INTERFERON

PRESENTER- DR. CHINMAYA DASH

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.

Definition

Interferons (IFNs) are naturally occurring cytokines with antiviral, immunomodulatory and antiproliferative properties.

• First cytokine to be recognized

CLASSIFICATION

A. In 1980, nomenclature was formally adopted classifying IFNs into three categories

Based on Antigenic Specificity:-

B. Their ability to bind to common Receptor Types :-

(Divided into TWO groups )

IFN categories Earlier Designation

Alpha (α) Leukocyte

Beta (β) Fibroblast

Gamma ( ) Immune IFN

IFN Types

IFNCategories

Receptors Prototypic cell of Origin

Type-I Alpha (α) I Leukocyte

Beta (β) I Fibroblast

Omega () I Leukocyte

Tao () I Ovine Trophoblast

Type-II Gamma- II T-CellNK-Cell

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

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

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)

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

MODE OF ACTIVATION OF IFN STIMULATED GENES(ISGs):-

These enzymes instrumental in development of the antiviral state.

dsRNA dependent protein kinase, PKR-

Phosphorylates 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

BIOLOGICAL PROPERTIES

A. Properties of IFN α & -

IFN-α &

TUMOR CELLS

MHC-I expression Tumor specific antigenic expressionAdhession molecule expression Direct cytostatic effect

ANTIANGIOGENIC

T-CELLS

NK-CELL/MACROPHAGES

Th1-DifferentiationGrowth Inhibition

IFN- productionIL-1 ProductionProliferation

IFN- TUMOR CELLS

• MHC-I upregulation.•Decreased proliferation

ANTIANGIOGENIC

T-CELLS

APC/MACROPHAGES

Increased Activation

MHC Class- II upregulation

B. Properties of IFN-:-

APPLICATIONS

A. Therapeutic Applications:-

Used to treat several neoplastic and non neoplastic diseases.

Clinical indications of INF as follows:-

i. Neoplastic Diseases- a. Lymphoma-

Non Hodgkin’s Lymphoma (NHL)

Follicular Lymphoma

b. Hematopoetic Malignacies-

Hairy Cell Leukemia

Chronic Myeloid Leukemia(CML)

c. Carcinoma-

Renal Cell Carcinoma (RCC)

Melanoma

ii. Non Neoplastic Diseases-

a. Chronic Hepatitis B Infection-

IFN-α / Peg IFN-α with Nucleoside Analogues (Lamivudin, Adefovir,Tenofovir etc)

b. Chronic Hepatitis C Infection-

Standard IFN and the combination of

Peg INF-α2a or 2b with or without Ribavirin therapy

c. Condyloma Acuminata-

Intralesional INF-α2b in previously resistant to Podophyllum

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

B. Preventive Application-

Common Cold (Rhinovirus infection)-

Intranasal IFN-α2

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.

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 )

VIRUS MECHANISMS TO COUNTERACT INTERFERON

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

Clinically there are four major side effect groups-

SIDE EFFECTS

I.CONSTITUTIONAL Fatigue (70%-100%)Anorexia(40%-70%), Weight loss, Fever, Myalgia,Headache

II.NEUROPSYCHIATRIC (upto 30%)

• Dizziness/Vertigo•Mood Disorder-( Confusion, pathological depression)•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.)

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.

THANK

YOU