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  2. 2. INTRODUCTION • In 1957 Isaacs and Linderman described a factor that have the property of viral interference. • Research has revealed diverse mechanism of action include antiviral, immune enhancing and cytostatic activities.
  3. 3. Definition Interferons (IFNs) are naturally occurring cytokines with antiviral, immunomodulatory and antiproliferative properties. • First cytokine to be recognized
  4. 4. CLASSIFICATION A. In 1980, nomenclature was formally adopted classifying IFNs into three categories Based on Antigenic Specificity:IFN categories Earlier Designation Alpha (α) Leukocyte Beta (β) Fibroblast Gamma ( ) Immune IFN B. Their ability to bind to common Receptor Types :(Divided into TWO groups )
  5. 5. IFN Types IFN Categories Receptors Prototypic cell of Origin Type-I Alpha (α) I Leukocyte Beta I Fibroblast Omega ( ) I Leukocyte Tao ( ) I Ovine Trophoblast Gamma- II T-Cell NK-Cell Type-II (β)
  6. 6. Properties Alpha Beta Gamma Current Nomenclature IFN-α IFN-β IFN- Former Designation Leukocyte Fibroblast Immune Interferon Type Designation Type I Type I Type II No. Of Genes that code for Family ≥20 1 1 Principal Cell Source Most Cell Types Most cell Types Lymphocytes Inducing Agent Viruses; dsRNA Viruses; dsRNA Mitogens Stability at pH 2.0 Stable Stable Labile Homology with IFN-α 80-95% 30% <10% Chromosomal location of genes 9 9 12 Size of secreted protein (Number of amino acids) 165 166 143 IFN receptors IFNAR IFNAR IFNGR Chromosomal location of IFN receptor genes 21 21 6
  7. 7. Important Features :• First recognized by their ability to interfere with viral infections in cultured cells. • Does not protect the virus infected cell that produces it. • Itself is not the antiviral agent. It moves to other cells where it induces an antiviral state.(By inhibiting viral replication) • Almost all cell types produce IFN-α &β and IFN- are produced in T-cells and NK-Cells
  8. 8. INDUCTION AND ACTIVATION OF IFNs A. IFN-α & β (Type-I- IFNs) When prototypic cell of origin is exposed to -Viruses -Double stranded RNA -Polypeptides And - Cytokines B. IFN(Type-II- IFNs) Following a number of immunological stimuli including :-T-cell specific antigen -Staphylococcal enterotoxin -A And -Mitogens ( Phyto haemagglutinin ,Phorbol Ester etc)
  9. 9. MODE OF ACTIVATION OF IFN STIMULATED GENES(ISGs):IFN binds with the respective IFN-Receptors(IFNRs) Oligomerization of the receptor followed by phosphorylation of the tail of receptor molecule Phosphorylated stat ( Signal Transducers and activators of transcription ) released from the receptor molecules and translocate to the nucleus Activation of trancription of IFN-Stimulated gene. This results in synthesis of several enzymes
  10. 10.  These enzymes instrumental in development of the antiviral state.  dsRNA dependent protein kinase, PKRPhosphorylates and inactivates cellular initiation factor elF-2 , thus prevents viral protein synthesis  2-5A synthetase (Oligonuceotide Synthetase)Activates a cellular endonuclease RNase L -» Degrade mRNA  Phosphodiesterase- inhibits peptide chain elongation  Nitric oxide synthetase, which is induced by IFN- in macrophages Fail to reveal why the antiviral state acts selectively against viral mRNA and not cellular mRNA
  11. 11. BIOLOGICAL PROPERTIES A. Properties of IFN α & Th1-Differentiation Growth Inhibition T-CELLS IFNproduction IL-1 Production Proliferation NK-CELL/ MACROPHAGES IFN-α & ANTIANGIOGENIC TUMOR CELLS  MHC-I expression  Tumor specific antigenic expression Adhession molecule expression Direct cytostatic effect
  12. 12. B. Properties of IFN- :Increased Activation T-CELLS MHC ClassII upregulation APC/ MACROPHAGES IFN- ANTIANGIOGENIC TUMOR CELLS • MHC-I upregulation. •Decreased proliferation
  13. 13. APPLICATIONS A. Therapeutic Applications:Used to treat several neoplastic and non neoplastic diseases. Clinical indications of INF as follows:i. Neoplastic Diseasesa. Lymphoma- Non Hodgkin’s Lymphoma (NHL) Follicular Lymphoma b. Hematopoetic MalignaciesHairy Cell Leukemia Chronic Myeloid Leukemia(CML) c. CarcinomaRenal Cell Carcinoma (RCC) Melanoma
  14. 14. ii. Non Neoplastic Diseasesa. Chronic Hepatitis B InfectionIFN-α / Peg IFN-α with Nucleoside Analogues (Lamivudin, Adefovir,Tenofovir etc) b. Chronic Hepatitis C InfectionStandard IFN and the combination of Peg INF-α2a or 2b with or without Ribavirin therapy c. Condyloma AcuminataIntralesional INF-α2b in previously resistant to Podophyllum
  15. 15. TYPE FDA- APPROVED INDICATIONS IFN-α2a -NHL, Hairy Cell Leukemia, CML -AIDS related KS, Chronic Hepatitis-C IFN-α2b -Follicular Lymphoma, Hairy Cell leukemia, AIDs related KS, Malignant melanoma, -Condyloma acuminata, Chronic hepatitis B, Chronic hepatitis C IFN-αn3 -Condyloma acuminata IFN- β1a -Relapsing remitting Multiple Sclerosis IFN-β1b -Relapsing remitting Multiple Sclerosis IFN- -Chronic Granulomatous Disease
  16. 16. B. Preventive Application- Common Cold (Rhinovirus infection)Intranasal IFN-α2
  17. 17. C. Diagnostic Application:- T Cell based interferon gamma (IFN- ) assay (IGRAs) for Mycobacterium tuberculosis specific antigens Helps in screening for Latent (LTBIs) and active tuberculosis infection.
  18. 18. VIRUS MECHANISMS TO COUNTERACT INTERFERON  Specific viral proteins may block induction of expression of IFN ( Herpesvirus, Papilloma virus, Hepatitis C virus, Rota virus)  May block the activation of the key PKR protein kinase ( Adenovirus, Herpes viruses)  May activate a cellular inhibitor of PKR ( Influenza, Poliovirus)  May block IFN induced signal transduction (Adenovirus, Herpes virus, Hepatitis B Virus)  May neutralize IFN- by acting as a soluble interferon receptor ( Myxoma virus )
  19. 19. SIDE EFFECTS  Depending upon the time interval between induction of therapy and appearance of side effects/toxicities classified as-  Acute Toxicities ( Occur usually between 3-6Hrs after receiving IFN )  Chronic Toxicities
  20. 20.  Clinically there are four major side effect groupsSIDE EFFECTS I.CONSTITUTIONAL Fatigue (70%-100%) Anorexia(40%-70%), Weight loss, Fever, Myalgia, Headache II. • Dizziness/Vertigo NEUROPSYCHIATRIC •Mood Disorder-( Confusion, pathological depression) (upto 30%) •Neuro endocrine disturbance( Perturbation of hypothalamo thyroid adrenalin axis) III.HEPATIC Transamnitis IV.HEMATOLOGICAL •Thrombocytopenia •Anemia •Leukopenia (The severity of side effects) α (Dose and Duration of IFN therapy.)
  21. 21. REFERENCES • Jonasch E and Haluska FG. Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities. Oncologist 2001;6(1):34-55. • Rijckborst V and Janssen Harry L.A. The Role of Interferon in Hepatitis B therapy. Curr Hepatitis Rep 2010;9:231-238 • Kanda T, Imazeki F and Yokosuka O. New Antiviral Therapies for Chronic Hepatitis C. Hepatol Int 2010;4:548-561 • Yoshihiro et al .Comparison of T Cell Interferon- y Release Assays for Mycobacterium tuberculosis – Specific Antigens in Patients with Active and Latent Tuberculosis. Lung 2010;188:283-287 • Hayden FG and Gwalthey JM jr. Intranasal interferon-alpha 2 treatment of experimental rhinoviral colds. J Infect Dis. 2003 Aug;150(2):174-80.
  22. 22. THANK YOU