Application of rDNA

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technology

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Cytokines and Interferons
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 Introduction to Biotherapies
• Bio therapies are designed to repair the capability of
the body's defense system to struggle the illness
and disease.

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• It is commonly used to treat different kinds of

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cancers, as well as other conditions. With the

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biotherapy, drugs change the way of working of cells
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and help to control the escalation in primary liver
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cancer.
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• However, few bio-therapies are primarily made to

destroy the cancer cells or others help the body to
attack the cancer.
 Biological therapy
• This kind of therapy frequently engage the use of
biological response modifiers (BRMs) [1], a kind of
secretory substances used by immune system. The

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body normally produces these substances in small

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amounts in response to infection and disease.

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• There are many BRMs, which can be produced in the
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laboratory such as different monoclonal antibodies,
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interferon, interleukin-2 (IL-2), and growth factors like
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colony-stimulating factors (CSF, GM- CSF, G-CSF).

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• Infact, interleukin-2 and interferons like of BRMs are

being used for the treatment of advanced melanomas.
 Brief introduction to the immune
system
• Our immune system is designed to protect us from various infections and
disorders.

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• Immunity is of two types, innate and adaptive immunity.

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• Innate immunity is always set immediately , whenever host come in contact

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with pathogen and It is not antigen specific and response is same on repeated

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exposure to bugs. Innate immunity involves, dendritic cells, monocytes,
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macrophages and to some extent B cells.

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• Adaptive immunity involves T and NKT cells cells and its very specific to

the pathogen, as T cells after exposure to pathogen become memory T cells so

on repeated exposures of pathogen, it recalls the memory and have more

greater impact that before.

 Introduction to Interferons
• The discovery of interferons was a result of research by Isaacs &
Lindenmann in the field of viral interference - the ability of an active or
inactivated virus to interfere with the growth of an unrelated virus.

• Until 1957, viral interference had been considered to be due directly to the
action of one virus on the pathologic activity of a second agent.

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• Most instances of viral interference were a result of the induction by the

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interfering agent of cellular products, interferons, later shown to be proteins

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that in turn activate a number of genes responsible for the biologic effects

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ascribed to the interferons in addition to their antiviral activity. These include

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significant anti-angiogenic, cell growth inhibitory, and immunoregulatory

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activities. Interferons play an important role in the innate immune response
to virus infections. P
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• Antibody to interferon exacerbates many viral diseases, and many viruses

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have developed mechanisms specifically to counteract the production or the

antiviral activity of interferons .

• Soon after their discovery, it was the antiviral activity of interferons that
attracted wide interest; it was expected that they would rapidly be
developed as agents to treat a variety of viral infections. This did not come
to pass for several reasons
 Interferons
• Recombinant IFN-α forms are widely employed with some success in the

treatment of chronic HBV and hepatitis C virus (HVC) infections and some

forms of cancer.

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• HCV is a widespread infection caused by contaminated blood products or

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drug injection with contaminated needles. Although modern blood bank

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technology has almost eliminated the former, the latter remains a major

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problem.
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• Chronic HBV infection is the other major antiviral application of interferons.

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HBV is a hepatotropic DNA virus. Like HCV, HBV infection is associated with

contaminated blood or blood products, also commonly - sexually transmitted.

• IFN-β treatment for MS is regularly used to limit exacerbations of MS.

• IFN-γ has been approved for clinical use only in a rare congenital disorder,
 Interferons
• IFN-α is also employed in the treatment of infection caused by
human herpes virus-8, the aetiological agent in Kaposi's sarcoma
(KS), formerly a rare form of cancer that has become prominent

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because of it association with AIDS.

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• Interferon-α has many roles including, upregulates genes like MHC

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class I, tumor antigens, and adhesion molecules. It also has anti-

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angiogenic property. Interferon-α is extremely active in the immune

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system and enhance the B and T-cell activity, as well as stimulate
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macrophages, dendritic cells and upregulates Fc receptors.

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 Cytokines
• Cytokines are a unique class of small signalling molecules or proteins - that

helps in cell communication with the other cell which regulate various

immunological processes leading to

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inflammation

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• Cytokines are proteins or glycoproteins and these are secreted by immune

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cells.

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• Cytokines function via endocrine, paracrine and autocrine fashion, so they
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act locally and in different targets.

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• Cytokines control the activity of both the innate immune system as well as

the adaptive immune system which includes natural killer (NK) cells,
macrophages, neutrophils T-cell and B cell.

• In a normal immune system, cytokines basically function in a cascade way.

Types of Cytokines used in therapy
• Interleukin 1 beta (IL-1 beta) already tested for cancer treatment but found
useless against it however it is useful as it reduces the toxicity of interleukin

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2 (IL-2).

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• The most promising cytokine is tumor necrosis factor (TNF) but leads to

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severe hypotension when used systemically.

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• Interleukin 4 (IL-4) shows very little anti-cancer activity and not very toxic.
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• Interleukin 6 (IL- 6) also has some activity against cancer cells, however
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found to be a growth factor for myeloma cells.

• Cytokines which facilitate type 1 helper T (Th1) cells-mediated immune
reactions provide an effective anti-tumor response
 Types of Cytokines used in therapy
•Interleukin-2 (IL-2) is known as T-cell growth factor that binds receptor on T
cells. High dose of IL-2 treated patients showed high anticancer response but
also caused severe toxicity in cancer patients especially in renal cell carcinoma

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•Anti- TNF (tumor necrosis factor) agents have been the first line treatment for

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moderate to severe ulcerative colitis and Crohn’s disease. Inhibiting the effects

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of tumor necrosis factor alpha (TNF-I) became important in various diseases
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like rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic

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arthritis, and ankylosing spondylitis. TNF therapy is approved by FDA in 1998

for its use in Crohn’s disease and in 2005 for ulcerative colitis.
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 Types of growth factors used in
therapy
•Transforming growth factor beta type I (TGF-beta) family of cytokines is
ubiquitous, multifunctional and essential for growth anddevelopment,

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inflammation, repair and host immunity by inhibiting epithelial cell proliferation.

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TGF-β works as a tumor suppressor which was confirmed in many

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gastrointestinal cancers where somatic mutations abrogate TGF-β signal

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•Granulocyte-monocyte colony stimulating factor (GMCSF) works best in stem

cell and bone marrow transplant to reconstitute the myeloid series.
Applications of GMCSF as monotherapy have proven results in chronic
melanoma patients. GM-CSF is also being evaluated as an adjuvant for
vaccine therapy