnatal HF diet decreased IFN-γ production through a site-specific and an age-dependent histone modification. These findings suggest a mechanism by which prenatal exposure to GC and a postnatal environment exert effects on fetal immunity programming.

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

The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ.

Science.gov (United States)

Ma, Feng; Xu, Sheng; Liu, Xingguang; Zhang, Qian; Xu, Xiongfei; Liu, Mofang; Hua, Minmin; Li, Nan; Yao, Hangping; Cao, Xuetao

2011-07-24

Interferon-γ (IFN-γ) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-γ and regulate IFN-γ production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin (BCG) downregulated miR-29 expression in IFN-γ-producing natural killer cells, CD4(+) T cells and CD8(+) T cells. Moreover, miR-29 suppressed IFN-γ production by directly targeting IFN-γ mRNA. We developed mice with transgenic expression of a 'sponge' target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-γ and lower L. monocytogenes burdens in L. monocytogenes-infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (T(H)1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis. Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-γ.

Blood Mononuclear Cell Mitochondrial Respiratory Chain Complex IV Activity is Decreased in Multiple Sclerosis Patients: Effects of β-Interferon Treatment

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Iain Hargreaves

2018-02-01

Full Text Available Objectives: Evidence of mitochondrial respiratory chain (MRC dysfunction and oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS. However, at present, there is no reliable low invasive surrogate available to evaluate mitochondrial function in these patients. In view of the particular sensitivity of MRC complex IV to oxidative stress, the aim of this study was to assess blood mononuclear cell (BMNC MRC complex IV activity in MS patients and compare these results to age matched controls and MS patients on β-interferon treatment. Methods: Spectrophotometric enzyme assay was employed to measure MRC complex IV activity in blood mononuclear cell obtained multiple sclerosis patients and aged matched controls. Results: MRC Complex IV activity was found to be significantly decreased (p < 0.05 in MS patients (2.1 ± 0.8 k/nmol × 10−3; mean ± SD] when compared to the controls (7.2 ± 2.3 k/nmol × 10−3. Complex IV activity in MS patients on β-interferon (4.9 ± 1.5 k/nmol × 10−3 was not found to be significantly different from that of the controls. Conclusions: This study has indicated evidence of peripheral MRC complex IV deficiency in MS patients and has highlighted the potential utility of BMNCs as a potential means to evaluate mitochondrial function in this disorder. Furthermore, the reported improvement of complex IV activity may provide novel insights into the mode(s of action of β-interferon.

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

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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.

Interferon lambda (IFN-λ) efficiently blocks norovirus transmission in a mouse model.

Science.gov (United States)

Rocha-Pereira, Joana; Jacobs, Sophie; Noppen, Sam; Verbeken, Eric; Michiels, Thomas; Neyts, Johan

2018-01-01

Human noroviruses are highly efficient in person to person transmission thus associated with explosive outbreaks of acute gastroenteritis. Outbreak control is limited to disinfection and isolation measures. Strategies to control the spread of noroviruses should be developed and models to study norovirus transmission will greatly facilitate this. Here, a mouse-to-mouse transmission model, in which mice develop acute murine norovirus (MNV)-induced diarrhea, was used to explore the role of interferon lambda (IFN-λ) in the control of a norovirus infection. Sentinel AG129 mice [deficient in IFN-α/β and IFN-γ receptors] that were co-housed with MNV-infected mice shedding high amounts of virus in their stool, developed a MNV-infection with associated diarrhea. Inoculation of such sentinel mice with an IFN-λ expression plasmid resulted in the production of circulating IFN-λ and upregulation of the expression of IFN-stimulated genes (ISGs) of the gut. Injection of the IFN-λ-expressing plasmid to sentinels prevents MNV-induced disease upon exposure to MNV-infected mice, as well as MNV replication in the small intestine, the associated signs of inflammation and the mounting of a specific IgG-based immune response. This demonstrates that IFN-λ can alone mediate protection against transmission of norovirus. The development of a simple delivery method for IFN-λ could be explored as a strategy to control norovirus outbreaks and protect vulnerable populations such as the elderly and immunocompromised. Copyright © 2017. Published by Elsevier B.V.

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.

Regulatory T cells and other lymphocyte subpopulations in patients with melanoma developing interferon-induced thyroiditis during high-dose interferon-α2b treatment.

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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.

Efficacy of immunomodulatory therapy with interferon-β or glatiramer acetate on multiple sclerosis-associated uveitis.

Science.gov (United States)

Velazquez-Villoria, D; Macia-Badia, C; Segura-García, A; Pastor Idoate, S; Arcos-Algaba, G; Velez-Escola, L; García-Arumí, J

2017-06-01

To analyse the role of interferon-β or glatiramer acetate in reducing the inflammatory episodes of intra-ocular inflammation in multiple sclerosis-associated uveitis. A study was conducted on a non-randomised, retrospective case series of 13 patients with proven multiple sclerosis and uveitis (minimum follow-up, 12 months). All patients were given immunomodulatory treatment (interferon-β or glatiramer acetate) to control the course of the multiple sclerosis. Patients were compared to themselves before initiating the treatment, in order to assess the difference in uveitis episodes. The main outcome measurements were the number of uveitis episodes with/without immunomodulatory treatment. Uveitis was bilateral in 10 (77%) out of 13 patients. Intermediate uveitis was observed in 11 patients, retinal vasculitis in 3 patients, and one patient was classified as a posterior uveitis. The patients had a mean of 4.15±3.1 episodes of uveitis (range 1-10) during the follow-up period (148.6±84.3 months). When compared to their pre-treatment status, patients on treatment with interferon-β or glatiramer acetate showed a significant decrease of 0.36 episodes of ocular inflammation per year (P=.02). Mild side effects related to immunomodulatory treatment were observed in 6 (46%) patients, 3 (23%) patients with a flu-like syndrome, and 3 (23%) patients with a skin rash. Interferon β or glatiramer acetate could be effective in reducing the uveitis episodes in patients with multiple sclerosis-associated uveitis, and was well tolerated in most patients. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

The efficacy of intravitreal interferon alpha-2b for the treatment of experimental endotoxin-induced uveitis

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Mehrdad Afarid

2016-01-01

Full Text Available Purpose: To study the efficacy of intravitreal interferon alpha-2b for endotoxin-induced uveitis. Materials and Methods: 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. Results: 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. Conclusion: Intravitreal interferon alpha-2b was effective in controlling endotoxin-induced uveitis.

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,

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

DEFF Research Database (Denmark)

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...

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...

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

BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells.

Science.gov (United States)

Combes, Alexis; Camosseto, Voahirana; N'Guessan, Prudence; Argüello, Rafael J; Mussard, Julie; Caux, Christophe; Bendriss-Vermare, Nathalie; Pierre, Philippe; Gatti, Evelina

2017-10-13

Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1 + late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3 +/ LAMP2 +/ LAMP1 - endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression. BAD-LAMP-silencing enhances TLR9 retention in this compartment and consequent downstream signalling events. Conversely, sustained BAD-LAMP expression in pDCs contributes to their lack of type I interferon production after exposure to a TGF-β-positive microenvironment or isolation from human breast tumours. Hence, BAD-LAMP limits interferon expression in pDCs indirectly, by promoting TLR9 sorting to late endosome compartments at steady state and in response to immunomodulatory cues.TLR9 is highly expressed by plasmacytoid dendritic cells and detects nucleic acids, but to discriminate between host and microbial nucleic acids TLR9 is sorted into different endosomal compartments. Here the authors show that BAD-LAMP limits type 1 interferon responses by sorting TLR9 to late endosomal compartments.

Negative Regulation of Interferon-β Production by Alternative Splicing of Tumor Necrosis Factor Receptor-Associated Factor 3 in Ducks

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Xiaoqin Wei

2018-03-01

Full Text Available Tumor necrosis factor receptor-associated factor 3 (TRAF3, an intracellular signal transducer, is identified as an important component of Toll-like receptors and RIG-I-like receptors induced type I interferon (IFN signaling pathways. Previous studies have clarified TRAF3 function in mammals, but little is known about the role of TRAF3 in ducks. Here, we cloned and characterized the full-length duck TRAF3 (duTRAF3 gene and an alternatively spliced isoform of duTRAF3 (duTRAF3-S lacking the fragment encoding amino acids 217–319, from duck embryo fibroblasts (DEFs. We found that duTRAF3 and duTRAF3-S played different roles in regulating IFN-β production in DEFs. duTRAF3 through its TRAF domain interacted with duMAVS or duTRIF, leading to the production of IFN-β. However, duTRAF3-S, containing the TRAF domain, was unable to bind duMAVS or duTRIF due to the intramolecular binding between the N- and C-terminal of duTRAF3-S that blocked the function of its TRAF domain. Further analysis identified that duTRAF3-S competed with duTRAF3 itself for binding to duTRAF3, perturbing duTRAF3 self-association, which impaired the assembly of duTRAF3-duMAVS/duTRIF complex, ultimately resulted in a reduced production of IFN-β. These findings suggest that duTRAF3 is an important regulator of duck innate immune signaling and reveal a novel mechanism for the negative regulation of IFN-β production via changing the formation of the homo-oligomerization of wild molecules, implying a novel regulatory role of truncated proteins.

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...

Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.

Directory of Open Access Journals (Sweden)

Oleg Garifulin

2007-09-01

Full Text Available Genetic makeup of the host plays a significant role in the course and outcome of infection. Inbred strains of mice display a wide range of sensitivities to Listeria monocytogenes infection and thus serve as a good model for analysis of the effect of genetic polymorphism. The outcome of L. monocytogenes infection in mice is influenced by the ability of this bacterium to induce expression of interferon beta mRNA, encoded in mouse by the Ifnb1 (interferon beta 1, fibroblast gene. Mouse strains that lack components of the IFN beta signaling pathway are substantially more resistant to infection. We found that macrophages from the ByJ substrain of the common C57BL/6 inbred strain of mice are impaired in their ability to induce Ifnb1 expression in response to bacterial and viral infections. We mapped the locus that controls differential expression of Ifnb1 to a region on Chromosome 7 that includes interferon regulatory factor 3 (Irf3, which encodes a transcription factor responsible for early induction of Ifnb1 expression. In C57BL/6ByJ mice, Irf3 mRNA was inefficiently spliced, with a significant proportion of the transcripts retaining intron 5. Analysis of the Irf3 locus identified a single base-pair polymorphism and revealed that intron 5 of Irf3 is spliced by the atypical U12-type spliceosome. We found that the polymorphism disrupts a U12-type branchpoint and has a profound effect on the efficiency of splicing of Irf3. We demonstrate that a naturally occurring change in the splicing control element has a dramatic effect on the resistance to L. monocytogenes infection. Thus, the C57BL/6ByJ mouse strain serves as an example of how a mammalian host can counter bacterial virulence strategies by introducing subtle alteration of noncoding sequences.

Tula and Puumala hantavirus NSs ORFs are functional and the products inhibit activation of the interferon-beta promoter.

Science.gov (United States)

Jääskeläinen, Kirsi M; Kaukinen, Pasi; Minskaya, Ekaterina S; Plyusnina, Angelina; Vapalahti, Olli; Elliott, Richard M; Weber, Friedemann; Vaheri, Antti; Plyusnin, Alexander

2007-10-01

The S RNA genome segment of hantaviruses carried by Arvicolinae and Sigmodontinae rodents encodes the nucleocapsid (N) protein and has an overlapping (+1) open reading frame (ORF) for a putative nonstructural protein (NSs). The aim of this study was to determine whether the ORF is functional. A protein corresponding to the predicted size of Tula virus (TULV) NSs was detected using coupled in vitro transcription and translation from a cloned S segment cDNA, and a protein corresponding to the predicted size of Puumala virus (PUUV) NSs was detected in infected cells by Western blotting with an anti-peptide serum. The activities of the interferon beta (IFN-beta) promoter, and nuclear factor kappa B (NF-kappaB)- and interferon regulatory factor-3 (IRF-3) responsive promoters, were inhibited in COS-7 cells transiently expressing TULV or PUUV NSs. Also IFN-beta mRNA levels in IFN-competent MRC5 cells either infected with TULV or transiently expressing NSs were decreased. These data demonstrate that Tula and Puumala hantaviruses have a functional NSs ORF. The findings may explain why the NSs ORF has been preserved in the genome of most hantaviruses during their long evolution and why hantavirus-infected cells secrete relatively low levels of IFNs. (c) 2007 Wiley-Liss, Inc.

Interaction between production control and quality control

NARCIS (Netherlands)

Bij, van der J.D.; Ekert, van J.H.W.

1999-01-01

Describes a qualitative study on interaction between systems for production control and quality control within industrial organisations. Production control and quality control interact in a sense. Good performance for one aspect often influences or frustrates the performance of the other. As far as

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.

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

Characteristics of alpha/beta interferon induction after infection of murine fibroblasts with wild-type and mutant alphaviruses

International Nuclear Information System (INIS)

Burke, Crystal W.; Gardner, Christina L.; Steffan, Joshua J.; Ryman, Kate D.; Klimstra, William B.

2009-01-01

We examined the characteristics of interferon alpha/beta (IFN-α/β) induction after alphavirus or control Sendai virus (SeV) infection of murine fibroblasts (MEFs). As expected, SeV infection of wild-type (wt) MEFs resulted in strong dimerization of IRF3 and the production of high levels of IFN-α/β. In contrast, infection of MEFs with multiple alphaviruses failed to elicit detectable IFN-α/β. In more detailed studies, Sindbis virus (SINV) infection caused dimerization and nuclear migration of IRF3, but minimal IFN-β promoter activity, although surprisingly, the infected cells were competent for IFN production by other stimuli early after infection. A SINV mutant defective in host macromolecular synthesis shutoff induced IFN-α/β in the MEF cultures dependent upon the activities of the TBK1 IRF3 activating kinase and host pattern recognition receptors (PRRs) PKR and MDA5 but not RIG-I. These results suggest that wild-type alphaviruses antagonize IFN induction after IRF3 activation but also may avoid detection by host PRRs early after infection.

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

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.

Plasmacytoid dendritic cells and type I interferon in the immunological response against warts.

Science.gov (United States)

Saadeh, D; Kurban, M; Abbas, O

2017-12-01

Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFNs), and are involved in the pathogenesis of several cutaneous infectious (especially viral), inflammatory/autoimmune and neoplastic entities. Their role in the pathogenesis and regression of human papilloma virus (HPV)-induced skin lesions has not been well studied. To investigate pDC occurrence and activity in HPV-induced skin lesions, including inflamed and uninflamed warts as well as epidermodysplasia verruciformis (EDV)-associated lesions. In total 20 inflamed and 20 uninflamed HPV-induced skin lesions (including 7 EDV lesions) were retrieved from our database, and the tissue was immunohistochemically tested for pDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies, respectively. pDCs were present in all 20 inflamed warts and absent from all 20 uninflamed cases. MxA expression was also diffuse and strong in 75% (15/20) inflamed warts, but not in any of the uninflamed warts. pDCs constitute a central component of the inflammatory host response in inflamed warts, possibly contributing to their regression through production of type I interferons. © 2017 British Association of Dermatologists.

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.

Evolution of vertebrate interferon inducible transmembrane proteins

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Hickford Danielle

2012-04-01

Full Text Available Abstract Background Interferon inducible transmembrane proteins (IFITMs have diverse roles, including the control of cell proliferation, promotion of homotypic cell adhesion, protection against viral infection, promotion of bone matrix maturation and mineralisation, and mediating germ cell development. Most IFITMs have been well characterised in human and mouse but little published data exists for other animals. This study characterised IFITMs in two distantly related marsupial species, the Australian tammar wallaby and the South American grey short-tailed opossum, and analysed the phylogeny of the IFITM family in vertebrates. Results Five IFITM paralogues were identified in both the tammar and opossum. As in eutherians, most marsupial IFITM genes exist within a cluster, contain two exons and encode proteins with two transmembrane domains. Only two IFITM genes, IFITM5 and IFITM10, have orthologues in both marsupials and eutherians. IFITM5 arose in bony fish and IFITM10 in tetrapods. The bone-specific expression of IFITM5 appears to be restricted to therian mammals, suggesting that its specialised role in bone production is a recent adaptation specific to mammals. IFITM10 is the most highly conserved IFITM, sharing at least 85% amino acid identity between birds, reptiles and mammals and suggesting an important role for this presently uncharacterised protein. Conclusions Like eutherians, marsupials also have multiple IFITM genes that exist in a gene cluster. The differing expression patterns for many of the paralogues, together with poor sequence conservation between species, suggests that IFITM genes have acquired many different roles during vertebrate evolution.

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

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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.

Interferon Treatment of Multiple Sclerosis

OpenAIRE

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...

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

International Nuclear Information System (INIS)

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

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.

Species difference in reactivity to lignin-like enzymatically polymerized polyphenols on interferon-γ synthesis and involvement of interleukin-2 production in mice.

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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.

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.

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

Science.gov (United States)

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.

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

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.

The CXC chemokines gamma interferon (IFN-gamma)-inducible protein 10 and monokine induced by IFN-gamma are released during severe melioidosis

NARCIS (Netherlands)

Lauw, F. N.; Simpson, A. J.; Prins, J. M.; van Deventer, S. J.; Chaowagul, W.; White, N. J.; van der Poll, T.

2000-01-01

Gamma interferon (IFN-gamma)-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) are related CXC chemokines which bind to the CXCR3 receptor and specifically target activated T lymphocytes and natural killer (NK) cells. The production of IP-10 and Mig by various cell types in vitro

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.

Comparison of the effect of interferon on two human hepatoma cell lines

Energy Technology Data Exchange (ETDEWEB)

Crespi, M; Schoub, B D; Lyons, S F; Chiu, M N [University of the Witwatersrand, Johannesburg (South Africa). Dept. of Virology

1985-06-01

Two human hepatoma cell lines, the PLC/PRF/5 and the Mahlavu cells, which differ in their production of the hepatitis B surface antigen (HBsAg), responded differently to interferon (IFN). After IFN treatment both cell lines were able to inhibit Sindbis virus replication. Oligo A synthetase (E enzyme) could be activated in the PLC/PRF/5 cells although they were not sensitive to exogenous 2 - 5 oligoadenylic acid (2 - 5 A). In contrast, the Mahlavu cells were sensitive to exogenous 2 - 5 A, but unable to activate the E enzyme. Both cell lines were unable to stimulate phosphorylation of the exogenous initiator factor eIF-2.

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

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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

The E5 protein of human papillomavirus type 16 perturbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon-γ

International Nuclear Information System (INIS)

Zhang Benyue; Li Ping; Wang Exing; Brahmi, Zacharie; Dunn, Kenneth W.; Blum, Janice S.; Roman, Ann

2003-01-01

Major histocompatibility complex (MHC) class II antigens are expressed on human foreskin keratinocytes (HFKs) following exposure to interferon gamma. The expression of MHC class II proteins on the cell surface may allow keratinocytes to function as antigen-presenting cells and induce a subsequent immune response to virus infection. Invariant chain (Ii) is a chaperone protein which plays an important role in the maturation of MHC class II molecules. The sequential degradation of Ii within acidic endocytic compartments is a key process required for the successful loading of antigenic peptide onto MHC class II molecules. Since human papillomavirus (HPV) 16 E5 can inhibit the acidification of late endosomes in HFKs, the E5 protein may be able to affect proper peptide loading onto the MHC class II molecule. To test this hypothesis, HFKs were infected with either control virus or a recombinant virus expressing HPV16 E5 and the infected cells were subsequently treated with interferon-γ. ELISAs revealed a decrease of MHC class II expression on the surface of E5-expressing cells compared with control virus-infected cells after interferon treatment. Western blot analysis showed that, in cells treated with interferon gamma, E5 could prevent the breakdown of Ii and block the formation of peptide-loaded, SDS-stable mature MHC class II dimers, correlating with diminished surface MHC class II expression. These data suggest that HPV16 E5 may be able to decrease immune recognition of infected keratinocytes via disruption of MHC class II protein function

Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections.

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Lee, Sanghyun; Baldridge, Megan T

2017-01-01

Interferon-lambda (IFN-λ) is a recently described cytokine found to be of critical importance in innate immune regulation of intestinal viruses. Endogenous IFN-λ has potent antiviral effects and has been shown to control multiple intestinal viruses and may represent a factor that contributes to human variability in response to infection. Importantly, recombinant IFN-λ has therapeutic potential against enteric viral infections, many of which lack other effective treatments. In this mini-review, we describe recent advances regarding IFN-λ-mediated regulation of enteric viruses with important clinical relevance including rotavirus, reovirus, and norovirus. We also briefly discuss IFN-λ interactions with other cytokines important in the intestine, and how IFN-λ may play a role in regulation of intestinal viruses by the commensal microbiome. Finally, we indicate currently outstanding questions regarding IFN-λ control of enteric infections that remain to be explored to enhance our understanding of this important immune molecule.

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

Role of type I interferon receptor signaling on NK cell development and functions.

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Jean Guan

Full Text Available Type I interferons (IFN are unique cytokines transcribed from intronless genes. They have been extensively studied because of their anti-viral functions. The anti-viral effects of type I IFN are mediated in part by natural killer (NK cells. However, the exact contribution of type I IFN on NK cell development, maturation and activation has been somewhat difficult to assess. In this study, we used a variety of approaches to define the consequences of the lack of type I interferon receptor (IFNAR signaling on NK cells. Using IFNAR deficient mice, we found that type I IFN affect NK cell development at the pre-pro NK stage. We also found that systemic absence of IFNAR signaling impacts NK cell maturation with a significant increase in the CD27+CD11b+ double positive (DP compartment in all organs. However, there is tissue specificity, and only in liver and bone marrow is the maturation defect strictly dependent on cell intrinsic IFNAR signaling. Finally, using adoptive transfer and mixed bone marrow approaches, we also show that cell intrinsic IFNAR signaling is not required for NK cell IFN-γ production in the context of MCMV infection. Taken together, our studies provide novel insights on how type I IFN receptor signaling regulates NK cell development and functions.

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

Interferon therapy of acute respiratory viral infections in children

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A.E. Abaturov

2017-04-01

Full Text Available The purpose of our study was to evaluate the efficacy and tolerability of nasal spray Laferobionum® (100,000 IU/ml in children with acute respiratory viral infections. Materials and methods. The study included 84 children aged 12 to 18 years. Children of the main group (42 persons received Laferobionum® spray in addition to the standard treatment for acute respiratory viral infections. The drug was administered to children of 12–14 years for 2 spray doses in each nasal passage 4–5 times a day at regular intervals (with the exception of sleep time, children aged 14–18 years received 3 spray-doses per each nasal passage 5–6 times a day at regular intervals (excluding sleep time. The course of treatment for all subjects was 5 days. Children of the control group received standard treatment for acute respiratory viral infections without Laferobionum®. Objective research included: auscultation of the heart and lungs, examination of the skin and mucous membranes, measurement of heart rate, blood pressure and body temperature. All patients underwent a general blood test, a general urinalysis, identification of the pathogen using the method of direct immunofluorescence (in smears taken from the nasal passages in the laboratory “Medical Diagnostic Center of Dnipropetrovsk Medical Academy”. Results. In the non-epidemic period, the respiratory syncytial virus and adenoviruses were the leading viral pathogens of acute respiratory viral infections. The main clinical manifestations of acute respiratory viral infection in the observed patients were signs of general inflammatory and catarrhal syndromes. All patients had not severe course of the disease. The data of the physical examination performed before the beginning of treatment indicated the absence of clinically significant deviations from the cardiovascular system in the children of the main and control groups. Arterial blood pressure and heart rate in the subjects of both groups were

Feasibility of commercial space manufacturing, production of pharmaceuticals. Volume 2: Technical analysis

Science.gov (United States)

1978-01-01

A technical analysis on the feasibility of commercial manufacturing of pharmaceuticals in space is presented. The method of obtaining pharmaceutical company involvement, laboratory results of the separation of serum proteins by the continuous flow electrophoresis process, the selection and study of candidate products, and their production requirements is described. The candidate products are antihemophilic factor, beta cells, erythropoietin, epidermal growth factor, alpha-1-antitrypsin and interferon. Production mass balances for antihemophelic factor, beta cells, and erythropoietin were compared for space versus ground operation. A conceptual description of a multiproduct processing system for space operation is discussed. Production requirements for epidermal growth factor of alpha-1-antitrypsin and interferon are presented.

Inhibition of interferon induction and action by the nairovirus Nairobi sheep disease virus/Ganjam virus.

Science.gov (United States)

Holzer, Barbara; Bakshi, Siddharth; Bridgen, Anne; Baron, Michael D

2011-01-01

The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.

Inhibition of interferon induction and action by the nairovirus Nairobi sheep disease virus/Ganjam virus.

Directory of Open Access Journals (Sweden)

Barbara Holzer

Full Text Available The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV. NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus. We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.

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.

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...

Association of interferon-gamma and interleukin 10 genotypes and serum levels with partial clinical remission in type 1 diabetes

DEFF Research Database (Denmark)

Alizadeh, B Z; Hanifi-Moghaddam, P; Eerligh, P

2006-01-01

We studied whether serum interferon (IFN)-gamma or interleukin (IL)-10 levels and their corresponding functional polymorphic genotypes are associated with partial remission of type 1 diabetes (T1D). A multi-centre study was undertaken in patients with newly diagnosed T1D and matched controls. T1D...

Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

OpenAIRE

Melki, Isabelle; Rose, Yoann; Uggenti, Carolina; Van Eyck, Lien; Frémond, Marie-Louise; Kitabayashi, Naoki; Rice, Gillian I; Jenkinson, Emma M; Boulai, Anaïs; Jeremiah, Nadia; Gattorno, Marco; Volpi, Sefano; Sacco, Olivero; Terheggen-Lagro, Suzanne W J; Tiddens, Harm A W M

2017-01-01

BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.METHODS...

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

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

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

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)

Persistent interferon transgene expression by RNA interference-mediated silencing of interferon receptors.

Science.gov (United States)

Takahashi, Yuki; Vikman, Elin; Nishikawa, Makiya; Ando, Mitsuru; Watanabe, Yoshihiko; Takakura, Yoshinobu

2010-09-01

The in vivo half-life of interferons (IFNs) is very short, and its extension would produce a better therapeutic outcome in IFN-based therapy. Delivery of IFN genes is one solution for providing a sustained supply. IFNs have a variety of functions, including the suppression of transgene expression, through interaction with IFN receptors (IFNRs). This suppression could prevent IFNs from being expressed from vectors delivered. Silencing the expression of IFNAR and IFNGR, the receptors for type I and II IFNs, respectively, in cells expressing IFNs may prolong transgene expression of IFNs. Mouse melanoma B16-BL6 cells or mouse liver were selected as a site expressing IFNs (not a target for IFN gene therapy) and IFN-expressing plasmid DNA was delivered with or without small interfering RNA (siRNA) targeting IFNRs. Transfection of B16-BL6 cells with siRNA targeting IFNAR1 subunit (IFNAR1) resulted in the reduced expression of IFNAR on the cell surface. This silencing significantly increased the IFN-beta production in cells that were transfected with IFN-beta-expressing plasmid DNA. Similar results were obtained with the combination of IFN-gamma and IFNGR. Co-injection of IFN-beta-expressing plasmid DNA with siRNA targeting IFNAR1 into mice resulted in sustained plasma concentration of IFN-beta. These results provide experimental evidence that the RNAi-mediated silencing of IFNRs in cells expressing IFN, such as hepatocytes, is an effective approach for improving transgene expression of IFNs when their therapeutic target comprises cells other than those expressing IFNs.

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.

5HT(4) agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes

NARCIS (Netherlands)

Zeinstra, Esther M.; Wilczak, Nadine; Wilschut, Jan C.; Glazenburg, Lisa; Chesik, Daniel; Kroese, Frans G. M.; De Keyser, Jacques

2006-01-01

A failure of tight control of MHC class II expression on astrocytes may play a role in the development of autoimmune responses in multiple sclerosis. The 5-HT4 serotonin receptor agonists cisapride and prucalopride, at concentrations between 10(-10) M and 10(-8) M, reduced interferon-gamma-induced

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway.

Science.gov (United States)

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A; Pfeffer, Lawrence M

2017-12-22

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro , and inhibited GBM tumorigenesis in vivo . Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro , and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway.

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...

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

Lifescience Database Archive (English)

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, ...

Pilot study of whole-blood gamma interferon response to the Vibrio cholerae toxin B subunit and resistance to enterotoxigenic Escherichia coli-associated diarrhea.

Science.gov (United States)

Flores, Jose; DuPont, Herbert L; Paredes-Paredes, Mercedes; Aguirre-Garcia, M Magdalena; Rojas, Araceli; Gonzalez, Alexei; Okhuysen, Pablo C

2010-05-01

Enterotoxigenic Escherichia coli (ETEC), which produces heat-labile toxin (LT), is a common cause of travelers' diarrhea (TD). The B subunit of ETEC LT is immunologically related to the B subunit of Vibrio cholerae toxin (CT). In this pilot study we evaluated the whole-blood gamma interferon response to CT B in 17 U.S. adults traveling to Mexico. Only one of nine subjects who demonstrated a cellular immune response as determined by whole-blood gamma interferon production to CT B on arrival to Mexico developed diarrhea, whereas five of eight without a cellular response developed diarrhea. Markers of the cellular immune response to ETEC LT could help in identifying individuals immune to ETEC LT, and these markers deserve additional study.

Effects of type I/type II interferons and transforming growth factor-beta on B-cell differentiation and proliferation. Definition of costimulation and cytokine requirements for immunoglobulin synthesis and expression.

Science.gov (United States)

Estes, D M; Tuo, W; Brown, W C; Goin, J

1998-12-01

In this report, we sought to determine the role of selected type I interferons [interferon-alpha (IFN-alpha) and interferon-tau (IFN-tau)], IFN-gamma and transforming growth factor-beta (TGF-beta) in the regulation of bovine antibody responses. B cells were stimulated via CD40 in the presence or absence of B-cell receptor (BCR) cross-linking. IFN-alpha enhanced IgM, IgG2 and IgA responses but did not enhance IgG1 responses. BCR signalling alone was more effective at inducing IgG2 responses with IFN-alpha than dual cross-linking with CD40. Recombinant ovine IFN-tau was less effective at inducing IgG2 responses when compared with IFN-alpha, though IgA responses were similar in magnitude following BCR cross-linking. At higher concentrations, IFN-tau enhanced IgA responses greater than twofold over the levels observed with IFN-alpha. Previous studies have shown that addition of IFN-gamma to BCR or pokeweed mitogen-activated bovine B cells stimulates IgG2 production. However, following CD40 stimulation alone, IFN-gamma was relatively ineffective at stimulating high-rate synthesis of any non-IgM isotype. Dual cross-linking via CD40 and the BCR resulted in decreased synthesis of IgM with a concomitant increase in IgA and similar levels of IgG2 production to those obtained via the BCR alone. We also assessed the effects of endogenous and exogenous TGF-beta on immunoglobulin synthesis by bovine B cells. Exogenous TGF-beta stimulates both IgG2 and IgA production following CD40 and BCR cross-linking in the presence of IL-2. Blocking endogenous TGF-beta did not inhibit the up-regulation of IgG2 or IgA by interferons.

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

Cost-effectiveness of different interferon beta products for relapsing-remitting and secondary progressive multiple sclerosis: Decision analysis based on long-term clinical data and switchable treatments.

Science.gov (United States)

Nikfar, Shekoufeh; Kebriaeezadeh, Abbas; Dinarvand, Rassoul; Abdollahi, Mohammad; Sahraian, Mohammad-Ali; Henry, David; Akbari Sari, Ali

2013-06-22

Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs). A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF β products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model. ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913. The Markov pharmacoeconomics model determined that

Cost-Effectiveness of Different Interferon Beta Products for Relapsing-Remitting and Secondary Progressive Multiple Sclerosis: Decision Analysis Based on Long-Term Clinical Data and Switchable Treatments

Directory of Open Access Journals (Sweden)

Shekoufeh Nikfar

2013-06-01

Full Text Available Multiple sclerosis (MS is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000. Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β and their copied biopharmaceuticals (CBPs and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs.Methods:A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS. Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS. A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER of cost/quality adjusted life year (QALY for all available INF β products (brands, biosimilars and CBPs were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model.Results:ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($ respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913.Conclusions:The Markov

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

Directory of Open Access Journals (Sweden)

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.

Rotavirus activates lymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasmacytoid dendritic cells.

Directory of Open Access Journals (Sweden)

Jessica A Pane

2014-03-01

Full Text Available It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I

Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

Science.gov (United States)

Pane, Jessica A.; Webster, Nicole L.; Coulson, Barbara S.

2014-01-01

It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon

A phase III comparison of radiation therapy with or without recombinant β-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04)

International Nuclear Information System (INIS)

Bradley, Jeffrey D.; Scott, Charles B.; Paris, Kristie J.; Demas, William F.; Machtay, Mitchell; Komaki, Ritsuko; Movsas, Benjamin; Rubin, Philip; Sause, William T.

2002-01-01

Purpose: The results of Phase I/II data testing β-interferon with radiation therapy in a non-small-cell lung cancer population were promising. Based on these data, the Radiation Therapy Oncology Group (RTOG) initiated a Phase III trial to test the efficacy of β-interferon in poor-risk patients with Stages IIIA and IIIB non-small-cell lung carcinoma. Methods: Between September 1994 and March 1998, 123 patients were accrued to this trial. Enrolled patients were not eligible for other chemoradiation studies within the RTOG. Eligibility criteria included histologically confirmed Stage IIIA or IIIB non-small-cell lung cancer (according to American Joint Committee on Cancer) considered clinically inoperable or unresectable at the time of surgery. Patients were required to have a Karnofsky performance status 50-70 or >70 and at least 5% weight loss over the preceding 3 months. Betaseron (recombinant human interferon beta ser , rHuIFN-β ser ,) was the chosen preparation of β-interferon. The patients randomized to the investigational arm received 16x10 6 IU of Betaseron by i.v. bolus given 3 days a week (Monday-Wednesday) on Weeks 1, 3, and 5. The Betaseron was given 30 minutes before radiation therapy for a total of nine doses. Irradiation was delivered at 2 Gy per fraction, 5 days a week, for a total of 60 Gy over 6 weeks and was identical for both arms. The primary end point of the trial was overall survival with local control as a secondary end point. Toxicities occurring within 90 days of therapy completion were defined as acute. Results: The median follow-up was 4 years (range: 2.5-6 years) for surviving patients. Seventy-six percent of all patients completed β-interferon. Toxicity was the primary reason for noncompliance. Radiotherapy (RT) compliance was excellent in the RT-alone arm, with 94% completing therapy, compared to 82% in the β-interferon arm (p=0.0475). Grade 3 and 4 acute toxicities were higher on the β-interferon arm (p=0.0249). Grade 3 and 4

Changes in growth hormone (GH) messenger RNA (GH mRNA) expression in the rat anterior pituitary after single interferon (IFN) alpha administration

International Nuclear Information System (INIS)

Romanowski, W.; Braczkowski, R.; Nowakowska-Zajdel, E.; Muc-Wierzgon, M.; Zubelewicz-Szkodzinska, B.; Kosiewicz, J.; Korzonek, I.

2006-01-01

Introduction: Interferon a (IFN-a) is a cytokine with pleiotropic effects which, via different pathways, influences the secretion of certain cytokines and hormones. Growth hormone (GH) secreted from the pituitary has physiological effects on various target tissues. The question is how IFN-a administered in various types of disease influences GH secretion. This study investigated the acute effect of IFN-a on GH mRNA expression in the rat anterior pituitary. Objective: The aim of the study was to measure the cellular expression of GH mRNA by in situ hybridisation in the anterior pituitary after a single administration of IFN-a. Material and methods: Rats were administered an intraperitoneal injection of IFN-a or saline. The rat pituitaries were taken 2 and 4 hours after IFN/saline administration and kept frozen until in situ hybridisation histochemistry. A 31 - base 35S -labelled oligonucleotide probe complementary to part of the exonic mRNA sequence coding for GH mRNA was used. All control and experimental sections were hybridised in the same hybridisation reaction. Results: Acute administration of interferon a increased GH mRNA expression in the anterior pituitary in the 4-hour group in comparison with the control group, and there was no difference between the control group and the 2-hour rats. Conclusion: A single IFN-a administration was found to exert an influence on anterior pituitary GH mRNA expression. These observations may pave the way for presenting a possible new action of IFN-a. (author) GH mRNA, anterior pituitary, interferon

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

Serotype 3 (T3) reoviruses induce substantially more type 1 interferon (IFN-I) secretion than serotype 1 (T1) strains. However, the mechanisms underlying differences in IFN-I production between T1 and T3 reoviruses remain undefined. Here, we found that differences in IFN-I production between T1 and T3 reoviruses correlate with activation of interferon regulatory factor 3 (IRF3), a key transcription factor for the production of IFN-I. T3 strain rsT3D activated IRF3 more rapidly and to a greater extent than the T1 strain rsT1L, in simian virus 40 (SV40) immortalized endothelial cells (SVECs). Differences in IRF3 activation between rsT1L and rsT3D were observed in the first hours of infection and were independent of de novo viral RNA and protein synthesis. NF-κB activation mirrored IRF3 activation, with rsT3D inducing more NF-κB activity than rsT1L. We also found that IRF3 and NF-κB are activated in a mitochondrial antiviral-signaling protein (MAVS)-dependent manner. rsT1L does not suppress IRF3 activation, as IRF3 phosphorylation could be induced in rsT1L-infected cells. Transfected rsT1L and rsT3D RNA induced IRF3 phosphorylation, indicating that genomic RNA from both strains has the capacity to activate IRF3. Finally, bypassing the normal route of reovirus entry by transfecting in vitro -generated viral cores revealed that rsT1L and rsT3D core particles induced equivalent IRF3 activation. Taken together, our findings indicate that entry-related events that occur after outer capsid disassembly, but prior to deposition of viral cores into the cytoplasm, influence the efficiency of IFN-I responses to reovirus. This work provides further insight into mechanisms by which nonenveloped viruses activate innate immune responses. IMPORTANCE Detection of viral nucleic acids by the host cell triggers type 1 interferon (IFN-I) responses, which are critical for containing and clearing viral infections. Viral RNA is sensed in the cytoplasm by cellular receptors that initiate

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

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.

Epstein-Barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-β

International Nuclear Information System (INIS)

Bentz, Gretchen L.; Liu Renshui; Hahn, Angela M.; Shackelford, Julia; Pagano, Joseph S.

2010-01-01

Activation of interferon regulatory factors (IRFs) 3 and 7 is essential for the induction of Type I interferons (IFN) and innate antiviral responses, and herpesviruses have evolved mechanisms to evade such responses. We previously reported that Epstein-Barr virus BZLF1, an immediate-early (IE) protein, inhibits the function of IRF7, but the role of BRLF1, the other IE transactivator, in IRF regulation has not been examined. We now show that BRLF1 expression decreased induction of IFN-β, and reduced expression of IRF3 and IRF7; effects were dependent on N- and C-terminal regions of BRLF1 and its nuclear localization signal. Endogenous IRF3 and IRF7 RNA and protein levels were also decreased during cytolytic EBV infection. Finally, production of IFN-β was decreased during lytic EBV infection and was associated with increased susceptibility to superinfection with Sendai virus. These data suggest a new role for BRLF1 with the ability to evade host innate immune responses.

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

Liver-targeting of interferon-alpha with tissue-specific domain antibodies.

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Edward Coulstock

Full Text Available Interferon alpha (IFNα is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR. Our results show that the murine IFNα2 homolog (mIFNα2 fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.

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

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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.

Overexpression of interleukin-1β and interferon-γ in type I thoracic aortic dissections and ascending thoracic aortic aneurysms: possible correlation with matrix metalloproteinase-9 expression and apoptosis of aortic media cells.

Science.gov (United States)

Zhang, Lei; Liao, Ming-fang; Tian, Lei; Zou, Si-li; Lu, Qing-sheng; Bao, Jun-min; Pei, Yi-fei; Jing, Zai-ping

2011-07-01

To examine the expression of interleukin-1β and interferon-γ and their possible roles in aortic dissections and aneurysms. Aortic specimens were obtained from patients with type I thoracic aortic dissection, ascending thoracic aortic aneurysms, and control organ donors. The expression of interleukin-1β, interferon-γ, matrix metalloproteinase-9, and signal transduction factors phospho-p38 and phosphorylated c-jun N-terminal kinase (phospho-JNK) were detected by real time reverse transcription-polymerase chain reaction (real time RT-PCR), Western blot, and immunohistochemistry, respectively. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was performed to detect apoptosis of media cells. The correlation of these factors and apoptosis was also studied. Apoptosis in the media of thoracic aortic dissection and in ascending thoracic aortic aneurysms was dramatically higher than in the control group. The expression of interleukin-1β gradually increased from the control group, thoracic aortic dissection to ascending thoracic aortic aneurysms (p matrix metalloproteinase-9 was significantly increased in the media of thoracic aortic dissection and ascending thoracic aortic aneurysms compared with the control group (p correlations between interleukin-1β versus matrix metalloproteinase-9, interleukin-1β versus phospho-p38 in thoracic aortic dissection (p matrix metalloproteinase-9, interferon-γ versus phospho-JNK, interferon-γ versus apoptosis, and interleukin-1β versus apoptosis in ascending thoracic aortic aneurysms (p = 0.02, 0.02, p matrix metalloproteinase-9 and the apoptosis of media cells in humans. Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Antagonist effect of interferon-γ aerosol inhalation on pulmonary remodeling after γ-ray irradiation

International Nuclear Information System (INIS)

Li Ming; Song Liangwen; Wang Shaoxia; Diao Ruiying; Xu Xinping; Luo Qingliang

2008-01-01

Objective: To observe the antagonistic effect of interferon-y aerosol inhalation on pulmonary remodeling after γ-ray irradiation, and explore its mechanisms. Methods: The Wistar rats were randomly divided into irradiation control group and irradiation + Interferon-γ antagonist group, which proceeded IFN-γ aerosol inhalation 3 days before 20 Gy 60 Co γ-ray irradiation, then were sacrificed at 10, 20, 30 days after irradiation. Conventional histopathological sections of lung tissue were prepared, which were stained immunohistochemically for α-SMA and Sirius red. The contents of collagen IV were determined by Western blot. The expression of MMP-2, MMP-9 and TIMP-1 in lung homogenate was detected by ELISA. Results: The widen degrees of interalveolar septum, the deposition of collagen I, III, and the expression of α-SMA decreased significantly in IFN-γ treatment group as compared with those in the irradiation control group. The expression of collagen IV appeared an elevation trend, but this phenomenon attenuated after IFN-γ was used. The levels of MMP-2 and TIMP-1 decreased 10 days after administration with IFN-γ but the opposite trend appeared for MMP- 9. The expression of MMP-2, MMP-9 and TIMP-1 decreased 30 days after administration with IFN-γ. Conclusion: IFN-γ is effective in alleviating pulmonary injuries induced by irradiation in rats, possibly by decreasing the expression of TIMP-1 to relieve the inhibition to MMP-9, then degrading collagen IV to antagonize remodeling after lung injury. (authors)

NSs protein of severe fever with thrombocytopenia syndrome virus suppresses interferon production through different mechanism than Rift Valley fever virus.

Science.gov (United States)

Zhang, S; Zheng, B; Wang, T; Li, A; Wan, J; Qu, J; Li, C H; Li, D; Liang, M

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified Phlebovirus that causes severe fever with thrombocytopenia syndrome. Our study demonstrated that SFTSV NSs functioned as IFN antagonist mainly by suppressing TBK1/IKKε-IRF3 signaling pathway. NSs interacted with and relocalized TANK-binding kinase 1 (TBK1) into NSs-induced cytoplasmic structures and this interaction could effectively inhibit downstream phosphorylation and dimerization of interferon regulatory factor 3 (IRF3), resulting in the suppression of antiviral signaling and IFN induction. Functional sites of SFTSV NSs binding with TBK1 were then studied and results showed that NSs had lost their IFN-inhibiting activity after deleting the 25 amino acids in N-terminal. Furthermore, the mechanism of Rift Valley fever virus (RVFV) NSs blocking IFN-β response were also investigated. Preliminary results showed that RVFV NSs proteins could neither interact nor co-localize with TBK1 in cytoplasm, but suppressed its expression levels, phosphorylation and dimerization of IRF3 in the subsequent steps, resulting in inhibition of the IFN-β production. Altogether, our data demonstrated the probable mechanism used by SFTSV to inhibit IFN responses which was different from RVFV and pointed toward a novel mechanism for RVFV suppressing IFN responses.

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.

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage.

Science.gov (United States)

Qian, Suhong; Fan, Wenchun; Liu, Tingting; Wu, Mengge; Zhang, Huawei; Cui, Xiaofang; Zhou, Yun; Hu, Junjie; Wei, Shaozhong; Chen, Huanchun; Li, Xiangmin; Qian, Ping

2017-08-15

Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-β (TRIF), and TRAF family member-associated NF-κB activator (TANK), via viral 3C protease (3C pro ). SVV 3C pro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-κB activation. SVV was also found to be sensitive to IFN-β. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules. IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3C pro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for

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.

Network-based production quality control

Science.gov (United States)

Kwon, Yongjin; Tseng, Bill; Chiou, Richard

2007-09-01

This study investigates the feasibility of remote quality control using a host of advanced automation equipment with Internet accessibility. Recent emphasis on product quality and reduction of waste stems from the dynamic, globalized and customer-driven market, which brings opportunities and threats to companies, depending on the response speed and production strategies. The current trends in industry also include a wide spread of distributed manufacturing systems, where design, production, and management facilities are geographically dispersed. This situation mandates not only the accessibility to remotely located production equipment for monitoring and control, but efficient means of responding to changing environment to counter process variations and diverse customer demands. To compete under such an environment, companies are striving to achieve 100%, sensor-based, automated inspection for zero-defect manufacturing. In this study, the Internet-based quality control scheme is referred to as "E-Quality for Manufacturing" or "EQM" for short. By its definition, EQM refers to a holistic approach to design and to embed efficient quality control functions in the context of network integrated manufacturing systems. Such system let designers located far away from the production facility to monitor, control and adjust the quality inspection processes as production design evolves.

Minocycline added to subcutaneous interferon β-1a in multiple sclerosis

DEFF Research Database (Denmark)

Sørensen, P S; Sellebjerg, F; Lycke, J

2016-01-01

BACKGROUND AND PURPOSE: Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) β-1a therapy. METHODS: This was a double......-blind, randomized, placebo-controlled multicentre study. Within 3 months (±1 month) of starting sc IFN β-1a 44 μg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN β-1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying...... were assessed. RESULTS: One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence...

INTERFERON IN THE TREATMENT OF WOMEN INFECTED WITH HIGH-RISK HUMAN PAPILLOMAVIRUS

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Кристина Владимировна Марочко

2017-02-01

Full Text Available Human papillomavirus (HPV is the most common sexually transmitted infection worldwide. About 99 % of cervical cancer is caused by persistent infection with high-risk types of HPV. It can take over 10 years from the time of an initial human papillomavirus infection until a cervical cancer. In most cases, HPV infections are transient and go away within 1 year. There is evidence that cell mediated immune responses of the host, both systemic and local, are important determinants of the course of infection, thus, it is reasonable to use immunocorrective therapy. Many studies have demonstrated the effectiveness of interferon alpha in complex therapy of HPV infection. The aim – to determine the efficacy of interferon alpha-2b in reducing the viral load of high-risk HPV among infected women of reproductive age. Materials and methods. 60 high-risk HPV positive women were included in the study. Qualitative and quantitative determination of high-risk HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 was carried out by PCR in real time. Patients were randomized into two groups: group 1 (n = 30 received alfa-interferon in the form of rectal suppositories; group 2 (n = 30 did not receive the drug. Control study was conducted 1 month later. The average age in group 1 was 31,7 ± 1,6 years, in group 2 – 35,0 ± 1,6 years (p = 0,08. In group 1 monoinfection diagnosed in 72,4 % of cases, mixed infection in 27,6 % of cases in group 2 – at 64,3 % and 35,7 %, respectively. Results. The average viral load was 3,5 ± 0,2 Lg (HPV on 105 cells in group 1 and 3,4 ± 0,3 in group 2 (p = 0,473. Сlinically significant viral load dominated in group 1 (41,4 %, insignificant viral load was dominated in group 2 (42,9 %. After 1 month the average viral load was 1,9 ± 0,3 Lg (HPV on 105 cells in group 1 and 2,8 ± 0,4 Lg in group 2 (р = 0,04. There were statistically significant difference in both groups before and after 1 month (p < 0

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

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.

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.



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.

The West Nile virus assembly process evades the conserved antiviral mechanism of the interferon-induced MxA protein

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Hoenen, Antje [School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane (Australia); Gillespie, Leah [Department of Microbiology, La Trobe University, Melbourne (Australia); Department of Microbiology and Immunology, University of Melbourne, Melbourne (Australia); Morgan, Garry; Heide, Peter van der [Institute for Molecular Bioscience, University of Queensland, Brisbane (Australia); Khromykh, Alexander [School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane (Australia); Australian Infectious Diseases Research Centre, University of Queensland, Brisbane (Australia); Mackenzie, Jason, E-mail: jason.mackenzie@unimelb.edu.au [Department of Microbiology, La Trobe University, Melbourne (Australia); Department of Microbiology and Immunology, University of Melbourne, Melbourne (Australia)

2014-01-05

Flaviviruses have evolved means to evade host innate immune responses. Recent evidence suggests this is due to prevention of interferon production and signaling in flavivirus-infected cells. Here we show that the interferon-induced MxA protein can sequester the West Nile virus strain Kunjin virus (WNV{sub KUN}) capsid protein in cytoplasmic tubular structures in an expression-replication system. This sequestering resulted in reduced titers of secreted WNV{sub KUN} particles. We show by electron microscopy, tomography and 3D modeling that these cytoplasmic tubular structures form organized bundles. Additionally we show that recombinant ER-targeted MxA can restrict production of infectious WNV{sub KUN} under conditions of virus infection. Our results indicate a co-ordinated and compartmentalized WNV{sub KUN} assembly process may prevent recognition of viral components by MxA, particularly the capsid protein. This recognition can be exploited if MxA is targeted to intracellular sites of WNV{sub KUN} assembly. This results in further understanding of the mechanisms of flavivirus evasion from the immune system. - Highlights: • We show that the ISG MxA can recognize the West Nile virus capsid protein. • Interaction between WNV C protein and MxA induces cytoplasmic fibrils. • MxA can be retargeted to the ER to restrict WNV particle release. • WNV assembly process is a strategy to avoid MxA recognition.

The nucleocapsid protein of measles virus blocks host interferon response

International Nuclear Information System (INIS)

Takayama, Ikuyo; Sato, Hiroki; Watanabe, Akira; Omi-Furutani, Mio; Sugai, Akihiro; Kanki, Keita; Yoneda, Misako; Kai, Chieko

2012-01-01

Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways. In this study, we confirmed the effects of MV P gene products of a wild MV strain on IFN pathways and examined that of other viral proteins on it. Interestingly, we found that N protein acts as an IFN-α/β and γ-antagonist as strong as P gene products. We further investigated the mechanisms of MV-N inhibition, and revealed that MV-N blocks the nuclear import of activated STAT without preventing STAT and Jak activation or STAT degradation, and that the nuclear translocation of MV-N is important for the inhibition. The inhibitory effect of the N protein was observed as a common feature of other morbilliviruses. The results presented in this report suggest that N protein of MV as well as P/V/C proteins is involved in the inhibition of host IFN signaling pathways.

The nucleocapsid protein of measles virus blocks host interferon response

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Takayama, Ikuyo; Sato, Hiroki; Watanabe, Akira; Omi-Furutani, Mio; Sugai, Akihiro; Kanki, Keita; Yoneda, Misako; Kai, Chieko, E-mail: ckai@ims.u-tokyo.ac.jp

2012-03-01

Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways. In this study, we confirmed the effects of MV P gene products of a wild MV strain on IFN pathways and examined that of other viral proteins on it. Interestingly, we found that N protein acts as an IFN-{alpha}/{beta} and {gamma}-antagonist as strong as P gene products. We further investigated the mechanisms of MV-N inhibition, and revealed that MV-N blocks the nuclear import of activated STAT without preventing STAT and Jak activation or STAT degradation, and that the nuclear translocation of MV-N is important for the inhibition. The inhibitory effect of the N protein was observed as a common feature of other morbilliviruses. The results presented in this report suggest that N protein of MV as well as P/V/C proteins is involved in the inhibition of host IFN signaling pathways.

Measurement of the heat production of bacteria in the bioreactor. Calorimetric regulation of bio-processes for the production of recombinant proteins; Messung der Waermeproduktion von Bakterien im Bioreaktor. Kalorimetrische Regelung von Bioprozessen zur Herstellung von rekombinanten Proteinen

Energy Technology Data Exchange (ETDEWEB)

Biener, Richard [Hochschule Esslingen (Germany); Steinkaempfer, Anne; Horn, Thomas; Hofmann, Johannes

2012-09-15

Recombinant proteins such as insulin or interferons are the most important products of the modern biotechnology. Recombinant proteins are produced with genetically engineered organisms. Here, besides microorganisms (E. coli or yeast cells) also animal cell cultures are used. In order to increase the productivity and the reproducibility of the cultivation process, an automated process control is required. The authors of the contribution under consideration report on the regulation of the specific rate of growth of microorganisms during cultivation in a bioreactor using standard calorimetric methods. This automation strategy results in a significant increase in productivity and reproducibility of the process.

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

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

RUNX2 Mediates Plasmacytoid Dendritic Cell Egress from the Bone Marrow and Controls Viral Immunity

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Michaël Chopin

2016-04-01

Full Text Available Plasmacytoid dendritic cells (pDCs represent a unique immune cell type that responds to viral nucleic acids through the rapid production of type I interferons. Within the hematopoietic system, the transcription factor RUNX2 is exclusively expressed in pDCs and is required for their peripheral homeostasis. Here, we show that RUNX2 plays an essential role in promoting pDC localization and function. RUNX2 is required for the appropriate expression of the integrin-mediated adhesion machinery, as well as for the down-modulation of the chemokine receptor CXCR4, which allows pDC egress into the circulation. RUNX2 also facilitates the robust response to viral infection through the control of IRF7, the major regulator of type I interferon production. Mice lacking one copy of Runx2 have reduced numbers of peripheral pDCs and IFN-α expression, which might contribute to the reported difficulties of individuals with cleidocranial dysplasia, who are haploinsufficient for RUNX2, to clear viral infections.

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.

Interferon lambda inhibits dengue virus replication in epithelial cells.

Science.gov (United States)

Palma-Ocampo, Helen K; Flores-Alonso, Juan C; Vallejo-Ruiz, Verónica; Reyes-Leyva, Julio; Flores-Mendoza, Lilian; Herrera-Camacho, Irma; Rosas-Murrieta, Nora H; Santos-López, Gerardo

2015-09-28

In viral disease, infection is controlled at the cellular level by type I interferon (IFN-I), but dengue virus (DENV) has the ability to inhibit this response. Type III interferon, also known as lambda IFN (IFN-III or IFN-λ), is a complementary pathway to the antiviral response by IFN-I. This work analyzed the IFN-λ (IFN-III) mediated antiviral response against DENV serotype 2 (DENV-2) infection. Dengue fever patients were sampled to determine their IFN-λ levels by ELISA. To study the IFN-λ response during DENV infection we selected the epithelial cell line C33-A, and we demonstrated that it is permissive to DENV-2 infection. The effect of IFN-λ on virus replication was determined in these cells, in parallel to the expression of IFN-stimulated genes (ISGs), and Suppressor of Cytokine Signaling (SOCS), genes measured by RT-qPCR. We found increased (~1.8 times) serological IFN-λ in dengue fever patients compared to healthy blood donors. IFN-λ inhibited DENV-2 replication in a dose-dependent manner in vitro. The reduction of viral titer corresponded with increased ISG mRNA levels (MX1 and OAS1), with the highest inhibition occurring at ISG's peak expression. Presence of IFN-negative regulators, SOCS1 and SOCS3, during DENV-2 infection was associated with reduced IFN-λ1 expression. Evidence described here suggests that IFN-λ is a good candidate inhibitor of viral replication in dengue infection. Mechanisms for the cellular and organismal interplay between DENV and IFN- λ need to be further studied as they could provide insights into strategies to treat this disease. Furthermore, we report a novel epithelial model to study dengue infection in vitro.

Development of Production Control in Small Batch Production

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Németh Péter

2016-01-01

Full Text Available Our aim with this paper is to develop a new performance measurement and control system for small batch production in the automotive industry. For this reason, we present our previous research results for warehouse performance measurement and adopt its methodology to production control. The proposed method is based on artificial intelligence (neural networks.

NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial

DEFF Research Database (Denmark)

Sorensen, Per Soelberg; Mellgren, Svein Ivar; Svenningsson, Anders

2009-01-01

BACKGROUND: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce...... was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; pSleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks......, these findings need to be corroborated in larger cohorts....

Smoking and risk of treatment-induced neutralizing antibodies to interferon β-1a.

Science.gov (United States)

Hedström, Anna Karin; Ryner, Malin; Fink, Katarina; Fogdell-Hahn, Anna; Alfredsson, Lars; Olsson, Tomas; Hillert, Jan

2014-04-01

Neutralizing antibodies (NAbs) to interferon β (IFNβ) products that develop during treatment are associated with a loss of clinical efficacy. The aim of this study was to investigate the influence of smoking habits on the risk of developing NAbs to IFNβ, in the treatment of multiple sclerosis (MS). This report is based on 695 MS patients treated with IFNβ-1a, included in two Swedish case-control studies that collected information on smoking habits. Using logistic regression, the development of NAbs to IFNβ-1a among current smokers was compared with that of non-smokers, by calculating the odds ratio (OR) with a 95% confidence interval (CI). Current smokers showed an increased risk of developing NAbs to IFNβ-1a, compared with non-smokers (OR 1.9; 95% CI 1.3-2.8; p = 0.002). There were no gender differences. We observed no association between past smoking and the risk of developing NAbs to IFNβ-1a. The finding that current smokers have an increased risk of developing NAbs to IFNβ-1a has implications, both for the practical care and the treatment of MS; it also provides an interesting perspective of the lungs as an immune-reactive organ, reacting upon irritation.

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...

Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels

International Nuclear Information System (INIS)

Wang, Dang; Fang, Liurong; Luo, Rui; Ye, Rui; Fang, Ying; Xie, Lilan; Chen, Huanchun; Xiao, Shaobo

2010-01-01

Research highlights: → FMDV L pro inhibits poly(I:C)-induced IFN-α1/β mRNA expression. → L pro inhibits MDA5-mediated activation of the IFN-α1/β promoter. → L pro significantly reduced the transcription of multiple IRF-responsive genes. → L pro inhibits IFN-α1/β promoter activation by decreasing IRF-3/7 in protein levels. → The ability to process eIF-4G of L pro is not necessary to inhibit IFN-α1/β activation. -- Abstract: The leader proteinase (L pro ) of foot-and-mouth disease virus (FMDV) has been identified as an interferon-β (IFN-β) antagonist that disrupts the integrity of transcription factor nuclear factor κB (NF-κB). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-α1/β expression caused by L pro was also associated with a decrease of interferon regulatory factor 3/7 (IRF-3/7) in protein levels, two critical transcription factors for activation of IFN-α/β. Furthermore, overexpression of L pro significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening L pro mutants indicated that the ability to process eIF-4G of L pro is not required for suppressing dsRNA-induced activation of the IFN-α1/β promoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-κB, L pro also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.

Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels

Energy Technology Data Exchange (ETDEWEB)

Wang, Dang; Fang, Liurong; Luo, Rui; Ye, Rui; Fang, Ying; Xie, Lilan; Chen, Huanchun [Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); Xiao, Shaobo, E-mail: shaoboxiao@yahoo.com [Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China)

2010-08-13

Research highlights: {yields} FMDV L{sup pro} inhibits poly(I:C)-induced IFN-{alpha}1/{beta} mRNA expression. {yields} L{sup pro} inhibits MDA5-mediated activation of the IFN-{alpha}1/{beta} promoter. {yields} L{sup pro} significantly reduced the transcription of multiple IRF-responsive genes. {yields} L{sup pro} inhibits IFN-{alpha}1/{beta} promoter activation by decreasing IRF-3/7 in protein levels. {yields} The ability to process eIF-4G of L{sup pro} is not necessary to inhibit IFN-{alpha}1/{beta} activation. -- Abstract: The leader proteinase (L{sup pro}) of foot-and-mouth disease virus (FMDV) has been identified as an interferon-{beta} (IFN-{beta}) antagonist that disrupts the integrity of transcription factor nuclear factor {kappa}B (NF-{kappa}B). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-{alpha}1/{beta} expression caused by L{sup pro} was also associated with a decrease of interferon regulatory factor 3/7 (IRF-3/7) in protein levels, two critical transcription factors for activation of IFN-{alpha}/{beta}. Furthermore, overexpression of L{sup pro} significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening L{sup pro} mutants indicated that the ability to process eIF-4G of L{sup pro} is not required for suppressing dsRNA-induced activation of the IFN-{alpha}1/{beta} promoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-{kappa}B, L{sup pro} also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.

Thyroid Peroxidase Antibodies in Non-Interferon Treated Hepatitis C Patients in Pakistan

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Muhammad Imtiaz Shafiq

2015-01-01

Full Text Available Objective. Interferon therapy of HCV infected patients is associated with development of thyroid dysfunctions. Patients with pretreatment presence of antithyroid peroxidase (TPO-Ab are at greater risk. This study, probably the first in Pakistan, was planned to determine TPO-Ab in sera of treatment-naive local HCV patients. Setting. Centre for Nuclear Medicine (CENUM, Mayo Hospital, Lahore. Patients and Methods. During July to December 2012, 190 patients (140 females, 50 males newly diagnosed for HCV infection were selected for this study. Their age range was 15–55 years (mean: 35.3 ± 9.1 years. 262 age matched healthy subjects (211 females and 50 males were recruited as control. Serum-free thyroxin (FT4 and thyroid stimulating hormone (TSH were detected by radioimmunoassay techniques. Serum TPO-Ab titer was determined by ELISA method using commercial kits. Results. Serum FT4 and TSH levels in HCV patients and controls were within normal range. Between two groups there was no significant difference in mean value of FT4 (16.0 ± 3.0 versus 16.2 ± 3.9; P=0.619 but mean TSH value was significantly lower in HCV patients (1.5 ± 0.8 versus 1.8 ± 0.9; P=0.003. Among HCV patients 51 (26.8% were TPO-Ab positive and among control subjects 18 (6.9% were TPO-Ab positive. The difference was statistically significant (P<0.001. Further analysis showed that among HCV patients 39 (27.8% females and 12 (24.0% males were TPO-Ab positive, respectively, and difference was not statistically significant (P=0.873. Moreover, TPO-Ab positive patients were older and had significantly higher serum TSH as compared to TPO-Ab negative HCV patients. Conclusion. Independent of patient’s gender and increasing with advancing age, about one-fourth of local untreated HCV patients are TPO-Ab positive and are at greater risk of developing thyroid disorders during and after interferon treatment.

Antiviral activity of Small interfering RNAs: Specificity testing using heterologous virus reveals interferon-related effects overlooked by conventional mismatch controls

DEFF Research Database (Denmark)

Schyth, Brian Dall; Lorenzen, Niels; Pedersen, Finn Skou

2006-01-01

to the viral glycoprotein gene of the target-virus efficiently inhibited viral multiplication in infected cell cultures, while two of three corresponding mismatched siRNAs did not have this effect. This suggested specific interference, but similar results were obtained when the same siRNAs were tested against...... a heterologous virus. Further analyses revealed that the siRNAs induced a non-target-specific anti-viral effect correlating with upregulation of the interferon induced Mx gene....

Effects of a single dose of enrofloxacin on body temperature and tracheobronchial neutrophil count in healthy Thoroughbreds premedicated with interferon-α and undergoing long-distance transportation.

Science.gov (United States)

Tsuchiya, Takeru; Hobo, Seiji; Endo, Yoshiro; Narita, Shoichi; Sakamoto, Koji

2012-07-01

To evaluate effects of a single dose of enrofloxacin (5 mg/kg, IV) on body temperature and tracheobronchial neutrophil count in healthy Thoroughbreds premedicated with interferon-α and undergoing long-distance transportation. 32 healthy Thoroughbreds. All horses received interferon-α (0.5 U/kg, sublingually, q 24 h) as an immunologic stimulant for 2 days before transportation and on the day of transportation. Horses were randomly assigned to receive enrofloxacin (5 mg/kg, IV, once; enrofloxacin group) or saline (0.9% NaCl) solution (50 mL, IV, once; control group) ≤ 1 hour before being transported 1,210 km via commercial vans (duration, approx 26 hours). Before and after transportation, clinical examination, measurement of temperature per rectum, and hematologic analysis were performed for all horses; a tracheobronchial aspirate was collected for neutrophil quantification in 12 horses (6/group). Horses received antimicrobial treatment after transportation if deemed necessary by the attending clinician. No adverse effects were associated with treatment. After transportation, WBC count and serum amyloid A concentration in peripheral blood samples and neutrophil counts in tracheobronchial aspirates were significantly lower in horses of the enrofloxacin group than in untreated control horses. Fever (rectal temperature, ≥ 38.5°C) after transportation was detected in 3 of 16 enrofloxacin group horses and 9 of 16 control horses; additional antimicrobial treatment was required in 2 horses in the enrofloxacin group and 7 horses in the control group. In horses premedicated with interferon-α, enrofloxacin appeared to provide better protection against fever and lower respiratory tract inflammation than did saline solution.

Interferon-alpha treatment of children with chronic hepatitis D virus infection: the Greek experience.

Science.gov (United States)

Dalekos, G N; Galanakis, E; Zervou, E; Tzoufi, M; Lapatsanis, P D; Tsianos, E V

2000-01-01

The therapeutic experience of interferon-alpha therapy against hepatitis D virus infection in affected children is rather limited. For this reason, we conducted a retrospective study (duration: 1991-1995) in order to evaluate the efficacy and the safety of interferon-alpha in children suffering from chronic hepatitis D in Northwestern Greece. Seven children who were found to be infected with HDV in a total of 324 children seropositive for hepatitis B virus infection during the 5-year period of the study were treated with interferon-alpha, 3 x 10(6) U/m2 body surface area, intramuscularly or subcutaneously, 3 times weekly for 1 year (after an informed consent obtained from their parents). Patients were assessed monthly by hematological serological and biochemical tests. Clinical progress, levels of serum alanine aminotransferase, hepatitis D ribonucleic acid (HDV-RNA) and hepatitis B deoxyribonucleic acid (HBV-DNA), seroconversion of hepatitis B surface antigen (HBsAg) and Hepatitis Be Antigen (HBeAg) and liver histology were used as response criteria. Posttreatment alanine transferase levels were significantly reduced (P < 0.05) but Immunoglobulin M and total anti-hepatitis D virus (anti-HDV) antibodies remained positive in all, while hepatitis D ribonucleic acid persisted positive in 4 cases. In addition, no seroconversion of HBsAg or HBeAg was noted and the liver histology progress was disappointing. Side effects including mild fever, arthralgias and malaise and reversible neutropenia and thrombocytopenia were common, but not particularly disturbing. Nevertheless, the children remained fully active on treatment, felt well and attended school. Initially 4 children had been below the 10th percentile for weight and height. All thrived during treatment and two crossed above the 10th percentile indicating height velocity and body mass index increase. The administration of regular interferon-alpha doses for treating children with chronic hepatitis D was safe as

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.

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...

Effect of soluble factors derived from oral cancer cells on the production of interferon-γ from peripheral blood mononuclear cells following stimulation with OK-432.

Science.gov (United States)

Ohe, Go; Sasai, Akiko; Uchida, Daisuke; Tamatani, Tetsuya; Nagai, Hirokazu; Miyamoto, Youji

2013-08-01

The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432.

[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 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

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.

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.

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...

Mycobacterium tuberculosis epitope-specific interferon-g production in healthy Brazilians reactive and non-reactive to tuberculin skin test

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Bosco Christiano Maciel da Silva

2014-12-01

Full Text Available The interferon (IFN-γ response to peptides can be a useful diagnostic marker of Mycobacterium tuberculosis (MTB latent infection. We identified promiscuous and potentially protective CD4+ T-cell epitopes from the most conserved regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2, phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm. Seven peptide sequences predicted to bind to multiple human leukocyte antigen (HLA-DR molecules were synthesised and tested with IFN-γ enzyme-linked immunospot (ELISPOT assays using peripheral blood mononuclear cells (PBMCs from 16 Mantoux tuberculin skin test (TST-positive and 16 TST-negative healthy donors. Eighty-eight percent of TST-positive donors responded to at least one of the peptides, compared to 25% of TST-negative donors. Each individual peptide induced IFN-γ production by PBMCs from at least 31% of the TST-positive donors. The magnitude of the response against all peptides was 182 ± 230 x 106 IFN-γ spot forming cells (SFC among TST-positive donors and 36 ± 62 x 106 SFC among TST-negative donors (p = 0.007. The response to GroEL2 (463-477 was only observed in the TST-positive group. This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort of individuals with latent tuberculosis (TB to evaluate its potential to diagnose latent TB and it may be included in ELISPOT-based IFN-γ assays to identify individuals with this condition.

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)

Human Cytomegalovirus Exploits Interferon-Induced Transmembrane Proteins To Facilitate Morphogenesis of the Virion Assembly Compartment

Science.gov (United States)

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

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-1a in moderately active ulcerative colitis

DEFF Research Database (Denmark)

Pena-Rossi, C; Schreiber, S; Golubovic, G

2008-01-01

Background Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms, and thus represents a potential treatment. Aim...

Interferon-alpha subtype 11 activates NK cells and enables control of retroviral infection.

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Kathrin Gibbert

Full Text Available The innate immune response mediated by cells such as natural killer (NK cells is critical for the rapid containment of virus replication and spread during acute infection. Here, we show that subtype 11 of the type I interferon (IFN family greatly potentiates the antiviral activity of NK cells during retroviral infection. Treatment of mice with IFN-α11 during Friend retrovirus infection (FV significantly reduced viral loads and resulted in long-term protection from virus-induced leukemia. The effect of IFN-α11 on NK cells was direct and signaled through the type I IFN receptor. Furthermore, IFN-α11-mediated activation of NK cells enabled cytolytic killing of FV-infected target cells via the exocytosis pathway. Depletion and adoptive transfer experiments illustrated that NK cells played a major role in successful IFN-α11 therapy. Additional experiments with Mouse Cytomegalovirus infections demonstrated that the therapeutic effect of IFN-α11 is not restricted to retroviruses. The type I IFN subtypes 2 and 5, which bind the same receptor as IFN-α11, did not elicit similar antiviral effects. These results demonstrate a unique and subtype-specific activation of NK cells by IFN-α11.

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis.

Science.gov (United States)

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.

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.

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.

Science.gov (United States)

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.

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 ...

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.

Related regulation of quality control of industrial products

International Nuclear Information System (INIS)

1983-04-01

This book introduce related regulation of quality control of industrial products, which includes regulations of industrial products quality control, enforcement ordinance of industrial products quality control, enforcement regulation of quality control of industrial products, designated items with industrial production quality indication, industrial production quality test, and industrial production quality test organization and management tips of factory quality by grade.

Association between product quality control and process quality control of bulk milk

NARCIS (Netherlands)

Velthuis, A.; Asseldonk, van M.A.P.M.

2010-01-01

Assessment of dairy-milk quality is based on product quality control (testing bulk-milk samples) and process quality control (auditing dairy farms). It is unknown whether process control improves product quality. To quantify possible association between product control and process control a

Plasma levels of interlukin-4 and Interferon- in patients with chronic or healed cutaneous leishmaniasis

OpenAIRE

Ahmad Reza Taheri; Vahid Mashayekhi Goyonlo; Yalda Nahidi; Nasrin Moheghi; Jalil Tavakkol Afshari

2014-01-01

Objective(s): In this study, the serum level of interferon-γ (IFN- γ) and interlukin-4 (IL-4) was evaluated as a marker of Th1 and Th2 immune response that influence the clinical course of cutaneous leishmaniasis . Materials and Methods: This cross-sectional study was conducted on 44 cases of cutaneous leishmaniasis (21 cases with healed lesions and 23 cases with chronic non-healing lesions. Thirty-two non-infected persons living in the area were considered as controls. Serum levels of IFN- γ...

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-1a in moderately active ulcerative colitis

DEFF Research Database (Denmark)

Pena-Rossi, C; Schreiber, S; Golubovic, G

2008-01-01

Background Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms, and thus represents a potential treatment. Aim To ex...

Superiority of Interferon-Free Regimens for Chronic Hepatitis C: The Effect on Health-Related Quality of Life and Work Productivity.

Science.gov (United States)

Younossi, Zobair M; Stepanova, Maria; Esteban, Rafael; Jacobson, Ira; Zeuzem, Stefan; Sulkowski, Mark; Henry, Linda; Nader, Fatema; Cable, Rebecca; Afendy, Mariam; Hunt, Sharon

2017-02-01

Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.

Development of a lion-specific interferon-gamma assay.

Science.gov (United States)

Maas, M; van Kooten, P J S; Schreuder, J; Morar, D; Tijhaar, E; Michel, A L; Rutten, V P M G

2012-10-15

The ongoing spread of bovine tuberculosis (BTB) in African free-ranging lion populations, for example in the Kruger National Park, raises the need for diagnostic assays for BTB in lions. These, in addition, would be highly relevant for zoological gardens worldwide that want to determine the BTB status of their lions, e.g. for translocations. The present study concerns the development of a lion-specific IFN-γ assay, following the production and characterization of monoclonal antibodies specific for lion interferon-gamma (IFN-γ). Recombinant lion IFN-γ (rLIFN-γ) was produced in mammalian cells and used to immunize mice to establish hybridoma cell lines producing monoclonal antibodies. These were used to develop a sensitive, lion IFN-γ-specific capture ELISA, able to detect rLIFN-γ to the level of 160 pg/ml. Recognition of native lion IFN-γ was shown in an initial assessment of supernatants of mitogen stimulated whole blood cultures of 11 known BTB-negative lions. In conclusion, the capture ELISA shows potential as a diagnostic assay for bovine tuberculosis in lions. Preliminary results also indicate the possible use of the test for other (feline) species. Copyright © 2012 Elsevier B.V. All rights reserved.

Interferons in Sjögren’s syndrome: genes, mechanisms, and effects

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He eLi

2013-09-01

Full Text Available Sjögren’s syndrome (SS is a common, progressive autoimmune exocrinopathy distinguished by dry eyes and mouth and affects ~0.7% of European population. Overexpression of transcripts induced by interferons (IFN, termed as an ‘IFN signature’, has been found in SS patients. Four microarray studies have been published in SS that identified dysregulated genes within type I IFN signaling in either salivary glands or peripheral blood of SS patients. The mechanism of this type I IFN activation is still obscure, but several possible explanations have been proposed, including virus infection-initiated and immune-complex-initiated type I IFN production by plasmacytoid dendritic cells (pDCs. Genetic predisposition to increased type I IFN signaling is supported by candidate gene studies showing evidence for association of variants within IFN-related genes. Once activated, IFN signaling may contribute to numerous aspects of SS pathophysiology, including lymphocyte infiltration into exocrine glands, autoantibody production, and glandular cell apoptosis. Thus, dysregulation of IFN pathways is an important feature that can be potentially used as a serum biomarker for diagnosis and targeting of new treatments in this complex autoimmune disease.

Guarding the frontiers: the biology of type III interferons

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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...

Patient subgroup analyses of the treatment effect of subcutaneous interferon beta-1a on development of multiple sclerosis in the randomized controlled REFLEX study

NARCIS (Netherlands)

Freedman, M.S.; De Stefano, N.; Barkhof, F.; Polman, C.H.; Comi, G.; Uitdehaag, B.M.J.; Casset-Semanaz, F.; Hennessy, B.; Lehr, L.; Stubinski, B.; Jack, D.L.; Kappos, L.

2014-01-01

The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) β-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to

Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses.

Science.gov (United States)

Qu, Lin; Lemon, Stanley M

2010-11-01

Hepatitis A and hepatitis C viruses (HAV and HCV) are both positive-strand ribonucleic acid (RNA) viruses with hepatotropic lifestyles. Despite several important differences, they share many biological and molecular features and similar genome replication schemes. Despite this, HAV infections are usually effectively controlled by the host with elimination of the virus, whereas HCV most often is able to establish lifelong persistent infection. The mechanisms underlying this difference are unknown. The cellular helicases RIG-I and MDA5, and Toll-like receptor 3, are pattern recognition receptors that sense virus-derived RNAs within hepatocytes in the liver. Activation of these receptors leads to their interaction with specific adaptor proteins, mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing adapter-inducing interferon-β (TRIF), respectively, which engage downstream kinases to activate two crucial transcription factors, nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). This results in the induction of interferons (IFNs) and IFN-stimulated genes that ultimately establish an antiviral state. These signaling pathways are central to host antiviral defense and thus frequent targets for viral interference. Both HAV and HCV express proteases that target signal transduction through these pathways and that block the induction of IFNs upon sensing of viral RNA by these receptors. An understanding of the differences and similarities in the early innate immune responses to these infections is likely to provide important insights into the mechanism underlying the long-term persistence of HCV. © Thieme Medical Publishers.

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

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...

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.

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.

Evolution and Antiviral Specificities of Interferon-Induced Mx Proteins of Bats against Ebola, Influenza, and Other RNA Viruses.

Science.gov (United States)

Fuchs, Jonas; Hölzer, Martin; Schilling, Mirjam; Patzina, Corinna; Schoen, Andreas; Hoenen, Thomas; Zimmer, Gert; Marz, Manja; Weber, Friedemann; Müller, Marcel A; Kochs, Georg

2017-08-01

Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned Mx1 cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat Mx1 genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat Mx1 genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts. IMPORTANCE Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity

Development of a new formulation of interferons (HEBERPAG for BCC treatment

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Bello-Rivero I

2013-12-01

Full Text Available Purpose: This work is aimed to show briefly, the clinical development of a new pharmaceutical formulation of interferons for the treatment of basal cell carcinoma. Methods: A rationale design of the combination of IFN-α2b and -γ based in their anti-proliferative synergism on several tumors cell lines identified adequate proportions to be combined to obtain the best clinical results. The potential mechanism of antitumoral effect was studied by qPCR mRNA quantification. HEBERPAG (anti-proliferative synergistic combination of co-formulated recombinant interferons-α2b and –γ was used in clinical trials in adult patients with non-melanoma skin cancer. Trials were conducted after approval by the ethics review boards of the institutions participating in trials; and the patients gave their written informed consent to be enrolled in the studies and receive HEBERPAG. Results: HEBERPAG inhibits the proliferation of several tumor cell lines in vitro and in vivo. The combination has improved pharmacodinamic properties. Several clinical trials have demonstrated the efficacy of HEBERPAG in BCC, with excellent cosmetic effect and well tolerable, mild side effects. HEBERPAG was approved by State Control Center for Drug, Medical Equipment and Devises in Cuba, for the treatment of basal cell carcinoma of any subtype, size and localization, and adjuvant to other treatments, surgical or not. After 3-year follow-up, a recurrence rate of 0.03% was detected in treated patients. Conclusions: HEBERPAG is a novel formulation of IFNs, more potent than separated IFNs for the treatment of basal cell carcinoma, with more rapid and prolonged clinical effect and excellent cosmetic effect and safety profile.

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.

The effect of interferon on the receptor sites to rabies virus on mouse neuroblastoma cells

International Nuclear Information System (INIS)

Briggs, D.J.

1989-01-01

The binding of rabies virus to mouse neuroblastoma cells (MNA) primed with alpha interferon (IFN-α), beta interferon (IFN-β), or alpha bungarotoxin (BTX) was examined. A saturable number of receptor sites to rabies virus was calculated by increasing the amount of 3 H-CVS added to a constant number of untreated MNA cells. MNA cells were then exposed to 20 I.U. of IFN-α, IFN-β, or 1 μg of BTX and assayed to determine if these treatments had an effect on the number of receptor sites to rabies virus. Total amount of 3 H-CVS bound to MNA cells was determined during a three hour incubation period. Cold competition assays using 1,000 fold excess unlabeled CVS were used to determine non-specific binding for each treatment. Specific binding was then calculated by subtracting non-specific binding from the total amount of CVS bound to MNA cells. A similar amount of total viral protein bound to untreated and IFN-β, and BTX treated cells after 180 minutes of incubation. The bound protein varied by only 0.07 μg. However, the amount of specific and non-specific binding varied a great deal between treatments. BTX caused an increase in non-specific and a decrease in specific binding of rabies virus. IFN-β produced variable results in non-specific and specific binding while IFN-α caused mainly specific binding to occur. The most significant change brought about by IFN-α was an increase in the rate of viral attachment. At 30 minutes post-infection, IFN-α treated cells had bound 90% of the total amount of virus bound to untreated cells after 180 minutes. The increased binding rate did not cause a productive infection of rabies virus. No viral production was evident after an incubation period of 48 hours in either IFN-α or IFN-β treated cells

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

Adjuvant interferon gamma in patients with drug – resistant pulmonary tuberculosis: a pilot study

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Carbonell Dalia

2004-10-01

Full Text Available Abstract Background Tuberculosis (TB is increasing in the world and drug-resistant (DR disease beckons new treatments. Methods To evaluate the action of interferon (IFN gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 106 IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly. Results Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed. Conclusions These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged.

Antigen induced production of υ-interferon ex vivo, in the peripheral blood of patients with active pulmonary tuberculosis

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Z. M. Zagdyn

2013-01-01

Full Text Available Tuberculosis (TB is one of the most significant problems in the Russian Health Care. Russia remains on the list of the 22 countries with a high TB incidence and on the third place in the world with a high prevalence of Drug Resistant TB [1]. It is urgently needed to develop new TB diagnostic methods as well as effective measures of the specific TB prevention, including a development of the novel vaccines, so we have to know better about the most immunogenic antigens of Mycobacterium Tuberculosis. We studied the Interferon-Q production in the whole blood after stimulating immune response with different proteins of Mycobacterium Tuberculosis in patients with active TB. The study results permitted us to evaluate the immunogenicity of the previously known proteins (Ag85a и ESAT-6 in comparison to the recently identified ones (Rv2957, Rv2958c и Rv0447, analyzing simultaneously their relation to tuberculin, as well as to antigens of the different viruses (Human Immunodeficiency Virus, Cytomegalovirus, Epstein-Barr Virus, Influenza Virus. Protein Rv2958c, unlike protein ESAT-6, showed the high immunogenicity in comparison to tuberculin. The expressed immunogenicity of protein Rv2958c might be indicated a possible greatest specificity of immune response to this antigen in TB patients. Meanwhile, bacillary tuberculosis was strongly associated with low immune response to this protein. Also we were found statistical differences in immune responses of patients to the different Mycobacterium Tuberculosis antigens depending on the drug sensitivity. In addition it was interesting to know about a significantly low immune response of patients with Drug Resistant TB to protein pp65 CMV.

[Allergic asthma and interleukins 2, 4, 5, 6 and 12 and gamma interferon levels].

Science.gov (United States)

Bastida Segura, Diana Lyzbeth; López Velásquez, Benjamin; Castrejón Vázquez, María Isabel; Galicia Tapía, Jorge; Cano Altamirano, Silvia; Miranda Feria, Alfonso Javier

2004-01-01

Asthma is an inflammatory chronic illness, in which mastocyt cells, basophils, T lymphocytes, eosinophils and cytokines play a role. Its association with the production of TH2 cytokines is not well known, but it is considered an aberrant immune response, yielding the activation and recruitment of a number of effector cells (mastocyts/eosinophils) and the appearance of clinical symptoms. To determine the serum values of the interleukins 2, 4, 5, 6 and 12 and gamma interferon in relation to the severity degree of asthma and the time of immunotherapy in patients with stable chronic allergic bronchial asthma. Clinical records of allergic asthmatic patients from the external consultation at Servicio de Alergia e Immunología Clínica were reviewed in a period of 12 months (1st January 2002 to 1st January 2003) and those of healthy volunteers, forming three groups: Group 1, allergic asthmatics with immunotherapy less than 24 months; Group 2, allergic asthmatics with more than 24 months of immunotherapy, and Group 3, healthy volunteers (control group). Previous informed consent, a serum sample was taken of all subjects. Ninety-two subjects were included: 41 (45%) allergic asthmatics and 51 (55%) healthy volunteers. Significant differences were found in interleukins 2, 4, 5, 6 and 12 levels between healthy volunteers and asthmatics without relating the immunotherapy time. In the total group gamma interferon levels were not found. A relation of interleukins Th2 levels with the severity degree of asthma was not found. Differences of serum interleukins Th1 and Th2 in allergic patients related to immunotherapy time were not significant; even though, irrespective of immunotherapy time, IgG levels were always high. Patients with allergic asthma have a predominance of serum interleukins Th2 and, despite of the immunotherapy, in the maintaining phase, these continue high, which may be due to an immune system dysregulation maybe including other factors. Immunotherapy continues

[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.

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

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.

Shutdown of interferon signaling by a viral-hijacked E3 ubiquitin ligase

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Kaitlin A. Davis

2017-11-01

Full Text Available Viruses manipulate cellular processes to create an environment favorable to replication. For most viruses, this includes subverting the expression of interferon (IFN, a signaling molecule that can stimulate production of a vast array of antiviral gene products. Rotavirus, a segmented double-stranded RNA virus that causes acute gastroenteritis in infants and young children, inhibits IFN expression through its nonstructural protein NSP1. This viral protein stifles IFN expression by inducing the degradation of host factors that are necessary for upregulating the activity of IFN genes. In the case of nearly all human and porcine rotavirus strains, NSP1 induces the ubiquitination-dependent proteasomal degradation of β-transducin repeat containing protein (β-TrCP, a host factor that plays an essential role in activating the IFN-transcription factor, NF-κB. Key to the process is the presence of a decoy sequence (degron at the C-terminus of NSP1 that causes β-TrCP to mistakenly bind NSP1 instead of its natural target, inhibitor-of-κB (IκB. In a recent report published by Davis et al [2017; mBio 8(4: e01213-17], we describe molecular requirements that govern NSP1 recognition of β-TrCP, including an essential degron phosphorylation event, and the step-wise incorporation of NSP1 into hijacked cullin-RING E3 ligases (CRLs that ubiquitinate and tag β-TrCP for degradation. Notably, although β-TrCP is chiefly recognized for its role as a master regulator of NF-κB signaling and IFN expression, β-TrCP also controls the stability of checkpoint proteins implicated in numerous other cellular pathways with antiviral activities, including autophagy and apoptosis. Thus, the impact of NSP1 on creating an intracellular environment favorable to virus replication may extend well beyond the IFN signaling pathway.

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 ...

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.

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.

The type I interferon response during viral infections: a "SWOT" analysis.

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Gaajetaan, Giel R; Bruggeman, Cathrien A; Stassen, Frank R

2012-03-01

The type I interferon (IFN) response is a strong and crucial moderator for the control of viral infections. The strength of this system is illustrated by the fact that, despite some temporary discomfort like a common cold or diarrhea, most viral infections will not cause major harm to the healthy immunocompetent host. To achieve this, the immune system is equipped with a wide array of pattern recognition receptors and the subsequent coordinated type I IFN response orchestrated by plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs). The production of type I IFN subtypes by dendritic cells (DCs), but also other cells is crucial for the execution of many antiviral processes. Despite this coordinated response, morbidity and mortality are still common in viral disease due to the ability of viruses to exploit the weaknesses of the immune system. Viruses successfully evade immunity and infection can result in aberrant immune responses. However, these weaknesses also open opportunities for improvement via clinical interventions as can be seen in current vaccination and antiviral treatment programs. The application of IFNs, Toll-like receptor ligands, DCs, and antiviral proteins is now being investigated to further limit viral infections. Unfortunately, a common threat during stimulation of immunity is the possible initiation or aggravation of autoimmunity. Also the translation from animal models to the human situation remains difficult. With a Strengths-Weaknesses-Opportunities-Threats ("SWOT") analysis, we discuss the interaction between host and virus as well as (future) therapeutic options, related to the type I IFN system. Copyright © 2011 John Wiley & Sons, Ltd.

Mx Is Not Responsible for the Antiviral Activity of Interferon-α against Japanese Encephalitis Virus

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Jing Zhou

2017-01-01

Full Text Available Mx proteins are interferon (IFN-induced dynamin-like GTPases that are present in all vertebrates and inhibit the replication of myriad viruses. However, the role Mx proteins play in IFN-mediated suppression of Japanese encephalitis virus (JEV infection is unknown. In this study, we set out to investigate the effects of Mx1 and Mx2 expression on the interferon-α (IFNα restriction of JEV replication. To evaluate whether the inhibitory activity of IFNα on JEV is dependent on Mx1 or Mx2, we knocked down Mx1 or Mx2 with siRNA in IFNα-treated PK-15 cells and BHK-21 cells, then challenged them with JEV; the production of progeny virus was assessed by plaque assay, RT-qPCR, and Western blotting. Our results demonstrated that depletion of Mx1 or Mx2 did not affect JEV restriction imposed by IFNα, although these two proteins were knocked down 66% and 79%, respectively. Accordingly, expression of exogenous Mx1 or Mx2 did not change the inhibitory activity of IFNα to JEV. In addition, even though virus-induced membranes were damaged by Brefeldin A (BFA, overexpressing porcine Mx1 or Mx2 did not inhibit JEV proliferation. We found that BFA inhibited JEV replication, not maturation, suggesting that BFA could be developed into a novel antiviral reagent. Collectively, our findings demonstrate that IFNα inhibits JEV infection by Mx-independent pathways.

Quality control of radioactive waste products

International Nuclear Information System (INIS)

Martens, B.R.; Warnecke, E.; Odoj, R.

1986-01-01

The variety of incoming untreated wastes, treatment methods, waste forms and containers requires a great variety of controlling methods and principles to be applied both during waste treatment and on the final product. The paper describes product control schemes and methods, sampling systems and transportable testing equipment for waste drums, and equipment for waste cementation using in-drum stirring and subsequent fixation of solid wastes in the flowable product. (DG) [de

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

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.

Bortezomib Enhances the Antitumor Effects of Interferon-β Gene Transfer on Melanoma Cells.

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Rossi, Ursula A; Finocchiaro, Liliana M E; Glikin, Gerardo C

2017-01-01

Malignant melanoma is a fast growing form of skin cancer with increasing global incidence. Clinically, canine malignant melanoma and human melanoma share comparable treatment-resistances, metastatic phenotypes and site selectivity. Both interferon-β (IFNβ) and bortezomib (BTZ) display inhibitory activities on melanoma cells. Here, we evaluated the cytotoxic effects of the combination of BTZ and IFNβ gene lipofection on cultured melanoma cell lines. Cell viability determined by the acid phosphatase method, cell migration mesasured by the wound healing assay, DNA fragmentation and cell cycle by flow cytometry after propidium iodide staining and reactive oxygen species (ROS) production by H2DCF-DA fluorescence. Four canine mucosal (Ak, Br, Bk and Ol) and two human dermal (A375 and SB2) melanoma cell lines were assayed. BTZ sub-pharmacological concentrations (5 nM) enhanced the cytotoxic effects of IFNβ transgene expression on melanoma cells monolayers and spheroids. The combination was also more effective than the single treatments when assayed for clonogenic survival and cell migration. The combined treatment produced a significant raise of apoptosis evidenced by DNA fragmentation as compared to either BTZ or IFNβ gene lipofection single treatments. Furthermore, BTZ significantly increased the intracellular ROS generation induced by IFNβ gene transfer in melanoma cells, an effect that was reversed by the addition of the ROS inhibitor N-acetyl-L-cystein. The present work encourages further studies about the potential of the combination of interferon gene transfer with proteasome inhibitors as a new combined therapy for malignant melanoma, both in veterinary and/or human clinical settings. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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?

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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.

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

Interferon versus methotrexate in intermediate uveitis with macular edema: results of a randomized controlled clinical trial.

Science.gov (United States)

Mackensen, Friederike; Jakob, Eva; Springer, Christina; Dobner, Bianca C; Wiehler, Ute; Weimer, Petra; Rohrschneider, Klaus; Fiehn, Christoph; Max, Regina; Storch-Hagenlocher, Brigitte; Becker, Matthias D

2013-09-01

To compare interferon (IFN) beta with methotrexate (MTX) in the treatment of intermediate uveitis with macular edema. Monocentric, prospective, randomized, controlled clinical trial. Specialized uveitis center at the University of Heidelberg. PATIENT OR STUDY POPULATION: Patients with either primary intermediate uveitis or uveitis associated with multiple sclerosis. MAIN INCLUSION CRITERIA: Visual acuity of 20/30 or worse (0.2 logarithm of the minimal angle of resolution) and macular edema of more than 250 μm (central 1-mm in optical coherence tomography; Stratus). Randomization into either IFN beta 44 μg subcutaneously 3 times weekly or 20 mg MTX subcutaneously once weekly. At 3 months, the primary outcome parameter of mean change in visual acuity was evaluated and efficacy was determined. Secondary parameters were macular edema by optical coherence tomography, inflammatory activity, and retinal sensitivity by microperimetry (MP-1; Nidek). In case of treatment failure, switching to the other treatment arm was possible. Nineteen patients were included. Ten were randomized to MTX, and 9 were randomized to IFN beta. At 3 months, visual acuity improved a mean 0.31 logarithm of the minimal angle of resolution (range, -0.02 to -0.96, 15.6 letters on the Early Treatment Diabetic Retinopathy Study chart) in the IFN beta group versus a mean 0.09 logarithm of the minimal angle of resolution (range, 0.12 to -0.38, 4.7 letters) in the MTX arm (P = .0435, Mann-Whitney U test). Macular thickness decreased by a mean of 206 μm (range, -41 to -416 μm) in the IFN arm, but increased by 47 μm (range, 108 to -28 μm) in the MTX group (P treatment of macular edema in the setting of intermediate uveitis. Copyright © 2013 Elsevier Inc. All rights reserved.

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....

2. Product quality control and assurance system

International Nuclear Information System (INIS)

1990-01-01

Product quality control and assurance are dealt with in relation to reliability in nuclear power engineering. The topics treated include product quality control in nuclear power engineering, product quality assurance of nuclear power plant equipment, quality assurance programs, classification of selected nuclear power equipment, and standards relating to quality control and assurance and to nuclear power engineering. Particular attention is paid to Czechoslovak and CMEA standards. (P.A.). 2 figs., 1 tab., 12 refs

INTERFERON BETA IN TREATMENT OF DISSEMINATED SCLEROSIS IN ADOLESCENTS — INFLUENCE ON NEUROPSYCHOLOGICAL STATUS AND PAROXYSMAL STATES

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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

Deregulation of Interferon Signaling in Malignant Cells

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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.

G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA.

Science.gov (United States)

Bidet, Katell; Dadlani, Dhivya; Garcia-Blanco, Mariano A

2014-07-01

Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV). We examined three conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2) infection and found them to be novel regulators of the interferon (IFN) response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs), and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells.

Interferon-associated therapies toward HIV control: The back and forth.

Science.gov (United States)

Noël, Nicolas; Jacquelin, Béatrice; Huot, Nicolas; Goujard, Cécile; Lambotte, Olivier; Müller-Trutwin, Michaela

2018-03-09

Human immunodeficiency virus (HIV) induces a persistent and incurable infection. However, the combined antiretroviral treatment (cART) has markedly changed the evolution of the infection and transformed a deadly disease into a manageable chronic infection. Withdrawal of cART generally leads though to resumption of the viral replication. The eradication of the virus from its cellular and anatomical reservoirs remains a goal-to-achieve for a cure. In this context, developing novel therapies contributing to this aim are an important field of research. Type I IFN has antiviral activity, which, before the presence of efficient anti-HIV drugs, has led to the testing of IFN-based therapeutic strategies during the early years of the pandemic. A historical overview of the results and its limitations that were put into light are reviewed here. In addition, several lessons could be drawn. For instance, the efficacy of the IFN-I depends on the timing of its administration and the context. Thus, the persistence of an endogenous IFN-signature, such as that generally observed in viremic patients, seems to be associated with a lower efficacy of IFN. Based on the lessons from previous trials, and in the context of cART and research for a cure, type I Interferon has regained interest and novel therapeutic approaches are currently tested in combination with cART, some with disappointing, other with encouraging results with regard to a reduction in the size of the HIV reservoir and/or delays in viral rebound after cessation of cART. Additional strategies are currently developed in addition to improve the antiviral function of the IFN-I, by using for instance other IFN subtypes than IFN-Iα2. In parallel, the development of innovative strategies aimed at counteracting the excessive activation of the IFN-pathways have been continued and their results are reviewed here as well. Altogether, the use of IFN-I in anti-HIV therapies has gone through distinct phases and many lessons could be

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

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 induced IFIT family genes in host antiviral defense.

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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.

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression.

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Law, Becker M P; Wilkinson, Ray; Wang, Xiangju; Kildey, Katrina; Lindner, Mae; Rist, Melissa J; Beagley, Kenneth; Healy, Helen; Kassianos, Andrew J

2017-07-01

Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3 - CD56 + ) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56 dim NK cell subset and particularly the CD56 bright NK cell subset were elevated in fibrotic kidney tissue. However, only CD56 bright NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56 bright NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56 bright NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56 bright NK cells (NKp46 + CD117 + ) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56 bright NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3.

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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

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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.

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.

Direct product quality control for energy efficient climate controlled transport of agro-material

NARCIS (Netherlands)

Verdijck, G.J.C.; Preisig, H.A.; Straten, van G.

2005-01-01

A (model-based) Product Quality Controller is presented for climate controlled operations involving agro-material, such as storage and transport. This controller belongs to the class of Model Predictive Controllers and fits in a previously developed hierarchical control structure. The new Product

Systematic Product Development of Control and Diagnosis Functionalities

Science.gov (United States)

Stetter, R.; Simundsson, A.

2017-01-01

In the scientific field of systematic product development a wide range of helpful methods, guidelines and tools were generated and published in recent years. Until now little special attention was given to design guidelines aiming at supporting product development engineers to design products that allow and support control or diagnosis functions. The general trend to ubiquitous computing and the first development steps towards cognitive systems as well as a general trend toward higher product safety, reliability and reduced total cost of ownership (TCO) in many engineering fields lead to a higher importance of control and diagnosis. In this paper a first attempt is made to formulate general valid guidelines how products can be developed in order to allow and to achieve effective and efficient control and diagnosis. The guidelines are elucidated on the example of an automated guided vehicle. One main concern of this paper is the integration of control and diagnosis functionalities into the development of complete systems which include mechanical, electrical and electronic subsystems. For the development of such systems the strategies, methods and tools of systematic product development have attracted significant attention during the last decades. Today, the functionality and safety of most products is to a large degree dependent on control and diagnosis functionalities. Still, there is comparatively little research concentrating on the integration of the development of these functionalities into the overall product development processes. The paper starts with a background describing Systematic Product Development. The second section deals with the product development of the sample product. The third part clarifies the notions monitoring, control and diagnosis. The following parts summarize some insights and formulate first hypotheses concerning control and diagnosis in Systematic Product Development.

Combination therapy with interferon and JAK1-2 inhibitor is feasible

DEFF Research Database (Denmark)

Bjørn, M E; de Stricker, K; Kjær, L

2014-01-01

We report a 55 year old woman with post-ET PV for 12 years, who experienced resolution of severe constitutional symptoms within 3 days, a marked reduction in splenomegaly and a rapid decline in the JAK2V617F allele burden during combination therapy with interferon-alpha2a and ruxolitinib. Within ...

Expression of biologically active human interferon alpha 2 in aloe vera

Science.gov (United States)

We have developed a system for transgenic expression of proteins in Aloe Vera. Using this approach we have generated plants expressing the human gene interferon alpha 2, IFNa2. IFNa2 is a small secreted cytokine that plays a vital role in regulating the body’s immune response to viral infections a...

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP)

DEFF Research Database (Denmark)

Fattovich, G; Giustina, G; Degos, F

1997-01-01

The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C....

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study.

Science.gov (United States)

Kalincik, Tomas; Brown, J William L; Robertson, Neil; Willis, Mark; Scolding, Neil; Rice, Claire M; Wilkins, Alastair; Pearson, Owen; Ziemssen, Tjalf; Hutchinson, Michael; McGuigan, Christopher; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grammond, Pierre; Alroughani, Raed; Pucci, Eugenio; Sola, Patrizia; Hupperts, Raymond; Lechner-Scott, Jeannette; Terzi, Murat; Van Pesch, Vincent; Rozsa, Csilla; Grand'Maison, François; Boz, Cavit; Granella, Franco; Slee, Mark; Spitaleri, Daniele; Olascoaga, Javier; Bergamaschi, Roberto; Verheul, Freek; Vucic, Steve; McCombe, Pamela; Hodgkinson, Suzanne; Sanchez-Menoyo, Jose Luis; Ampapa, Radek; Simo, Magdolna; Csepany, Tunde; Ramo, Cristina; Cristiano, Edgardo; Barnett, Michael; Butzkueven, Helmut; Coles, Alasdair

2017-04-01

Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], pmultiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly

Automatic control algorithm effects on energy production

Science.gov (United States)

Mcnerney, G. M.

1981-01-01

A computer model was developed using actual wind time series and turbine performance data to simulate the power produced by the Sandia 17-m VAWT operating in automatic control. The model was used to investigate the influence of starting algorithms on annual energy production. The results indicate that, depending on turbine and local wind characteristics, a bad choice of a control algorithm can significantly reduce overall energy production. The model can be used to select control algorithms and threshold parameters that maximize long term energy production. The results from local site and turbine characteristics were generalized to obtain general guidelines for control algorithm design.

Management Control in New Product Development

DEFF Research Database (Denmark)

Jørgensen, Brian; Messner, Martin

2009-01-01

organizations to better manage tensions between efficiency and flexibility, which is arguably a key issue in many organizations today. Our paper contributes to this stream of research by detailing how enabling control functions in the particular setting of new product development. To this end, we draw upon......Several studies in management control have drawn upon the concepts of coercive and enabling forms of bureaucracy (Adler and Borys 1996) to discuss how the features of a control system may affect employees' attitudes toward control. This question is relevant because enabling forms of control allow...... and flexibility. In addition, our paper sets out to explore how strategic change can influence the operation of enabling control. Focusing on the introduction of a new product strategy in our case organization, we describe employees' repair efforts in adapting the control system to their own needs. We find...

Frequency of depression and somatic symptoms in patients on interferon alpha/ribavirin for chronic hepatitis C

International Nuclear Information System (INIS)

Shakoor, A.; Shafqat, F.; Mehmud, T.H.; Akram, M.; Riaz, S.; Iqbal, Z.; Khan, A.A.

2010-01-01

Large numbers of patients suffering from Chronic Hepatitis C (HCV) are seeking treatment with interferon alpha (IFN) because of significant advances in overall improvement in the course of HCV and its complications. Objectives were to estimate the frequency of depression and somatic symptoms in patients on interferon alpha/ribavirin treatment for chronic hepatitis C. Methods: It was an observational study conducted in the out-patient Department of Gastroenterology Shaikh Zayed Hospital, Lahore during a period of three months, i.e., from September to November 2008. One hundred consecutive patients undergoing interferon alpha/ ribavirin treatment for chronic HCV were included in the study. All patients, irrespective of age, sex or duration of treatment were administered with a check list of common physical complaints and DSM-IV symptoms for Major Depressive Episode. Results: Out of a total of 100 subjects 37 were male and 63 were female. In all, 39 (39%) patients fulfilled the diagnostic criteria of DSM-IV for Major Depressive Episode. Major Depression was more common in female 28 (44.4%) as compared to male 11 (28.7%) patients. Somatic symptoms were common in all the patients but they were reported more frequently by patients with Major Depression compared to those without Major Depression. Myalgias, headache, joint pain, nausea/vomiting, abdominal pain and palpitation were the most common physical symptoms. Conclusion: Major Depression and somatic complaints are a common consequence of interferon alpha/ribavirin treatment for chronic hepatitis C. All patients receiving this treatment should be periodically assessed for the detection of these side effects to promptly address relevant treatment options. (author)

Identification and function analysis of canine stimulator of interferon gene (STING).

Science.gov (United States)

Zhang, Yuxiang; Zhu, Mengyan; Li, Gairu; Liu, Jie; Zhai, Xiaofeng; Wang, Ruyi; Zhang, Junyan; Xing, Gang; Gu, Jinyan; Yan, Liping; Lei, Jing; Sun, Haifeng; Shi, Zhiyu; Liu, Fei; Hu, Boli; Su, Shuo; Zhou, Jiyong

2017-12-01

Stimulator of interferon gene (STING) plays an important role in the cyclic GMP-AMP synthase (cGAS)-mediated activation of type I IFN responses. In this study, we identified and cloned canine STING gene. Full-length STING encodes a 375 amino acid product that shares the highest similarity with feline STING. Highest levels of mRNA of canine STING were detected in the spleen and lungs while the lowest levels in the heart and muscle. Analysis of its cellular localization showed that STING is localizes to the endoplasmic reticulum. STING overexpression induced the IFN response via the IRF3 and NF-κB pathways and up-regulated the expression of ISG15 and viperin. However, knockdown of STING did not inhibit the IFN-β response triggered by poly(dA:dT), poly(I:C), or SeV. Finally, overexpression of STING significantly inhibited the replication of canine influenza virus H3N2. Collectively, our findings indicate that STING is involved in the regulation of the IFN-β pathway in canine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Place of Interferon-γ Assay for Diagnosis of Congenital Toxoplasmosis.

Science.gov (United States)

Chapey, Emmanuelle; Wallon, Martine; L'Ollivier, Coralie; Piarroux, Renaud; Peyron, François

2015-12-01

The diagnosis of congenital toxoplasmosis relies mainly on serology. When results are doubtful, pediatricians have difficulties with respect to treatment. We report interferon-γ responses after the stimulation of blood by Toxoplasma gondii antigen in 17 infected infants and 80 infants free of infection. Sensitivity and specificity were 93.75% (95% confidence interval: 67%-99%) and 98.75% (95% confidence interval: 92%-99%), respectively.

Association between Interferon-Inducible Protein 6 ( Polymorphisms and Hepatitis B Virus Clearance

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Geun-Hee Park

2013-03-01

Full Text Available CD8+ T cells are key factors mediating hepatitis B virus (HBV clearance. However, these cells are killed through HBV-induced apoptosis during the antigen-presenting period in HBV-induced chronic liver disease (CLD patients. Interferon-inducible protein 6 (IFI6 delays type I interferon-induced apoptosis in cells. We hypothesized that single nucleotide polymorphisms (SNPs in the IFI6 could affect the chronicity of CLD. The present study included a discovery stage, in which 195 CLD patients, including chronic hepatitis B (HEP and cirrhosis patients and 107 spontaneous recovery (SR controls, were analyzed. The genotype distributions of rs2808426 (C > T and rs10902662 (C > T were significantly different between the SR and HEP groups (odds ratio [OR], 6.60; 95% confidence interval [CI], 1.64 to 26.52, p = 0.008 for both SNPs and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively. The distribution of diplotypes that contained these SNPs was significantly different between the SR and HEP groups (OR, 6.58; 95% CI, 1.63 to 25.59; p = 0.008 and OR, 0.15; 95% CI, 0.04 to 0.61; p = 0.008, respectively and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively. We were unable to replicate the association shown by secondary enrolled samples. A large-scale validation study should be performed to confirm the association between IFI6 and HBV clearance.

Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases.

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David Wong

Full Text Available BACKGROUND: Dermatomyositis (DM is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood. METHODOLOGY AND FINDINGS: We analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN g, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin. CONCLUSIONS AND SIGNIFICANCE: As in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue.

21 CFR 820.70 - Production and process controls.

Science.gov (United States)

2010-04-01

...) MEDICAL DEVICES QUALITY SYSTEM REGULATION Production and Process Controls § 820.70 Production and process... used as part of production or the quality system, the manufacturer shall validate computer software for... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Production and process controls. 820.70 Section...

Viral kinetics of hepatitis C virus RNA in patients with chronic hepatitis C treated with 18 MU of interferon alpha daily

NARCIS (Netherlands)

Sentjens, Roel E.; Weegink, Christine J.; Beld, Marcel G.; Cooreman, Michel C.; Reesink, Henk W.

2002-01-01

BACKGROUND: A rapid decrease of hepatitis C virus (HCV) RNA is interferon (IFN) dose-dependent, and a 3-log decline of HCV-RNA is a strong predictor of sustained virological response. In this study, viral kinetics of HCV RNA in patients treated with 18 MU interferon alpha (IFN-alpha) daily for 2

Open-pit production and control at Roessing

International Nuclear Information System (INIS)

Hodson, D.; Rich, C.

1986-01-01

In recent years metal prices have been severely depressed and most companies have directed efforts to controlling costs in order to stay in business. Roessing Uranium has consistently kept uranium production cost increases well below the domestic inflation rate and this has been the result of a firm commitment to production and cost control, which is the main theme of this paper. The subject of cost analysis is briefly presented and the paper then gives more technical detail under the main headings of grade control, production control and engineering projects. The main communication channels, which are used to ensure that different departments on the mine are all working for the same objectives, are mentioned. The paper, however, is intended to be a general overview of the engineering aspects of open-pit cost control

Radiological control of food importation products

International Nuclear Information System (INIS)

Aguirre G, J.

2003-01-01

Nowadays exists the possibility of marketing products possibly polluted with radioactive isotopes, by that some countries like Mexico, they have been given to the task of creating legal bases and the necessary infrastructure with the end of carrying out the radiological surveillance of nutritious import products. In this work the legal bases that our country has established for the radiological control are presented besides the results of this radiological control carried out through the gamma spectroscopy analysis of nutritious import products sent to our country through diverse companies that import foods produced mainly in European countries. (Author)

Product Control of Waste Products with New Coating Materials

International Nuclear Information System (INIS)

Krumbach, H.; Steinmetz, H.J.; Odoj, R.; Wartenberg, W.; Grunau, H.

2009-01-01

In Germany, with the shaft KONRAD a repository for low radioactive waste will be available at the earliest in the year 2013. The previously conditioned radioactive waste has to be suitable for a longer-term interim storage. They have to be treated in a way that they are chemically stable and that their integrity is guaranteed for a long time. That is why the waste product or the container is covered/ coated for special waste such as hygroscopic waste or waste that includes aluminium. The Product Control Group for radioactive waste (PKS) has to proof the suitability of the so-treated waste for the repository KONRAD on behalf of the Federal Office for Radiation Protection (BfS). This has to be done before the delivering. In this context the PKS also assesses the suitability of new coating materials for low radioactive waste products or containers and their correct technical application. The characteristics and the technical application of polyurethane coatings as well as the control of the so-coated waste for the disposal in the shaft KONRAD are described in this poster. The Poster shows the development stages of the coating and the filling. There are also shown the boundary conditions and the investigations of the Product Control Group for the use of the new coating material for radioactive waste. (authors)

Fluoxetine regulates cell growth inhibition of interferon-α.

Science.gov (United States)

Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

2016-10-01

Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

Effect of Interferon, Polyacrylic Acid, and Polymethacrylic Acid on Tail Lesions in Mice Infected with Vaccinia Virus

Science.gov (United States)

De Clercq, E.; De Somer, P.

1968-01-01

Intravenous inoculation of mice with vaccinia virus produced characteristic lesions of the tail surface which were suppressed by intraperitoneal administration of interferon and polyacrylic acid (PAA). Polymethacrylic acid (PMAA) stimulated the formation of vaccinia virus lesions. For full activity, both interferon and PAA must be given prior to infection. PAA was still significantly effective at small dose levels (3 mg/kg) and achieved protection for at least 4 weeks. Protection increased with increasing molecular weight of the polymer. The mode of action of PAA is discussed. PMID:5676405

Immunostimulatory effects of natural human interferon-alpha (huIFN-alpha) on carps Cyprinus carpio L.

Science.gov (United States)

Watanuki, Hironobu; Chakraborty, Gunimala; Korenaga, Hiroki; Kono, Tomoya; Shivappa, R B; Sakai, Masahiro

2009-10-15

Human interferon-alpha (huIFN-alpha) is an important immunomodulatory substance used in the treatment and prevention of numerous infectious and immune-related diseases in animals. However, the immunostimulatory effects of huIFN-alpha in fish remain to be investigated. In the current study, the immune responses of the carp species Cyprinus carpio L. to treatment with huIFN-alpha were analyzed via measurement of superoxide anion production, phagocytic activity and the expression of cytokine genes including interleukin-1beta, tumor necrosis factor-alpha and interleukin 10. Low doses of huIFN-alpha were administered orally once a day for 3 days, and sampling was carried out at 1, 3 and 5 days post-treatment. Our results indicate that a low dose of huIFN-alpha significantly increased phagocytic activity and superoxide anion production in the carp kidney. The huIFN-alpha-treated fish also displayed a significant upregulation in cytokine gene expression. The current study demonstrates the stimulatory effects of huIFN-alpha on the carp immune system and highlights the immunomodulatory role of huIFN-alpha in fish.

Modern control of mineral wool production process

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Stankov Stanko P.

2013-01-01

Full Text Available In this paper, the control of the plant for mineral wool production consisting of a number of the technological units of different sizes and complexity is considered. The application of modern equipment based on PLC (Programmable Logic Controller and SCADA (Supervisory Control And Data Acquisition configuration provides optimal control of technological process. Described supervisory and control system is consisting of a number of units doing decentralized distributed control of technological entities where all possible situation are considered during work of machines and devices, which are installed in electric drive and are protected from technological and electrical accident. Transformer station and diesel engine, raw materials transport and dosage, processes in dome oven, centrifuges, polycondensation (PC chamber, burners, compressor station, binder preparation and dosage, wool cutting, completed panel packing and their transport to storehouse are controlled. Process variables and parameters like as level, flow, velocity, temperature, pressure, etc. are controlled. Control system is doing identification of process states changes, diagnostic and prediction of errors and provides prediction of behavior of control objects when input flows of materials and generates optimal values of control variables due to decreasing downtime and technic - economical requires connected to wool quality to be achieved. Supervisory and control system either eliminates unwanted changes in the production line or restricts them within the allowable limits according to the technology. In this way, the optimization of energy and raw materials consumption and appropriate products quality is achieved, where requirements are satisfied in accordance with process safety and environmental standards. SCADA provides a visual representation of controlled and uncontrolled parts of the technological process, processing alarms and events, monitoring of the changes of relevant

THE RATIONALE FOR ALPHA-INTERFERON IMMUNOTHERAPY IN INFANTS WITH FUNCTIONAL GASTROINTESTINAL DISORDERS AND ACUTE INVASIVE INTESTINAL INFECTION

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E. R. Meskina

2015-01-01

Full Text Available Background: Acute intestinal  infections  in children are a considerable  medical and social problem  worldwide. Immune therapy  could  help  to reduce the frequency of post-infectious functional intestinal dysfunction  in patients  with comorbidities. Aim: To evaluate  the  efficacy of human  recombinant interferon  alpha-2b, administered at acute  phase  of an acute  invasive intestinal  infection to infants in the first months  of age, suffering from functional  bowel  disorders. Materials and methods: This  was  an  open-label,  randomized (envelope method, prospective  study in two parallel groups. The study included  59 infants of the  first months  of life, who were breastfed, had a history of intestinal  dysfunction  and were hospitalized  to  an  infectious  department. We studied  efficacy of recombinant interferon  alpha-2b administered in rectal suppositories  at a dose  of   chromatography with measurement of short-chain fatty acids. Results: Standard treatment was ineffective in 63.3% (95% CI 43.9–80.0% of patients. Administration   of  interferon   alpha-2b   reduced the rate of treatment failure by day 14 to 32% (95% CI 9–56% and  the  risk of persistent  diarrhea  for more than  one month  to 29% (95% CI 5–53%. In those patients  who were administered interferon, inflammation at days 25 to 55 was less severe and the levels of i-forms of short-chain fatty acids were lower. Conclusion: Immunotherapy with recombinant interferon alpha-2b seems to be a promising way to improve  combination treatment of acute invasive intestinal infections in infants with a history of intestinal dysfunction, as it reduces the risk of post-infectious intestinal disorders.

Insight into Gene Polymorphisms Involved in Toll-Like Receptor/Interferon Signalling Pathways for Systemic Lupus Erythematosus in South East Asia

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Hwa Chia Chai

2014-01-01

Full Text Available Polymorphisms in genes involved in toll-like receptor/interferon signalling pathways have been reported previously to be associated with SLE in many populations. This study aimed to investigate the role of seven single nucleotide polymorphisms within TNFAIP3, STAT4, and IRF5, which are involved in upstream and downstream pathways of type I interferon production, in SLE in the South East Asian populations. Genotyping of 360 Malaysian SLE patients and 430 normal healthy individuals revealed that minor alleles of STAT4 rs7574865 and rs10168266 were associated with elevated risk of SLE in the Chinese and Malay patients, respectively (P=0.028, odds ratio (OR=1.42; P=0.035, OR=1.80, respectively. Polymorphisms in TNFAIP3 and IRF5 did not show significant associations with SLE in any of the ethnicities. Combined analysis of the Malays, Chinese, and Indians for each SNP indicated that STAT4 rs10168266 was significantly associated with the Malaysian SLE as a whole (P=0.014; OR=1.435. The meta-analysis of STAT4 rs10168266, which combined the data of other studies and this study, further confirmed its importance as the risk factor for SLE by having pooled OR of 1.559 and P value of <0.001.

Insight into Gene Polymorphisms Involved in Toll-Like Receptor/Interferon Signalling Pathways for Systemic Lupus Erythematosus in South East Asia

Science.gov (United States)

Chua, Kek Heng; Lim, Soo Kun; Phipps, Maude Elvira

2014-01-01

Polymorphisms in genes involved in toll-like receptor/interferon signalling pathways have been reported previously to be associated with SLE in many populations. This study aimed to investigate the role of seven single nucleotide polymorphisms within TNFAIP3, STAT4, and IRF5, which are involved in upstream and downstream pathways of type I interferon production, in SLE in the South East Asian populations. Genotyping of 360 Malaysian SLE patients and 430 normal healthy individuals revealed that minor alleles of STAT4 rs7574865 and rs10168266 were associated with elevated risk of SLE in the Chinese and Malay patients, respectively (P = 0.028, odds ratio (OR) = 1.42; P = 0.035, OR = 1.80, respectively). Polymorphisms in TNFAIP3 and IRF5 did not show significant associations with SLE in any of the ethnicities. Combined analysis of the Malays, Chinese, and Indians for each SNP indicated that STAT4 rs10168266 was significantly associated with the Malaysian SLE as a whole (P = 0.014; OR = 1.435). The meta-analysis of STAT4 rs10168266, which combined the data of other studies and this study, further confirmed its importance as the risk factor for SLE by having pooled OR of 1.559 and P value of <0.001. PMID:24741605

Analysis of tick-borne encephalitis virus-induced host responses in human cells of neuronal origin and interferon-mediated protection

Czech Academy of Sciences Publication Activity Database

Selinger, Martin; Wilkie, G. S.; Tong, L.; Gu, Q.; Schnettler, E.; Grubhoffer, Libor; Kohl, A.

2017-01-01

Roč. 98, č. 8 (2017), s. 2043-2060 ISSN 0022-1317 R&D Projects: GA ČR GA15-03044S Institutional support: RVO:60077344 Keywords : blood- brain -barrier * long noncoding RNAs * double-stranded-RNA * interferon * immune-response * gene-expression * stimulated genes * human astrocytes * viral-infection * protein * tick-borne encephalitis virus * neuronal cells * transcriptome analysis * host response * interferon Subject RIV: EE - Microbiology, Virology OBOR OECD: Virology Impact factor: 2.838, year: 2016

G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA.

Directory of Open Access Journals (Sweden)

Katell Bidet

2014-07-01

Full Text Available Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV. We examined three conserved host RNA-binding proteins (RBPs G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2 infection and found them to be novel regulators of the interferon (IFN response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs, and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA, which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells.

Critical review: assessment of interferon-β immunogenicity in multiple sclerosis

DEFF Research Database (Denmark)

Bendtzen, Klaus

2010-01-01

This review discusses type I interferon (IFN) immunogenicity with focus on methods of detection of anti-IFN antibodies in patients treated with human recombinant IFN-β. Pitfalls involved in the clinical use of various types of assays for binding antibodies and neutralizing antibodies against IFN-...... for individualized or personalized medicine, ie, optimizing therapies according to individual needs rather than using standardized trial-and-error regimens to all patients, is highlighted....

Critical review: assessment of interferon-ß immunogenicity in multiple sclerosis

DEFF Research Database (Denmark)

Bendtzen, Klaus

2010-01-01

This review discusses type I interferon (IFN) immunogenicity with focus on methods of detection of anti-IFN antibodies in patients treated with human recombinant IFN-ß. Pitfalls involved in the clinical use of various types of assays for binding antibodies and neutralizing antibodies against IFN-...... for individualized or personalized medicine, ie, optimizing therapies according to individual needs rather than using standardized trial-and-error regimens to all patients, is highlighted....

The Effect of Interferon-γ and Lipopolysaccharide on the Growth of Francisella tularensis LVS in Murine Macrophage-like Cell Line J774

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Monika Holická

2009-01-01

Full Text Available Background: Francisella tularensis, a causative agent of human tularemia, displaying the ability to proliferate inside the human cells. Aims: To evaluate the growth potential of F. tularensis LVS strain in macrophage-like cell line J774 modulated by recombinant interferon γ and E. coli derived lipopolysaccharide. Results: Stimulation of J774 cells either by interferon-γ or lipopolysaccharide alone, or especially in combination before infection F. tularensis, revealed protective effects. Higher concentrations of stimulating agents were needed to inhibit ongoing F. tularensis infection. Conclusions: Stimulation of J774 cell line by combination of interferon-γ with lipopolysaccharide inhibits the intracellular growth of F. tularensis.

The Role of Interferons in Inflammation and Inflammasome Activation.

Science.gov (United States)

Kopitar-Jerala, Nataša

2017-01-01

Inflammation is an essential physiological process, which enables survival during infection and maintains tissue homeostasis. Interferons (IFNs) and pro- and anti-inflammatory cytokines are crucial for appropriate response to pathogens, damaged cells, or irritants in inflammatory response. The inflammasom is multiprotein complex, which initiates cleavage of pro-inflammatory cytokines IL-1β and IL-18 into active forms. In addition, inflammasomes initiate pyroptotic cell death. In the present review, I summarize and analyze recent findings regarding the cross talk of IFNs and inflammasomes.

Production process and quality control for the HTTR fuel

International Nuclear Information System (INIS)

Yoshimuta, S.; Suzuki, N.; Kaneko, M.; Fukuda, K.

1991-01-01

Development of the production and inspection technology for High Temperature Engineering Test Reactor (HTTR) fuel has been carried out by cooperative work between Japan Atomic Energy Research Institute (JAERI) and Nuclear Fuel Industries, Ltd (NFI). The performance and the quality level of the developed fuel are well established to meet the design requirements of the HTTR. For the commercial scale production of the fuel, statistical quality control and quality assurance must be carefully considered in order to assure the safety of the HTTR. It is also important to produce the fuel under well controlled process condition. To meet these requirements in the production of the HTTR fuel, a new production process and quality control system is to be introduced in the new facilities. The main feature of the system is a computer integrated control system. Process control data at each production stage of products and semi-products are all gathered by terminal computers and processed by a host computer. The processed information is effectively used for the production, quality and accountancy control. With the aid of this system, all the products will be easily traceable from starting materials to final stages and the statistical evaluation of the quality of products becomes more reliable. (author). 8 figs

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.

Antiviral Activity of Lambda Interferon in Chickens

Science.gov (United States)

Reuter, Antje; Soubies, Sebastien; Härtle, Sonja; Schusser, Benjamin; Kaspers, Bernd

2014-01-01

Interferons (IFNs) are essential components of the antiviral defense system of vertebrates. In mammals, functional receptors for type III IFN (lambda interferon [IFN-λ]) are found mainly on epithelial cells, and IFN-λ was demonstrated to play a crucial role in limiting viral infections of mucosal surfaces. To determine whether IFN-λ plays a similar role in birds, we produced recombinant chicken IFN-λ (chIFN-λ) and we used the replication-competent retroviral RCAS vector system to generate mosaic-transgenic chicken embryos that constitutively express chIFN-λ. We could demonstrate that chIFN-λ markedly inhibited replication of various virus strains, including highly pathogenic influenza A viruses, in ovo and in vivo, as well as in epithelium-rich tissue and cell culture systems. In contrast, chicken fibroblasts responded poorly to chIFN-λ. When applied in vivo to 3-week-old chickens, recombinant chIFN-λ strongly induced the IFN-responsive Mx gene in epithelium-rich organs, such as lungs, tracheas, and intestinal tracts. Correspondingly, these organs were found to express high transcript levels of the putative chIFN-λ receptor alpha chain (chIL28RA) gene. Transfection of chicken fibroblasts with a chIL28RA expression construct rendered these cells responsive to chIFN-λ treatment, indicating that receptor expression determines cell type specificity of IFN-λ action in chickens. Surprisingly, mosaic-transgenic chickens perished soon after hatching, demonstrating a detrimental effect of constitutive chIFN-λ expression. Our data highlight fundamental similarities between the IFN-λ systems of mammals and birds and suggest that type III IFN might play a role in defending mucosal surfaces against viral intruders in most if not all vertebrates. PMID:24371053

Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins

Energy Technology Data Exchange (ETDEWEB)

Edwards, Megan R.; Liu, Gai; Mire, Chad E.; Sureshchandra, Suhas; Luthra, Priya; Yen, Benjamin; Shabman, Reed S.; Leung, Daisy W.; Messaoudi, Ilhem; Geisbert, Thomas W.; Amarasinghe, Gaya K.; Basler, Christopher F.

2016-02-11

Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitory domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.

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

Elevation in Type I Interferons Inhibits HCN1 and Slows Cortical Neuronal Oscillations

NARCIS (Netherlands)

Stadler, Konstantin; Bierwirth, Claudia; Stoenica, Luminita; Battefeld, Arne; Reetz, Olivia; Mix, Eilhard; Schuchmann, Sebastian; Velmans, Tanja; Rosenberger, Karen; Bräuer, Anja U.; Lehnardt, Seija; Nitsch, Robert; Budt, Matthias; Wolff, Thorsten; Kole, Maarten H. P.; Strauss, Ulf

2014-01-01

Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced

Pancreatitis induced by pegylated interferon alfa-2b in a patient affected by chronic hepatitis C.

Science.gov (United States)

Cecchi, Enrica; Forte, Paolo; Cini, Elisabetta; Banchelli, Grazia; Ferlito, Chiara; Mugelli, Alessandro

2004-01-01

A middle-aged man was admitted to the ED because of nausea and vomiting, abdominal distention and fainting. A blood analysis revealed high levels of serum amylase and lipase, confirming a diagnosis of acute pancreatitis. The history showed that the patient had self-administered a single dose of pegylated interferon alfa-2b and ribavirin daily for 7 days for chronic hepatitis C. The medications were stopped and his condition gradually improved. In agreement with the literature and the Naranjo algorythm result, pegylated interferon alfa-2b is associated with acute pancreatitis. Identification of a few signs and symptoms is the first 'signal' in preventing a serious drug-induced adverse event.

[Health risks from pest control products].

Science.gov (United States)

Pieper, C; Holthenrich, D; Schneider, H

2014-05-01

According to European biocide legislation, pest control products require assessment and authorization by the responsible national or European authorities. Biocidal products can only be authorized if they have no unacceptable effects on human health. The health risk assessment performed for authorization comprises (a) the derivation of reference values for the active substances and substances of concern contained in the biocidal product and (b) an exposure assessment. These parameters are required for risk characterization. No unacceptable health risks are expected if the determined exposure is less than the relevant reference value. In addition, the toxicological information is used for classification of the biocidal product. The assessment may, where necessary, result in specific conditions for use or other restrictions aimed at minimizing risk. The risk to human health from pest control products is mainly based on the toxicological properties of their active substances. Commonly, the coformulants used in pest control products are of less concern than the active substances (e.g., food ingredients and animal feed products). For example, most rodenticides belong to the group of anticoagulants, which are also effective in humans. Regarding intoxications through insecticides, the group of pyrethroids is of particular importance. Fumigants containing metal phosphides, hydrogen cyanide, or sulfuryl difluoride are particularly toxic. This toxicity is linked to the high acute inhalation toxicity of the gaseous active substances themselves or, in the case of phosphides, of the released gas phosphane. The aim of health risk assessment for the authorization of biocidal products is to ensure their safe application for users and all other persons involved, assuming an adequate and label-compliant use.

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

Directory of Open Access Journals (Sweden)

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.

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....

Interferon in chronic myeloid leukaemia: past and future.

Science.gov (United States)

Guilhot, François; Roy, Lydia; Saulnier, Pierre-Jean; Guilhot, Joëlle

2009-09-01

Imatinib has revolutionized the therapy of chronic myeloid leukaemia. However the complete eradication of leukaemic stem cells is still a matter of discussion. Interferon (IFN) has been used in the past with success. However the proportion of patients who achieved sustained complete cytogenetic response was small. Recently, in addition to its direct antineoplastic effect and immunomodulatory activity, IFN has been shown to stimulate the quiescent leukaemic stem cells. Thus there is now a rational for combining Imatinib and IFN. Large prospective phase III trials are in good progress to demonstrate in humans the usefullness of a combination therapy using Imatinib and IFN.

Inhibitory effect of interferon-γ on experimental tooth movement in mice.

Science.gov (United States)

Kohara, Haruka; Kitaura, Hideki; Yoshimatsu, Masako; Fujimura, Yuji; Morita, Yukiko; Eguchi, Toshiko; Yoshida, Noriaki

2012-09-01

The aim of this study was to investigate the effects of interferon (IFN)-γ on experimental tooth movement in mice using a murine experimental tooth movement model. An Ni-Ti closed-coil spring was inserted between the upper-anterior alveolar bones and the upper-left first molars in mice. We evaluated the relationship between local Ifn-γ mRNA levels and orthodontic tooth movement. In other experiments, IFN-γ was injected adjacent to each first molar every other day during tooth movement. After 12 days, the amount of tooth movement was measured. Tartrate-resistant acid phosphatase (TRAP)-positive cells at the pressure side of each experimental tooth were counted as osteoclasts. Local Ifn-γ mRNA expression increased with orthodontic tooth movement. The number of TRAP-positive cells increased on the pressure side of the first molar. In contrast, the degree of tooth movement and the number of TRAP-positive cells on the pressure side in IFN-γ-injected mice were less than those of control mice. IFN-γ was induced in experimental tooth movement, and could inhibit mechanical force-loaded osteoclastogenesis and tooth movement. These results suggest that IFN-γ might be useful in controlling orthodontic tooth movement because of its inhibitory action on excessive osteoclastogenesis during this movement.

Strategies of Production Control as Tools of Efficient Management of Production Enterprises

Science.gov (United States)

Budynek, Mateusz; Celińska, Elżbieta; Dybikowska, Adrianna; Kozak, Monika; Ratajczak, Joanna; Urban, Jagoda; Materne, Karolina

2016-03-01

The paper discusses the problem of principle methods of production control as a strategy supporting the production system and stimulating efficient solutions in respect management in production enterprises. The article describes MRP, ERP, JIT, KANBAN and TOC methods and focuses on their main goals, principles of functioning as well as benefits resulting from their application. The methods represent two diverse strategies of production control, i.e. pull and push strategies. Push strategies are used when the plans apply to the first and principle part of production and are based on the demand forecasts. Pull strategies are used when all planning decisions apply to the final stage and depend on the actual demand or orders from customers.

Regression of esophageal varices and splenomegaly in two patients with hepatitis-C-related liver cirrhosis after interferon and ribavirin combination therapy

Directory of Open Access Journals (Sweden)

Soon Jae Lee

2016-09-01

Full Text Available Some recent studies have found regression of liver cirrhosis after antiviral therapy in patients with hepatitis C virus (HCV-related liver cirrhosis, but there have been no reports of complete regression of esophageal varices after interferon/peg-interferon and ribavirin combination therapy. We describe two cases of complete regression of esophageal varices and splenomegaly after interferon-alpha and ribavirin combination therapy in patients with HCV-related liver cirrhosis. Esophageal varices and splenomegaly regressed after 3 and 8 years of sustained virologic responses in cases 1 and 2, respectively. To our knowledge, this is the first study demonstrating that complications of liver cirrhosis, such as esophageal varices and splenomegaly, can regress after antiviral therapy in patients with HCV-related liver cirrhosis.

De novo Cryoglobulinaemic Mononeuritis Multiplex during Treatment of Chronic Hepatitis C Infection: A Viral Effect or Induced by Pegylated Interferon Alpha

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J.R. Potts

2012-03-01

Full Text Available Cryoglobulinaemic mononeuritis multiplex (MNM is an extrahepatic manifestation of chronic hepatitis C virus (HCV infection for which interferon-based antiviral therapy is currently the treatment of choice. Rarely MNM can be associated with HCV treatment though generally in the setting of pre-existing cryoglobulinaemia and detectable HCV viraemia. We report an unusual case of de novo MNM occurring late during the course of pegylated interferon and ribavirin therapy for chronic HCV infection, following a prolonged period of viral suppression. The patient had no evidence of cryoglobulinaemia prior to HCV treatment and undetectable HCV RNA levels at the time of presentation with MNM. The case raises the possibility that MNM could develop as an adverse immunomodulatory effect of pegylated interferon therapy.

Interferon gamma increases survival in urine experimental cryptococcosis El Interferon gamma incrementa la sobrevida de un modelo experimental murino de criptococosis

Directory of Open Access Journals (Sweden)

Amadeo J. Bava

1995-10-01

Full Text Available Systemic disease by Cryptococcus neoformans (C. neoformans is a common opportunistic infection in immunodeficient patients. Cellular immunity seems to be the most important determinant of resistance. The aim of this study was to assess the effect of recombinant rat interferon gamma (IFN-gamma in murine cryptococcosis (Balb/c mice infected by IP route with the Rivas strain of C. neoformans, evaluating survival time, macroscopic and microscopic examination of the organs, and massive seeding of brain homogenate. IFN-gamma treatment, at a daily dose of 10,000 IU, did not modify significantly these variables when mice were challenged with a high inoculum (10(7 yeasts and treatment was delayed to 5 days after infection (median survival 21 days in control mice vs. 23 days in IFN-treated. Another set of experiments suggested that IFN-gamma treatment, at a dose of 10,000 IU/day, begun at the moment of infection could be useful (it prolonged survival from 20 to 28 days, although the difference did not achieve statistical signification. When used simultaneously with infection by 3.5 x 10(5 yeasts, IFN-gamma at 10,000 IU/day for 15 days significantly prolonged survival of mice (p = 0.004. These results suggest that, depending on the experimental conditions, IFN-gamma can improve survival of mice infected with a lethal dose of C. neoformans.Se evaluó la efectividad del interferon-gamma (IFN-gamma recombinante de rata en un modelo experimental de criptococosis desarollado en ratones Balb/C inoculados por vía intraperitoneal con la cepa Rivas de Cryptococcus neoformans (C. neoformans. Se tuvieron en cuenta el tiempo de sobrevida de los animales, el aspecto macroscópico de los órganos en la autopsia, la presencia de levaduras capsuladas en los tejidos y la siembra masiva de un homogenato de cerebro. El tratamiento con IFN-gamma, en dosis diarias de 10.000 UI, no modificó estos parámetros cuando la dosis infectante fue de 10(7 levaduras y el tratamiento se

A comparison of interferon-γ and IP-10 for the diagnosis of tuberculosis

DEFF Research Database (Denmark)

Holm, Line Lindebo; Rose, Michala Vaaben; Kimaro, Godfather

2014-01-01

OBJECTIVE: Interferon-γ and IP-10 release assays are diagnostic tests for tuberculosis infection. We have compared the accuracy of IP-10 and QuantiFERON-TB Gold In-tube [QFT-IT] in Tanzanian children suspected of having active tuberculosis (TB). METHODS: Hospitalized Tanzanian children...

Enhanced endogenous type I interferon cell-driven survival and inhibition of spontaneous apoptosis by Riluzole

International Nuclear Information System (INIS)

Achour, Ammar; M'Bika, Jean-Pierre; Biquard, Jean-Michel

2009-01-01

Highly active antiretroviral therapy (HAART), although effective in improving the survival of HIV-1-infected individuals, has not been able to reconstitute the adaptive immune response. We have described the use of novel chemical agents to restore T-cell survival/proliferation by inducing cytokine production. Due to its cationic amphiphilic structure, these molecules appear to enhance immune restoration. In this study, we investigated the action of Riluzole (2-amino-6-trifuromethoxybenzothiazole) in HIV-1 infection. Riluzole is able to increase (effective dose from 1 to 1000 nM) the cell-survival of T cells from HIV-1-infected patients and inhibit spontaneous apoptosis. The immunomodulatory effect of riluzole-sensitized cells was ascribed to endogenous type I interferon (IFN) derived from monocytes. Riluzole might be used for restoring the cell survival of immunocompromised patients and eliminating latent infected cells upon HIV-1 reactivation

Inflammation Activates the Interferon Signaling Pathways in Taste Bud Cells

OpenAIRE

Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan

2007-01-01

Patients with viral and bacterial infections or other inflammatory illnesses often experience taste dysfunctions. The agents responsible for these taste disorders are thought to be related to infection-induced inflammation, but the mechanisms are not known. As a first step in characterizing the possible role of inflammation in taste disorders, we report here evidence for the presence of interferon (IFN)-mediated signaling pathways in taste bud cells. IFN receptors, particularly the IFN-γ rece...

The Role of Interferons in Inflammation and Inflammasome Activation

Directory of Open Access Journals (Sweden)

Nataša Kopitar-Jerala

2017-07-01

Full Text Available Inflammation is an essential physiological process, which enables survival during infection and maintains tissue homeostasis. Interferons (IFNs and pro- and anti-inflammatory cytokines are crucial for appropriate response to pathogens, damaged cells, or irritants in inflammatory response. The inflammasom is multiprotein complex, which initiates cleavage of pro-inflammatory cytokines IL-1β and IL-18 into active forms. In addition, inflammasomes initiate pyroptotic cell death. In the present review, I summarize and analyze recent findings regarding the cross talk of IFNs and inflammasomes.

[Solubilization Specificities Interferon beta-1b from Inclusion Bodies].