I N T E R F E R O N

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I N T E R F E R O N

• 1?
• 200603765 ???
• 200603769 ???
• 200603774 ???
• 200603794 ???
• 200603797 ???

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C O N T E N T S

• Interferon? ??
• Interferon ??
• Cytokine
• Interferon ??Interferon signaling pathway
• Interferon type?, ? ??? ? ??
• Interferon-a, ß ? ????? ??
• Interferon- ? ? Immunoregulatory action
• Interferon-a, ß ? ? ?? / ?????

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Interferon ??? ?????

• 1957? ?? ???? A.Issacs
• ??? ????? J.Lindenmann
• ????? ???? ??? ???? ?????
• ????? ??? ??
• ???? virus? ?? ?? ??? ??? ? ??? ? virus ?? ??
  
• ???? ??? ?? ???? ???? ? ?? ??? ?
• ???? (interference) ? ??? ????? ??? ????? ???
  ????? ? ? ?? ????? ?? ????? ????? ???? ????? ??
  ???? ???? ??
• Cytokine ? ?? from interfere

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Cytokine

• cyto (??) kinesis (???)
• ?? ?? ???? ???? ?? ? ??? ?? ????? ???? ??? ???,
  ????
• ? ??? ????? ??? ? Monokine
• ? T???? ??? ? Lymphokine
• ? ????? ???? ?? ???? ??? ? Interleukin
• ???? ??(????, ??, ?, ??, T??? antigen
  interaction) ?? induction
• Autocrine, Paracrine , Endocrine
• Target cell receptor? binding?? ligand? ??? ????
• Nonspecific/specific ???? ??? ??(??? ??,?? ?? ??
  ???? ??, apoptosis ?? )

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Types of Interferon

• ???? receptor type? ??
• - Interferon type I  (??) IFN-a, IFN-ß and
  IFN-?
• ?????,
  ???
• IFN-a
  receptor ( IFNAR )
• - Interferon type  II IFN-?
• ??????
• IFNGR

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Interferon type ?(IFNa/ß) type?(IFN?)
IFN a IFN ß IFN ?
?? ??? Leukocyte IFN Fibroblast IFN Immune IFN
Main producer B ???, macrophage Fibroblast, ???? T ???, NK Cell
Inducer (????) Virus, double-stranded RNA, microbial proteins, ?? ??? Virus, double-stranded RNA, microbial proteins, ?? ??? Virus, mytogen, phorbol ester, Ca ionophore
Gene? ?? 20 ?? 1 1
Species Specificity ??? specific ? ???? ?? ???? ??
Amino acid ? 143 145 143
??? (kDa) 17.5-23 18-23 17
? ??? stable stable Labile
Glocosylated Not glycosylated glycoslyated glycosylated
Antiviral state? ?? ?? ?? ??
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Interferon signaling pathway JAK/STAT signaling
pathway
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Biological Activities of Interferon

• Inhibition of viral replication(paracrine IFN
  from infected cell protects uninfected cells )
• class I MHC expression ?(killing by CTLs ?)
• TH1??? ?? ??
• Macrophage, NK cell cytolytic activity ?

• Immunoregulatory activity
• antiviral, antitumor activity? ??
• Enhances activities of IFNa ß

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antiviral effect of Interferon-a,ß

• Double-stranded RNA Interferon-a,ß ? ???
  inducer
• Infected cell??? ??
• ??/??? cell?? interferon receptor? binding
• Signal transduction (JAK/STAT)
• Viral replication ???? protein?? ??
• Nonspecific for virus
• Species specific (????)

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antiviral effect of Interferon-a,ß

• OligoAdenylate synthetase induction activation
• ATP? 2-5 ?? polyadenylate? polymerization (2-5
  A)
• Endonuclease (RN ase L)activation
• Viral RNA degradation

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antiviral effect of Interferon-a,ß

• Double-stranded RNA Interferon-a,ß ? ???
  inducer
• Infected cell??? ??
• ??/??? cell?? interferon receptor? binding
• Signal transduction (JAK/STAT)
• Viral replication ???? protein?? ??
• Nonspecific for virus
• Species specific (????)

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antiviral effect of Interferon-a,ß

• PKR kinase activated by double-stranded RNA
  (from viral replication)
• eIF2a phosphorylation(protein initiation
  factor)
• GEF trapped(guanine nucleotide exchange factor)
• Host cell??? translation ??viral replication ??

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Biological Activities of Interferon

• Inhibition of viral replication(paracrine IFN
  from infected cell protects uninfected cells )
• class I MHC expression ?(killing by CTLs ?)
• TH1??? ?? ??
• Macrophage, NK cell cytolytic activity ?

• Immunoregulatory activity
• antiviral, antitumor activity? ??
• Enhances activities of IFNa ß

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Immunoregulatory activity of Interferon-?

• Macrophage activating factor (MAF) NK cell?
  cytolytic activity ?
• MHC molecule expression ?
• Naïve helper T cell?, TH1??? ?? ??
• Cytotoxic T Lymphocyte? antitumor activity ?
• Regulation of B cell differentiation

• Macrophage major target cell activated by IFN-?
  
• ?Macrophage ????, NOS (Nitric Oxide Synthase)
  ? transcription activation ?ROI (Reactive
  Oxygen Intermediate), RNI (Reactive Nitrogen
  Intermediate) ?? ??
• Activate NK Cells to kill Virus-infected cells

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Immunoregulatory activity of Interferon-?

• Macrophage activating factor (MAF) NK cell?
  cytolytic activity ?
• MHC molecule expression ?
• Naïve helper T cell?, TH1??? ?? ??
• Cytotoxic T Lymphocyte? antitumor activity ?
• Regulation of B cell differentiation

• APC ??? class I II MHC molecule expression ??
• TAP, proteasome ?? protein expression ??
• Costimulatory molecule (?. B7-2/CD80) induction

? Increased Antigen Presentation
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Immunoregulatory activity of Interferon-?

• Macrophage activating factor (MAF) NK cell?
  cytolytic activity ?
• MHC molecule expression ?
• Naïve helper T cell?, TH1??? ?? ??
• Cytotoxic T Lymphocyte? antitumor activity ?
• Regulation of B cell differentiation

• Th1 responsible for cellular immunityTh2
  stimulate humoral immunity
• IFN-? ? IL-12 receptor chain expression ???
  TH1??? differentiation ???? transcription factor
  ?? ??
• ? Th1?? ??, inhibit Th2 proliferation

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Immunoregulatory activity of Interferon-?

• Macrophage activating factor (MAF) NK cell?
  cytolytic activity ?
• MHC molecule expression ?
• Naïve helper T cell?, TH1??? ?? ??
• Cytotoxic T Lymphocyte? antitumor activity ?
• Regulation of B cell differentiation

• CD8 T lymphocyte? ???? stimulatory effect

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Immunoregulatory activity of Interferon-?

• Macrophage activating factor (MAF) NK cell?
  cytolytic activity ?
• MHC molecule expression ?
• Naïve helper T cell?, TH1??? ?? ??
• Cytotoxic T Lymphocyte? antitumor activity ?
• Regulation of B cell differentiation

• B cell? ???? ? IgG2a?? isotype switching
  stimulation? IgE (IL-4-dependent isotype)???
  switching inhibition
• Stimulate phagocytosis of microbe

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Interferon-a application

• ? Treatment of Viral Infection
• ???, ??????, ????? ??
• B? ??(HBV), C? ??(HCV)
• Laryngeal cancer (Human papillomavirus)
• ????(Varicella-zoster), CMV
  (cytomegalovirus) infection
• ? Recombinant IFN-a C? ??
• ????? ???(Herpetic keratitis)
• ?????(Kaposis sarcoma)
• ????? ??? (hairy-cell leukemia)

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Interferon-a ?? ???
?? ??? ??? ? ?? ??
???? PFS PEGASYS PFS ???? Prefilled syringe Peg interferon alfa-2a 135microg/0.5mL - ???? B????? ??? ???? ??(transaminase??, ?)? ??? ?? B? ?? ?? ?? C? ???? ??? ???? ?? (transaminase ??, HCV-RNA ?? anti-HCV)? ??? ?? C? ?? ?? ?? Pegylated interferon alfa linear ?? branched PEG moiety? ????? ????? ???, ???? ???? less frequent dose ???? ?? ? ?? ?? ???? ?????, ????? ??? ??? ?? ?? \ 162,931/0.5mL
????? ? PEG-INTRON INJ ??-??? ??? PEG-interferon alfa-2b 50, 80, 100,120, 150 microg C? ???? ??? ???? ??? ?? ?? C? ?? ?? ???, ???, ??????, HIV???? ?? ? ?? ?? \98,188/V 80 microg
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Interferon-? immunological application

• IFN? has a proven curative effect -Virus???
  (herpes simplex 1, 2, herpes zoster, human
  papillomavirus)-??? ??? (mycobacteria? ?? ??)
  -Fibroproliferative disease (Systemic sclerosis)
  -Metabolic disorder (Chronic Granulomatous
  Disease, Allergy, Osteopetrosis)
• IFN? has a Certain effect, but doesnt lead to
  final recovery-Malignant disease (Renal cell
  carcinoma, Melanoma, ???) -Virus ??? (HIV virus
  - ????? ???, latent period? ??? ??)-Metabolic
  disorder (Rheumatoid arthritis)
• Experimental effect, but clinical administration
  not been established-Maglignant tumors (HPV? ??
  ?????, ???)
• IFN? is contraindicated- Multiple sclerosis,
  Kaposis's sarcoma, Systemic lupus erythematosus

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(Interferon-? application 1)
Mycobacterial Infection

• Mycobacterium tueberculosis - One of the most
  dangerous intracellular pathogens
• Tuberculosis (TB)???, ?? ?? ?? reactivation
  ??? ??
• Effector T cell, macrophagecontrol of
  tuberculosis
• IFN, TNF macrophage activator ? NO, ROI?? ??
• Active tuberculosis, BCG?? ? TH1 type
  immune response ???

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(Interferon-? application 2)
Fibroproliferative disease

• Disturbance of Cytokine network
• Fibrosis ? fibroblast ??? activation ?
  collagen overproduction (IL-4, TGF ß, ??
  ??)
• Systemic Sclerosis (???????)Scleroderma
  (?????)- connective tissue? ??? ??
• ? Interferon action fibroblast??? collagen??
  ?? ?IL-4 receptor ?? ??
  ?propyl-4-hydroxylase?? fibrinolysis ??

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(Interferon-? application 3)
Chronic Granulomatous Disease

• Inherited defect of Immune System
• ?? ??? granuloma, ?? ??
• Leukocytes? phagocytosis ? ?????
• NADPH oxidase system??cytochrom b heavy chain
  ?? (X??? ??)cytosolic 47-kDa ??? ?? (????
  ??)(phagocyte oxidative metabolism activation)
  ? Reactive Toxic Oxygen Metabolite
  ?? X ingested bacteria ??? ??

• Action of Interferon ? cytochrom b heavy chain
  ?? ??? phagocyte? ?? superoxide ?? ??
  ? killing
  of ingested bacteria
• Application Interferon-? 1b ???, prevention of
  infection in CGD patients

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Interferon-? application

• combined use of interferons - IFN-a? ?? ????
  IFN-?? ?? ?? ??
• ???? combined drug therapy?? ??? ?? ??? ??
• Frequent side effects -??, ??, ??, ??, ????,
  ??, ??, ??????
• Rare and very rare side effects -???? ?? - ???
  ? ???? ?? - ???- ????

??? ?? ??? ??? ? ?? ??
???? ?? ? INTERMAX GAMMA INJ ?????? Recombinant Interferon gamma 2000KIU ????? ??? ?? ??? ??? ?? ???? ?? ???? ???? ?? \24,761/V
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• ? ? ? ? ?