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. Definition
Interferons (IFNs) are naturally occurring cytokines
with antiviral, immunomodulatory and antiproliferative
properties.
• First cytokine to be recognized
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 )
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. 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. 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. 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. 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
12. 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
14. 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
15. 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
18. 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.
19. 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 )
20. 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
21. 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.)
22. 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.