DOCSLIB.ORG

“The Biological Basis for the Correct Interferon Usage in Clinical Practice.”

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
“The Biological Basis for the Correct Interferon Usage in Clinical Practice.” Summer School ESCMID 2011 Treviso – Italy OLL “The biological basis for the correct interferon usage in clinical practice.” Guido AntonelliAuthor Virology Laboratory Department of Molecular Medicine ESCCMID“ Sapienza”©by University of Rome OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Papers Reporting the Discovery of Interferon Proc. Royal Soc. London 147:258-267,Author 1957 Proc. Royal Soc. London 147:268-273, 1957 NaganoESCCMID Y and Kojima Y. Inhibition de l’infection©by vaccinale par la virus homologue Seances Soc. Biol. Fil. 152: 1627-1630, 1958. OLL Author ESCCMID©by Paper Reporting the Discovery of IFN-γ Wheelock, EF. Science 149:310-311, 1965 Nature. 1980 Mar 27;284(5754):316-20. Synthesis in E. coli of a polypeptide with human leukocyte interferon activity Nagata S, Taira H, Hall A, Johnsrud L, Streuli M, Ecsodi J, Boll W, Cantell K, Weissmann C. OLL Author ESCCMID©by OLL Author ESCCMID©by Major milestones and discoveries in 50 years of interferon research (1) OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author MAIN APPROVED USES OF INTERFERONS Type of Interferon Indications Interferon alfa-2a (Roferon®) hairy cell leukemia AIDS-related Kaposi's sarcoma chronic hepatitis C Pegylated Interferon alfa-2a (PEGASYS®) chronic hepatitis C andOLL B Interferon alfa-2b (Intron-A®) genital warts chronic hepatitis B chronic hepatitis C hairy cell leukemia AIDS-related Kaposi's sarcoma adjuvant therapy for malignant melanoma in combination with chemotherapy for non-Hodgkin's lymphoma (follicularAuthor lymphoma) Pegylated Interferon alfa-2b (PEG-Intron®) chronic hepatitis C Interferon alfa-n3 (Alferon®) condylomata acuminata Interferon alfacon-1 (Infergen®) chronic hepatitis C Interferon beta-1a ESCCMID(Avonex®, Rebif®) relapsing forms of multiple sclerosis Interferon beta-1b (Betaseron®) ©byrelapsing-remitting multiple sclerosis Interferon gamma (Actimmune®) chronic granulomatous disease malignant osteopetrosis 1 Main IFNs in clinical trials Indication/ Trade name / product Company Clinical phase application PegIntron (pegylated rh- Schering- IFN-α2b) Plough/Enzon OLL phase III CML malignant phase III melanoma phase I solid tumors PEG-alfacon-1 (pegylated IFN-alfacon-1 IntermuneAuthor phase I hepatitis C Hemispherx Alferon LDO (IFN-αn3) Biopharma phase I / II HIV infection Hemispherx West Nile virus Alferon (IFN-αESCCMIDn3) Biopharma phase II encephalitis ©by first trials started in Recombinant IFN-α2b Biolex Q1/2005 hepatitis C 2 Main IFNs in clinical trials Clinical Indication/ Trade name / product Company phase application Veldona (natural-oral IFN-α) Amarillo Bioscience phase III Sjogren's syndrome fibromyalgia OLLphase II syndrome phase II pulmonary fibrosis oral warts (HIV- phase II positive) phase II / III Behçets disease Albuferon-α (Albumin-IFN- Human Genome α2a) Science Authorphase II b CHC r-IFN-α2b XL Flamel Technologies phase I / II hepatitis B hepatitis C CHC in Asian r-IFN-β ESCCMIDAres-Serono phase III patients ©by polyneuropathy Avonex (IFN-β1a) Biogen IDEC phase II (CIDP) OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Author ESCCMID©by XXX X X PEG-IFN X OLL Author ESCCMID©by OLL Science News Newly Discovered Interferon Response May Offer Early Control Of H5N1 Influenza Virus ScienceDaily (June 21, 2009) — Researchers from Georgia suggest that the cell-signaling protein, interferon type 1, reduced H5N1Author influenza virus replication in mice and may offer some degree of protection in the early stages of infection. ESCCMID©by OLL Author ESCCMID©by OLL Author ESCCMID©by Leukemia. 2011 Jan 28. [Epub ahead of print] Interferon-α in acute myeloid leukemia: an old drug revisited. Anguille S, Lion E, Willemen Y, Van Tendeloo VF, Berneman ZN,OLL Smits EL. 1] Laboratory of Experimental Hemato logy, Vaccine and Infectious Disease Institute, Faculty of Medicine, University of Antwerp, Antwerp, Belgium [2] Division of Hematology, Antwerp University Hospital, Edegem, Belgium [3] Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium. Interferon-α (IFN-α), a type I IFN, is a well-known antitumoral agent. The investigation of its clinical properties in acute myeloid leukemia (AML) has been prompted by its pleiotropic antiproliferative and immune effects. So far, integration of IFN-α in the therapeutic arsenal against AML has been modest in view of the divergent results of clinical trials. Recent insightsAuthor into the key pharmacokinetic determinants of the clinical efficacy of IFN along with advances in its pharmaceutical formulation, have sparked renewed interest in its use. This paper reviews the possible applicability of IFN-α in the treatment of AML and provides a rational basis to re-explore its efficacy in clinical trials.Leukemia advance onlineESCCMID publication, 28 January©by 2011; doi:10.1038/leu.2010.324. The Rockefeller University Press J. Exp. Med. Vol. 207 No. 10 2053-2063 www.jem.org/cgi/doi/10.1084/jem.20101664 • Type I interferon: friend or foe? • Giorgio Trinchieri OLL • Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, • Although the role of type I interferon (IFN) in the protection against viral infections has been known and studiedAuthor for decades, its role in other immunologically relevant scenarios, including bacterial infections, shock, autoimmunity, and cancer, is less well defined and potentiallyESCCMID©by much more complicated. OLL Author ESCCMID©by The Interferon System MAIN TYPES OF IFNs (an update to 2009) Most types of cells T lymphocyte, Most types of cells NK cells OLL Type I - IFNs Type II - IFN Type III - IFN α β Others: γ λ ω δ, ε, ξ, κ, τ, ?? Author ≥13 1 gene genes* 1 gene 1 gene 1 gene 3 genes - For IFN alpha the main producing cells are pDC -The IFN alpha subspeciesESCCMID do not compensate for the loss of IFN beta - Some type I IFNs may be tissue restricted©by - For sure, type III IFN are not highly expressed in hematopoietic cells and act predominantly at epithelial surfaces OLL Author ESCCMID©by Virus Infection IFN gene Type III IFN expression IFNλ Type I IFN IFNβ OLL Type II IFN IFNα IFN secretion IFNγ Binding to IFN receptor Transcription of IFN Author Stimulated Genes (ISG) Biological activities • antiviral activity ESCCMID• inhibition of cell growth Expression©by of ISGs • blockage of protein synthesis • immune response modulation Modificata da John Hiscott • apoptosis OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Author ESCCMID©by OLL Author ESCCMID©by OLL Author ESCCMID©by Extracytoplasmic pathways for Cytoplasmic pathways for induction induction (RNA Helycase: retinoic acid-inducible gene I (RIG-I) and (Toll like Receptors-TLRs) Melanoma differentiation associated protein 5 (MDA-5) OLL Author ESCCMID©by OLL Author ESCCMID©by Online Lecture Library Slide withheld at request of author OLL Author ESCCMID©by Nature Reviews - December 2007 - Borden et al. interferon stimulated response element GAS interferon gamma activated sites OAS protein accumulates in the cell cytoplasm as an inactive monomer. Following activation by viral double-stranded RNA, the enzyme oligomerizes to form a tetramer that synthetizes oligoadenylates that, in turn, activate the constitutively expressed inactive ribonucleases L (RNaseL). The binding of 2’,5’ – oligoadenylates to RNaseL triggers the dimerization of enzymes monomers, through their kinase like domains, and this then enables RNaseL to cleave viral and cellular RNA. OLL Author ESCCMID©by OAS protein accumulates in the cell cytoplasm as an inactive monomer. Following activation by viral double-stranded RNA, the enzyme oligomerizes to form a tetramer that synthetizes oligoadenylates that, in turn, activate the constitutively expressed inactive ribonucleases L (RNaseL). The binding of 2’,5’ – oligoadenylates to RNaseL triggers the dimerization of enzymes monomers, through their kinase like domains, and this then enables RNaseL to cleave viral and cellular RNA. Picornaviridae Reoviridae OLL Togaviridae Paramixoviridae Orthomixoviridae Flaviridae RetroviridaeAuthor ESCCMID©by PKR accumulates in the nucleus and cytoplasm as an inactive monomer. It is activated directly by viral RNAs and by several other ligands. Following activation, PKR monomers are phosphorylated and dimerize to form the active enzyme. Activated PKR regulates several cell signalling pathways through unknown mechanisms. A crucial function of PKR in viral defence is the inhibition of translation by phosphorylation of eukaryotic traslation initiation factor 2 alpha. OLL Author ESCCMID©by PKR accumulates in the nucleus and cytoplasm as an inactive monomer. It is activated directly by viral RNAs and by several other ligands. Following activation, PKR monomers are phosphorylated and dimerize to form the active enzyme. Activated PKR regulates several cell signalling pathways through unknown mechanisms. A crucial function of PKR in viral defence is the inhibition of translation by phosphorylation of eukaryotic traslation initiation factor 2 alpha. Picornaviridae (EMC, FMDV) Herpesviridae (HSV-1)OLL Flaviridae (WNV, HCV) Viroid (HDV) Retroviridae (HIV-1) Author ESCCMID©by OLL Author ESCCMID©by
Load more

Recommended publications
  • Porvac® Subunit Vaccine E2-CD154 Induces Remarkable Rapid Protection Against Classical Swine Fever Virus
    Article Porvac® Subunit Vaccine E2-CD154 Induces Remarkable Rapid Protection against Classical Swine Fever Virus Yusmel Sordo-Puga 1, Marisela Suárez-Pedroso 1 , Paula Naranjo-Valdéz 2, Danny Pérez-Pérez 1, Elaine Santana-Rodríguez 1, Talia Sardinas-Gonzalez 1, Mary Karla Mendez-Orta 1, Carlos A. Duarte-Cano 1, Mario Pablo Estrada-Garcia 1 and María Pilar Rodríguez-Moltó 1,* 1 Animal Biotechnology Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Havana 10600, Cuba; [email protected] (Y.S.-P.); [email protected] (M.S.-P.); [email protected] (D.P.-P.); [email protected] (E.S.-R.); [email protected] (T.S.-G.); [email protected] (M.K.M.O.); [email protected] (C.A.D.); [email protected] (M.P.E.) 2 Central Laboratory Unit for Animal Health (ULCSA), Havana 11400, Cuba; [email protected] * Correspondence: [email protected]; Tel.: +53-7-2504419 Abstract: Live attenuated C-strain classical swine fever vaccines provide early onset protection. These vaccines confer effective protection against the disease at 5–7 days post-vaccination. It was previously reported that intramuscular administration of the Porvac® vaccine protects against highly virulent Citation: Sordo-Puga, Y.; classical swine fever virus (CSFV) “Margarita” strain as early as seven days post-vaccination. In Suárez-Pedroso, M.; Naranjo-Valdéz, order to identify how rapidly protection against CSFV is conferred after a single dose of the Porvac® P.; Pérez-Pérez, D.; subunit vaccine E2-CD154, 15 swine, vaccinated with a single dose of Porvac®, were challenged Santana-Rodríguez, E.; 3 intranasally at five, three, and one day post-vaccination with 2 × 10 LD50 of the highly pathogenic Sardinas-Gonzalez, T.; Mendez-Orta, Cuban “Margarita” strain of the classical swine fever virus.
    [Show full text]
  • Antigen-Specific Induced Foxp3 Regulatory T Cells Are Generated
    Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade Ivana R. Ferrer, Maylene E. Wagener, Minqing Song, Allan D. Kirk, Christian P. Larsen, and Mandy L. Ford1 Emory Transplant Center and Department of Surgery, Emory University, Atlanta, GA 30322 Edited by James P. Allison, Memorial Sloan-Kettering Cancer Center, New York, NY, and approved November 4, 2011 (received for review April 7, 2011) Blockade of the CD40/CD154 pathway potently attenuates T-cell in vivo accumulation of Treg and deletion of graft-specific ef- responses in models of autoimmunity, inflammation, and trans- fectors after CD40/CD154 blockade has not been investigated. plantation. Indeed, CD40 pathway blockade remains one of the To address these questions, we used an ovalbumin (OVA)- most powerful methods of prolonging graft survival in models of expressing transgenic mouse model (20), which allowed us to di- + + transplantation. But despite this effectiveness, the cellular and rectly track both donor-reactive CD4 and CD8 T-cell responses molecular mechanisms underlying the protective effects of CD40 simultaneously over time. Although previous studies have used pathway blockade are incompletely understood. Furthermore, the transgenic models to assess the degree of T-cell deletion after CD154/CD40 blockade (16, 21), none has systematically inter- relative contributions of deletion, anergy, and regulation have not + been measured in a model in which donor-reactive CD4+ and CD8+ rogated the impact of anti-CD154 on the kinetics of both CD4 and CD8+ T-cell deletion and acquisition of effector function. T-cell responses can be assessed simultaneously. To investigate the fi Our results indicated that although CD40/CD154 blockade alone impact of CD40/CD154 pathway blockade on graft-speci c T-cell delayed donor-reactive CD4+ and CD8+ T-cell expansion and responses, a transgenic mouse model was used in which recipients differentiation, the addition of DST was required for antigen- fi + + containing ovalbumin-speci cCD4 and CD8 TCR transgenic T specific T-cell deletion.
    [Show full text]
  • Interferon Gamma Release Assay (IGRA) Interferon Gamma Release Assay (IGRA) Is a Blood Test That Has Recently Been Introduced As Another Method to Diagnose LTBI
    Section 4: TB Screening These cases also included patients that did not have previous exposure to tuberculin. It is imperative that health care providers should have Epinephrine Hypochloride solution (1:1000) and other appropriate agents available for immediate use in the case of a hypersensitivity reaction. As per NACI, recommendations all patients must be monitored for 15 minutes after inoculation. Interferon Gamma Release Assay (IGRA) Interferon gamma release assay (IGRA) is a blood test that has recently been introduced as another method to diagnose LTBI. Therefore, it can complement the TST in certain situations. In general, IGRAs are more specific than the TST in populations vaccinated with BCG, especially if BCG is given after infancy or multiple times. When a person is exposed to MTB it produces many immune cells, which produce various proteins. Among these proteins are interferon gamma or IFN-y. The interferon gamma release assay (IGRA) is a blood test that measures IFN-y. Therefore, if a person has been exposed and infected with TB, IFN-y can be detected with this test. There are two IGRA tests used in Canada, the T-SPOT.TB test and the QuantiFERON®-TB Gold test. Provincial Laboratory (ProvLab) Alberta uses QuantiFERON®-TB Gold (QFT) test in the NWT. Specimens must be received by the regional laboratory and incubated for 16–24 hours. This limits availability of this test in the NWT. IGRA can only be ordered through the Office of the Chief Public Health Officer and Stanton Regional Hospital Specialists who are involved in TB management and treatment. IGRAs require laboratories with adequate equipment and trained personnel to perform the assays.
    [Show full text]
  • Interferon-Based Biopharmaceuticals: Overview on the Production, Purification, and Formulation
    Review Interferon-Based Biopharmaceuticals: Overview on the Production, Purification, and Formulation Leonor S. Castro 1,†, Guilherme S. Lobo 1,†, Patrícia Pereira 2 , Mara G. Freire 1 ,Márcia C. Neves 1,* and Augusto Q. Pedro 1,* 1 CICECO–Aveiro Institute of Materials, Chemistry Department, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal; [email protected] (L.S.C.); [email protected] (G.S.L.); [email protected] (M.G.F.) 2 Centre for Mechanical Engineering, Materials and Processes, Department of Chemical Engineering, University of Coimbra, Rua Sílvio Lima-Polo II, 3030-790 Coimbra, Portugal; [email protected] * Correspondence: [email protected] (M.C.N.); [email protected] (A.Q.P.) † These authors contributed equally to this work. Abstract: The advent of biopharmaceuticals in modern medicine brought enormous benefits to the treatment of numerous human diseases and improved the well-being of many people worldwide. First introduced in the market in the early 1980s, the number of approved biopharmaceutical products has been steadily increasing, with therapeutic proteins, antibodies, and their derivatives accounting for most of the generated revenues. The success of pharmaceutical biotechnology is closely linked with remarkable developments in DNA recombinant technology, which has enabled the production of proteins with high specificity. Among promising biopharmaceuticals are interferons, first described by Isaacs and Lindenmann in 1957 and approved for clinical use in humans nearly thirty years later. Interferons are secreted autocrine and paracrine proteins, which by regulating several biochemical Citation: Castro, L.S.; Lobo, G.S.; pathways have a spectrum of clinical effectiveness against viral infections, malignant diseases, Pereira, P.; Freire, M.G.; Neves, M.C.; and multiple sclerosis.
    [Show full text]
  • 2010 Hepatitis C Treatment Updates
    2010 Hepatitis C Treatment Updates Summer 2010 Treatment Options Conventional Interferon Alone (Monotherapy) Studies in adults have demonstrated that monotherapy with conventional interferon is effective for adults 10-15% of the time. Although children typically respond better than adults to this treatment (27% for genotype 1 and 71% for genotype 2 and 3), subsequent study has confirmed that using conventional interferon in combination with ribavirin produces better treatment outcomes for both adults and children. Thus, conventional interferon alone is no longer recommended for the majority of children requiring HCV therapy. Conventional Interferon Alpha-2b in Combination with Ribavirin (Rebetron for Children) Rebetron was the first drug to be FDA-approved to treat children with hepatitis C. It’s approved for use in children between the ages of 5 and 16 years. Rebetron is a combination drug that contains both Intron A (an interferon alfa-2b) and Rebetol (which is ribavirin). Rebetron is administered as a weight-based dose of oral Rebetol that is taken twice a day. (Rebetol should never be used alone to treat hepatitis C.) The Intron A portion of the treatment is a subcutaneous injection that is given three times weekly for 24 to 48 weeks. Sometimes, problems with anemia or depression can develop with this treatment. When this occurs, doses should be reduced temporarily or permanently until the problem is reversed. Additionally, if uncontrollable thyroid abnormalities (such has hypothyroidism) occur, treatment should be discontinued. Use of conventional interferon alpha-2b in combination with ribavirin has been shown to improve treatment outcomes in adults when compared to using conventional interferon alone.
    [Show full text]
  • High Sensitivity Immunoassays for Detecting Ifn-Gamma in Cytokine Release Syndrome
    APPLICATION NOTE HIGH SENSITIVITY IMMUNOASSAYS FOR DETECTING IFN-GAMMA IN CYTOKINE RELEASE SYNDROME INTRODUCTION T cell expansion with increased Interferon Gamma (IFN-γ) release. Note that increased IFN-γ is also an early and prominent element of CRS. IFN , along with IL-6, IL-10 and TNF-alpha are the Cytokine Release Syndrome (CRS), also known as the “Cytokine -γ core cytokines involved in CRS (2). IFN activates macrophages Storm”, is a systemic inflammatory response characterized at the -γ which secrete excessive amounts of other cytokines such as cellular level by the rapid release of excessive concentrations IL-6, TNF and IL-10. Lastly, it is important to keep in mind that of cytokines (1,2). Patient symptoms range from mild fever to α IFN is pleiotropic and has both harmful and beneficial effects. hypotension, multiorgan system failure, neurotoxicity and death. -γ Although IFN has a harmful role in CRS, it also been correlated CRS is caused by a variety of events, including viral infection, -γ with antiproliferative, proapoptotic and antitumor activities in the antibody-based immunotherapy and cellular immunotherapy. context of cancer (4). In antibody-based immunotherapies, the incidence of CRS is relatively low, however, onset can occur within days and up to We previously described the new 3rd generation R&D Systems® weeks of infusion in cellular immunotherapy. Evidence suggests IFN-γ Quantikine® ELISA kit. Learn more about that assay here. that the risk and severity of CRS is influenced by the type of Here, we describe the R&D Systems® Human IFN-γ Quantikine® therapy, disease burden and patient characteristics, such as age.
    [Show full text]
  • Betaferon Data Sheet
    NEW ZEALAND DATA SHEET 1 PRODUCT NAME BETAFERON® Interferon beta-1b 8 MIU Injection with diluent 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Lyophilisate and solvent for solution for injection. BETAFERON® Recombinant Interferon beta-1b 0.25 mg (8.0 million IU) per mL when reconstituted. 1 mL of the reconstituted solution for injection contains 8 million IU (0.25 mg) of interferon beta-1b. 1 mL solution for injection contains 5.4 mg sodium chloride. Interferon beta-1b is produced in Escherichia coli cells by recombinant DNA technology from a strain of Escherichia coli that bears a genetically engineered plasmid containing a modified human interferon beta gene. BETAFERON contains mannitol. For the full list of Excipients, see section 6.1 List of excipients. 3 PHARMACEUTICAL FORM BETAFERON is presented as a sterile lyophilised white to off-white cake or powder and solvent for solution for injection. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications BETAFERON is indicated for: • the treatment of patients with a single clinical event suggestive of multiple sclerosis and at least two clinically silent magnetic resonance imaging (MRI) lesions characteristic of multiple sclerosis, if alternative diagnoses have been excluded, • the treatment of ambulatory patients, with relapsing-remitting multiple sclerosis (MS) characterised by at least two attacks of neurological dysfunction over a two year period followed by complete or incomplete recovery. • the reduction of frequency and severity of clinical relapses and for slowing the progression of disease in patients with secondary progressive multiple sclerosis 4.2 Dose and method of administration General Treatment with BETAFERON should be initiated under the supervision of a physician experienced in the treatment of multiple sclerosis.
    [Show full text]
  • A Randomised Trial to Compare the Pharmacokinetic, Pharmacodynamic, and Antiviral Effects of Peginterferon Alfa-2B and Peginterf
    Journal of Hepatology 45 (2006) 204–213 www.elsevier.com/locate/jhep A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE) Marcelo Silva1,*, Jorge Poo2, Frank Wagner3, Mary Jackson4, David Cutler4, Michael Grace4, Ronald Bordens4, Connie Cullen4, Joann Harvey4, Mark Laughlin4 1Hospital Universitario Austral, Pilar, Argentina 2CIF-BIOTEC/Hospital Medical Sur, Mexico City, Mexico 3Clinical Research, Berlin, Germany 4Schering-Plough Research Institute, Kenilworth, NJ, USA See Editorial, pages 172–173 Background/Aims: To compare the pharmacokinetics, pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1. Methods: Thirty-six patients were randomised to peginterferon alfa-2b (1.5 lg/kg/week) or peginterferon alfa-2a (180 lg/week) for 4 weeks, then in combination with ribavirin (13 mg/kg/day) for a further 4 weeks. The pharmacokinetic profile of both peginterferons, mRNA expression of a selected group of interferon-induced gene transcripts, and serum HCV-RNA levels were assessed. Results: Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a. Correspondingly, patients treated with peginterferon alfa-2b also had a significantly greater log10 maximum and log10 time-weighted average decrease in serum HCV-RNA. A greater propor- tion of peginterferon alfa-2b patients achieved a P2.0 log10 reduction in serum HCV-RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a patients, P = 0.09). There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a.
    [Show full text]
  • Identification of an IL-27/Osteopontin Axis in Dendritic Cells and Its
    Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-γ limits IL-17–mediated autoimmune inflammation Gopal Murugaiyan1, Akanksha Mittal1, and Howard L. Weiner2 Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 Edited* by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, and approved May 17, 2010 (received for review February 24, 2010) Dendritic cells (DCs) play a central role in determining the induc- entiation of CD4+ T cells into functional subsets including IL- tion of T cell responses. IL-27 production by DCs favors induction 17–producing pathogenic Th17 cells and IL-10–producing regu- of IL-10–producing regulatory T cells, whereas osteopontin (OPN) latory Tr1 cells. For example, IL-10 or IL-27 production by DCs promotes pathogenic IL-17 T cell responses. The regulatory mech- favors generation of IL-10–producing Tr1 cells (6, 25), whereas anisms in DCs that control these two cells types are not under- OPN production by DCs promotes IL-17–producing Th17 cells stood well. Here, we show that IFN-γ induces IL-27 while inhi- (16, 17). However, it is unknown how IL-27 and OPN expression biting OPN expression in DCs both in vitro and in vivo and that in DCs are modulated to regulate both IL-10 and IL-17 pro- engagement of IFN-γR expressed by DCs leads to suppression duction by T cells. of IL-17 production while inducing IL-10 from T cells. DCs modi- Here, we show that IFN-γ induces IL-27 while inhibiting OPN − − fied by IFN-γ acquire IL-27–dependent regulatory function, pro- expression in DCs both in vitro and in vivo.
    [Show full text]
  • Potential Role and Mechanism of IFN-Gamma Inducible Protein-10 on Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) Ex
    Lee et al. Arthritis Research & Therapy 2011, 13:R104 http://arthritis-research.com/content/13/3/R104 RESEARCHARTICLE Open Access Potential role and mechanism of IFN-gamma inducible protein-10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rheumatoid arthritis Eun Young Lee1, MiRan Seo2, Yong-Sung Juhnn2, Jeong Yeon Kim1, Yoo Jin Hong1, Yun Jong Lee1, Eun Bong Lee1 and Yeong Wook Song1* Abstract Introduction: IFN-gamma inducible protein-10 (CXCL10), a member of the CXC chemokine family, and its receptor CXCR3 contribute to the recruitment of T cells from the blood stream into the inflamed joints and have a crucial role in perpetuating inflammation in rheumatoid arthritis (RA) synovial joints. Recently we showed the role of CXCL10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in an animal model of RA and suggested the contribution to osteoclastogenesis. We tested the effects of CXCL10 on the expression of RANKL in RA synoviocytes and T cells, and we investigated which subunit of CXCR3 contributes to RANKL expression by CXCL10. Methods: Synoviocytes derived from RA patients were kept in culture for 24 hours in the presence or absence of TNF-a. CXCL10 expression was measured by reverse transcriptase polymerase chain reaction (RT-PCR) of cultured synoviocytes. Expression of RANKL was measured by RT-PCR and western blot in cultured synoviocytes with or without CXCL10 and also measured in Jurkat/Hut 78 T cells and CD4+ T cells in the presence of CXCL10 or dexamethasone. CXCL10 induced RANKL expression in Jurkat T cells was tested upon the pertussis toxin (PTX), an inhibitor of Gi subunit of G protein coupled receptor (GPCR).
    [Show full text]
  • Interferon Alfa(BAN, Rinn)
    Inosine Pranobex/Interferon Alfa 885 Interferon Alfa (BAN, rINN) rarely, aplastic anaemia), cardiovascular disorders not affect bone marrow transplants, although 3 patients experi- (hypo- or hypertension, supraventricular arrhythmias enced fever and chills, 4 had more than a 60% reduction in abso- IFN-α; Interferón-α; Interferon-α; Interferón alfa; Interféron alfa; lute peripheral granulocyte counts, and 4 had a 37 to 80% reduc- Interferon alpha; Interferoni alfa; Interferonialfa; Interferonum Al- and myocardial infarction), endocrine disorders (such tion in absolute platelet counts.8 Lymphocytes were increased in fa; Ro-22-8181 (interferon alfa-2a); Sch-30500 (interferon alfa- as thyroid disorders and diabetes mellitus), pulmonary all patients; blood counts returned to normal when interferon 2b). disorders (dyspnoea, pneumonia, bronchiolitis obliter- therapy stopped. Interferon alfa produced a decline in CD4+ T- Интерферон Альфа ans, interstitial pneumonitis and sarcoidosis), colitis lymphocytes resulting in opportunistic infections in 2 HIV-posi- tive patients being treated for chronic hepatitis C.9 CAS — 74899-72-2 (interferon alfa); 76543-88-9 (inter- (ulcerative and hemorrhagic or ischaemic colitis), pan- 1. Akard LP, et al. Alpha-interferon and immune hemolytic ane- feron alfa-2a); 99210-65-8 (interferon alfa-2b); 118390- creatitis, and ophthalmologic disorders (such as de- mia. Ann Intern Med 1986; 105: 306. 30-0 (interferon alfacon-1); 198153-51-4 (peginterferon crease or loss of vision, retinopathy including macular 2. McLaughlin P, et al. Immune thrombocytopenia following α-in- alfa-2a); 215647-85-1 (peginterferon alfa-2b). oedema and retinal thrombosis or haemorrhages, optic terferon therapy in patients with cancer. JAMA 1985; 254: 1353–4.
    [Show full text]
  • Type I and II Interferons in the Anti-Tumor Immune Response
    cancers Review Type I and II Interferons in the Anti-Tumor Immune Response Sarah E. Fenton 1,2, Diana Saleiro 1,2 and Leonidas C. Platanias 1,2,3,* 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA; [email protected] (S.E.F.); [email protected] (D.S.) 2 Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA 3 Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA * Correspondence: [email protected] Simple Summary: Interferons are cytokines that play key roles in the activation of cellular com- ponents of the immune response, such as dendritic cells, macrophages and T cells. Generally, these cytokines promote anti-tumor immune responses, but under some circumstances, prolonged exposure to them can lead to suppression of the immune response. This review focuses on the immunostimulatory versus immunosuppressive roles of interferons and the mechanisms mediating such effects on both malignant cells and cells of the immune system. Abstract: The interferons (IFNs) are essential components of the immune response against infec- tions and malignancies. IFNs are potent promoters of the anti-tumor response, but there is also evidence that feedback mechanisms regulated by IFNs negatively control immune responses to avoid hyper-activation and limit inflammation. This balance of responses plays an important role in cancer surveillance, immunoediting and response to anticancer therapeutic approaches. Here we review the roles of both type I and type II IFNs on the control of the immune response against malignancies in the context of effects on both malignant cells and cells of the immune system in the Citation: Fenton, S.E.; Saleiro, D.; tumor microenvironment.
    [Show full text]