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