Interferons are small proteins released by macrophages, lymphocytes, and tissue cells infected with a virus. When a tissue cell is infected by a virus, it releases interferon. The exact mechanism oI type I interIerons is not Iuly understood, but this is an idea oI what happens.
Interferons are small proteins released by macrophages, lymphocytes, and tissue cells infected with a virus. When a tissue cell is infected by a virus, it releases interferon. The exact mechanism oI type I interIerons is not Iuly understood, but this is an idea oI what happens.
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Interferons are small proteins released by macrophages, lymphocytes, and tissue cells infected with a virus. When a tissue cell is infected by a virus, it releases interferon. The exact mechanism oI type I interIerons is not Iuly understood, but this is an idea oI what happens.
Copyright:
Attribution Non-Commercial (BY-NC)
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Download as PPT, PDF, TXT or read online from Scribd
iscovery oI InterIerons 1957 Isaacs and Lindenmann id an experiment using chicken cell cultures Found a substance that interIered with viral replication and was thereIore named interIeron Nagano and Kojima also independently discovered this soluble antiviral protein hat are InterIerons? Naturally occurring proteins and glycoproteins Secreted by eukaryotic cells in response to viral inIections, tumors, and other biological inducers Produce clinical beneIits Ior disease states such as hepatitis, various cancers, multiple sclerosis, and many other diseases Strucurally, they are part oI the helical cytokine Iamily which are characterized by an amino acid chain that is 145-166 amino acids long nterferons are small proteins released by macrophages, lymphocytes, and tissue cells infected with a virus. When a tissue cell is infected by a virus, it releases interferon. nterferon will diffuse to the surrounding cells. When it binds to receptors on the surface of those adjacent cells, they begin the production of a protein that prevents the synthesis of viral proteins. This prevents the spread of the virus throughout the body. eneral Action oI InterIerons Three types oI interIerons: alpha, beta and gamma. Type I InterIerons Type I: alpha and beta Alpha interIerons are produced by leukocytes Beta interIerons are produced by Iibroblasts Both bind to interIeron cell receptors type 1 and both encoded on chromosome 9 They have diIIerent binding aIIinities but similar biological eIIects Viral inIection is the stimulus Ior alpha and beta expression Used to mobilize our 1 st line oI deIense against invading organisms Largest group and are secreted by almost all cell types The exact mechanism oI type I interIerons are not Iully understood, but this is an idea oI what happens: Alpha and beta bind to heterodimeric receptor on cell surIace. Alpha receptor is made up oI at least 2 polypeptide chains: IFNa-R1 and IFNa-R2 IFNa-R1 is involved in signal transduction IFNa-R2 is the ligand-binding chain that also plays a role in signal transduction Ligation induces oligomerisation and initiation oI the signal transduction pathway This results in phosphorylation oI signal transductors and activators oI transcription proteins, which translocate to the nucleous as a trimeric complex, ISF-3. ISF-3 activates transcription oI interIeron stimulated genes, with many biological eIIects. Type II InterIeron (gamma) Bind to type 2 receptors and its genes are encoded on chromosome 12 Initially believed that T helper cell type 1 lymphocytes, cytotoxic lymphocytes and natural killer cells only produced IFNg, now evidence that B cells, natural killer T cells and proIessional antigen-presenting cells secrete IFNg also. amma production Iollows activation with immune and inIlammatory stimuli rather than viral inIection. This production is controlled by cytokines secreted by interleukin 12 and 18. InterIeron amma Receptor Composed oI two ligand binding IFNg-R1 chains associated with two signal transducing IFNg-R2 chains The IFNg-R2 chain is generally the limiting Iactor in IFNg responsiveness, as the IFNg-R1 chain is usually in excess. The IFNg-R1 intracellular domain contains binding spots Ior the Jak 1, latent cytosolic Iactor, signal transducer and activator oI transcription (Stat1) IFNg only associates with IFNg-R2 when the IFNg-R1 chain is present. InterIeron amma Receptor and Signalling Pathway Receptors are encoded by separate genes (# and #, respectively) that are located on diIIerent chromosomes. As the ligand-binding (or -) chains interact with IFN- they dimerise and become associated with two signal-transducing chains. Receptor assembly leads to activation oI the Janus kinases JAK1 and JAK2 and phosphorylation oI a tyrosine residue on the intracellular domain oI IFN-R1. This leads to the recruitment and phosphorylation oI STAT1, which Iorms homodimers and translocates to the nucleus to activate a range oI IFN--responsive genes. AIter this, the ligand-binding chains are internalised and dissociate. The chains are then recycled to the cell surIace. iIIerent InterIeron rugs InterIerons are broken down into recombinant versions oI a speciIic interIeron subtype and puriIied blends oI natural human interIeron. Many oI these are in clinical use and are given intramuscularly or subcutaneously Recombinant Iorms oI alpha interIeron include: Alpha-2a drug name RoIeron Alpha-2b drug name Intron A Alpha-n1 drug name ellIeron Alpha-n3 drug name AlIeronN Alpha-con1 drug name InIergen Recombinant Iorms oI beta interIeron include: Beta-1a drug name Avonex Beta-1b drug name Betaseron Recombinant Iorms oI gamma interIeron include: amma-1b drug name Acimmune Alpha InterIeron-2a (RoIeron A) Protein chain that is 165 amino acids long Produced using recombinant NA technology Non-glycosylated protein Short halI liIe, short terminal elimination oI halI liIe, a large volume oI distribution, and a larger reduction in renal clearance. These problems were resolved by pegylating alpha-2a resulting in peginterIeron alpha-2a that is named Pegasys. Pegylated InterIeron-2a (Pegasys) Background: First developed by avis, Abuchowski and colleagues in the 1970s In early 1990s PE attached to alpha-2a, but it lacked the required proIile oI improving pharmacokinetics Pegylation oI interIeron alpha-2b was achieved with the addition oI a linear PE, designed to degrade to allow the Iull potency oI the interIeron, while achieving a longer halI-liIe. Pegasys is recombinant interIeron alpha-2a that is covalently conjugated with bis- monomethoxy polyethylene glycol (PE) Structure: CH3(OCH2CH2)n--OH mPEOO2CCNH mPEOO2CNH(CH2)4 O PE moieties are inert, longchain amphiphilic molecules that are produced by linking repeating units oI ethylene oxide. Can be linear or branched in their structure Increasing the size with PE, the absorption and liIe are prolongued and the clearance oI the IFN is decreased. oal oI pegylation is to decrease clearence, retention oI biological activity, get a stable linkage and enhance water solubility Pegylation is achieved by the covalent attachment oI PE derivatives that utilize amino groups oI lysines and the N-terminus oI polypeptide molecules as the modiIication site InterIeron Beta-2a (Avonex) FA approval on May 17 1996 Ior Relapsing Remitting MS Clinical trials showed that it slowed MS progression and had an extra beneIit oI slowing or preventing the development oI MS-related brain atropy. The exact mechanism oI IFN beta activity in treating MS is unknown, but studies have shown that interlukin 10 levels in the cerebrospinal Iluid were increased in patients Structurally IFNb-2a is a 166 amino acid glycoprotein. Produced by recombinant NA technology using genetically engineered mammalian cells which the human beta gene has been introduced into Amino acid sequence is the same as human beta interIeron. They are both glycosylated at the asparagines residue at position 80 Some side eIIects include: Flu-like symptoms Muscle aches Chills Combination Therapy with Ribavirin Many times interIerons and peginterIerons are used in combination with Ribavirin It is a purine nucleoside analogue with a modiIied base and a -ribose sugar moiety 1 st made in 1970 by rs. Joseph itkowski and Roland Robins It inhibits the replication oI a variety oI RNA and NA viruses and is serves as an immunomodulator to enhance type 1 cytokine production. This increases the end oI treatment response and reduces post-treatment relapse. Mechanism is not well known, but there are 4 proposed mechanisms Conclusion InterIerons have overlapping but diIIerent biological activities Their mechanisms oI action are not Iully understood, thereIore there is a lot oI room Ior Iuture growth within this Iield InterIeron based strategies can possibly be Iurther tailored to each individual patient according to early response dynamics Other immunomodulatiors that are being tested include: Zadaxin and Ceplene ReIerences 1. Al-Hasso, Shahla. 'InterIerons: An Overview. US Pharmacist 26:06 2. Alm, unner V. 'Role oI Natural InterIeron-alpha Producing cells (Plasmacytoid endritic cells) in Autoimmunity. Autoimmunity 36 (2003): 463-472. 3. ecatris, Marios. 'Potential oI InterIeron-alIa in Solid Tumours. Biodrugs 16 (2002): 261-268. 4. oodsell, avid S. 'The Molecular Perspective: InterIerons The Oncologist 6 (2001): 374-375. 5. Hertzog, Paul J. 'InterIeron-gamma: an overview oI signals, mechanisms and Iunctions. Journal oI Leukocyte Biology 75 (2004): 163-179. 6. Lau, Johnson Y.N. 'Mechanism oI Action oI Ribavirin in the Combination Treatment oI Chronic HVC InIection. Perspectives in Clinical Hepatology 35 (2002): 1002-1007. 7. Matthews, James S. 'PeginterIeron AlIa-2a: A Review oI Approval and Investigational Uses. Clinical Therapeutics 26 (2004): 991-998. 8. Pedder, Simon C.J. 'Pegylation oI InterIeron AlIa: Structural and Pharmacokinetic Properties. Seminars in Liver isease 23 (2003): 19-21. 9. Schreiber, regory H. 'InterIeron gamma. The Cytokine Handbook 4 (2003):567-569. 10. Vrolijk, J.M. 'The treatment oI hepatitis C: history, presence and Iuture. Journal oI Medicine 62 (2004): 76-82.