Interferons are proteins naturally produced by cells in response to viral infections and other pathogens. They were discovered in 1957 by Alick Isaacs and Jean Lindenmann who found that a substance from infected chicken cells interfered with viral replication. There are three main types of interferons - alpha, beta, and gamma - which have similar but distinct mechanisms of action involving inducing antiviral genes. Interferons are now used clinically to treat hepatitis C, various cancers, and multiple sclerosis. Recombinant and pegylated versions of interferons have been developed to improve pharmacokinetics. Combination therapy with ribavirin is also commonly used.

1. Ahmed A. Fouad
MBBCh – Ain Shams University

2. Discovery of Interferons
The British virologist Alick Isaacs and
the Swiss researcher Jean
Lindenmann, at the National Institute
for Medical Research in London.
 in 1957.
 Did an experiment using chicken cell
cultures
 Found a substance that interfered with
viral replication and was therefore
named interferon
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3. What are Interferons?
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Naturally occurring proteins and
glycoproteins.
Secreted by eukaryotic cells in
response to viral infections, tumors,
and other biological inducers.
Produce clinical benefits for disease
states such as hepatitis, various
cancers, multiple sclerosis, and many
other diseases.

4. What are Interferons?

Interferons are made by cells in
response to an appropriate stimulus,
and are released into the surrounding
medium; they then bind to receptors
on target cells and induce transcription
of approximately 20-30 genes in the
target cells, and this results in an antiviral state in the target cells.

5. What are Interferons?

Structurally, they are part of the helical
cytokine family which are
characterized by an amino acid chain
that is 145-166 amino acids long.

6. Mechanism of Action
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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.
Interferon 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.

9. Type I Interferons
•
Type I: alpha and beta
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Alpha Interferons are produced by
leukocytes
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Beta Interferons are produced by
fibroblasts
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Both bind to interferon cell receptors
type 1 and both encoded on
chromosome 9
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They have different binding affinities
but similar biological effects
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Viral infection is the stimulus for
alpha and beta expression
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Used to mobilize our 1st line of
defense against invading organisms
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Largest group and are secreted by
almost all cell types

10. Mechanism of Action Of Type I
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The exact mechanism of type I
Interferons are not fully
understood.
Alpha and beta bind to
heterodimeric receptor on cell
surface.
Alpha receptor is made up of at
least 2 polypeptide chains: IFNaR1 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

11. Mechanism of Action Of Type I
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Ligation induces
oligomerisation and
initiation of the signal
transduction pathway.
This results in
phosphorylation of signal
transductors and activators
of transcription proteins,
which translocate to the
nucleous as a trimeric
complex, ISGF-3.
ISGF-3 activates
transcription of interferon
stimulated genes, with
many biological effects.

12. Mechanism of Action Of Type I

13. Type II Interferon
Interferon-gamma
(immune interferon)
is produced by
certain activated Tcells and NK cells.
 Interferon-gamma is
made in response
to antigen (including
viral antigens) or
mitogen stimulation
of lymphocytes.
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14. Mechanism of Action
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Bind to type 2 receptors and its genes are
encoded on chromosome 12
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Initially believed that T helper cell type 1
lymphocytes, cytotoxic lymphocytes and natural
killer cells only produced IFN , now evidence
that B cells, natural killer T cells and professional
antigen-presenting cells secrete IFN also.
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Gamma production follows activation with
immune and inflammatory stimuli rather than viral
infection.
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This production is controlled by cytokines
secreted by interleukin 12 and 18.

15. Interferon Receptor and
Signaling Pathway
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Receptors are encoded by separate genes
(IFN R1 and IFN R2, respectively) that are
located on different chromosomes.
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As the ligand-binding (or ) chains interact
with IFN- they dimerise and become
associated with two signal-transducing chains.
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Receptor assembly leads to activation of the
Janus kinases JAK1 and JAK2 and
phosphorylation of a tyrosine residue on the
intracellular domain of IFN- R1.
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This leads to the recruitment and
phosphorylation of STAT1, which forms
homodimers and translocates to the nucleus
to activate a range of IFN- -responsive genes.
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After this, the ligand-binding chains are
internalised and dissociate.
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The chains are then recycled to the cell
surface.

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Interferons-alpha and -beta have been used to
treat various viral infections.
One currently approved use for various types of
interferon-a is in the treatment of certain cases of
acute and chronic hepatitis C and chronic hepatitis
B.
Interferon-gamma has been used to treat a variety
of disease in which macrophage activation might
play an important role in recovery, eg. lepromatous
leprosy, leishmaniasis, toxoplasmosis.
Since interferons have anti-proliferative effects,
they have also been used to treat certain tumors
such as melanoma and Kaposi’s sarcoma.

17. Common side effects of Interferons:
fever, malaise, fatigue, muscle pains
High levels of interferons can cause kidney,
liver, bone marrow and heart toxicity.

18. Different Interferon Drugs
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Interferons are broken down into recombinant versions of a specific interferon
subtype and purified blends of natural human interferon.
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Many of these are in clinical use and are given intramuscularly or subcutaneously
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Recombinant forms of alpha interferon include:
• Alpha-2a drug name Roferon
• Alpha-2b drug name Intron A
• Alpha-n1 drug name Wellferon
• Alpha-n3 drug name AlferonN
• Alpha-con1 drug name Infergen
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Recombinant forms of beta interferon include:
• Beta-1a drug name Avonex
• Beta-1b drug name Betaseron
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Recombinant forms of gamma interferon include:
• Gamma-1b drug name Acimmune

19. Alpha Interferon-2a
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Protein chain that is 165
amino acids long
Produced using recombinant
DNA technology
Non-glycosylated protein
Short half life, short terminal
elimination of half life, a
large volume of distribution,
and a larger reduction in
renal clearance.
These problems were
resolved by pegylating
alpha-2a resulting in
peginterferon alpha-2a that
is named Pegasys.

20. Pegylated Interferon-2a
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Pegasys is
recombinant
interferon alpha-2a
that is covalently
conjugated with bismonomethoxy
polyethylene glycol
(PEG)

21. Structure:
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PEG moieties are inert, longchain amphiphilic
molecules that are produced by linking repeating
units of ethylene oxide.
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Can be linear or branched in their structure
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Increasing the size with PEG, the absorption and ½
life are prolonged and the clearance of the IFN is
decreased.
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Goal of pegylation is to decrease clearance,
retention of biological activity, get a stable linkage
and enhance water solubility
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Pegylation is achieved by the covalent attachment
of PEG derivatives that utilize amino groups of
lysines and the N-terminus of polypeptide
molecules as the modification site

22. Interferon Beta-2a
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FDA approval on May 17 1996 for Relapsing Remitting MS
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Clinical trials showed that it slowed MS progression and had an
extra benefit of slowing or preventing the development of MS-related
brain atrophy.
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The exact mechanism of IFN beta activity in treating MS is unknown,
but studies have shown that interleukin 10 levels in the cerebrospinal
fluid were increased in patients
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Structurally IFNb-2a is a 166 amino acid glycoprotein.
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Produced by recombinant DNA technology using genetically
engineered mammalian cells which the human beta gene has been
introduced into
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Amino acid sequence is the same as human beta interferon. They
are both glycosylated at the asparagines residue at position 80

23. Interferon Beta-2a
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Some side effects include:

24. Combination Therapy with
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Many times interferons and peginterferons are used in
combination with Ribavirin.
It is a purine nucleoside analogue with a modified base and
a D-ribose sugar moiety
1st made in 1970 by Drs. Joseph Witkowski and Roland
Robins
It inhibits the replication of a variety of RNA and DNA
viruses and is serves as an immunomodulator to enhance
type 1 cytokine production.
This increases the end of treatment response and reduces
post-treatment relapse.
Mechanism is not well known.

25. Interferons have overlapping but
different biological activities
 Their mechanisms of action are not
fully understood, therefore there is a
lot of room for future growth within this
field
 Interferon based strategies can
possibly be further tailored to each
individual patient according to early
response dynamics
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