It has been amply proved and widely accepted that the body’s cell-mediated defense system
usually makes use of such cells that are not essentially the T cells***. Further, certain lymphocytes that
are known as natural killer (NK) cells, are quite capable of causing destruction to other cells, particularly
(a) tumour cells, and (b) virus-infected cells. However, the NK cells fail to be immunologically
specific i.e., they need not be stimulated by an antigen. Nevertheless, the NK cells are not found to be
phagocytic in nature, but should definitely get in touch (contact) with the target cell to afford a lysing
effect.
Interferons [IFNs]
Issacs and Lindenmann (1957)* at the National Institute of Medical Research, London (UK)
discovered pioneerly the interferons (IFNs) while doing an intensive study on the various mechanisms
associated with the ‘viral interference’**.
It is, however, an established analogy that viruses exclusively depend on their respective host
cells to actually cater for several functions related to viral multiplication ; and, therefore, it is almost
difficult to inhibit completely viral multiplication without affecting the host cell itself simultaneously.
Importantly, interferons [IFNs] do handle squarely the ensuing infested host viral infections.
Interferons [IFNs] designate — ‘a particular class of alike antiviral proteins duly generated
by some animal cells after viral stimulation’.
It is, therefore, pertinent to state here that the critical interference caused specifically with viral
multiplication is the prime and most predominant role played by the interferons.
Salient Features : The salient features of interferons may be summarized as stated
under :
(1) Interferons are found to be exclusively host-cell-specific but not virus-specific
(2) Interferon of a particular species is active against a plethora of different viruses.
(3) Not only do various animal species generate interferon variants, but also altogether various
kinds of cells in an animal give rise to interferon variants.
(4) All interferons [IFNs] are invariably small proteins having their molecular weights ranging
between 15,000 to 30,000. They are observed to be fairly stable at low pH range (acidic),
and are quite resistant to heat (thermostable).
(5) Interferons are usually produced by virus-infected host cells exclusively in very small
quantum.
(6) Interferon gets diffused into the uninfected neighbouring cells as illustrated in Fig. 9.7.
Explanation : The various steps involved are as follows :
(1) Interferon happens to interact with plasma or nuclear membrane receptors, including the
uninfected cells to produce largely mRNA essentially required for the critical synthesis of
antiviral proteins (AVPs).
(2) In fact, AVPs are enzymes which causes specific disruption in the different stages of viral
multiplication.
Examples : These are as given under :
(a) One particular AVP inducts the inhibition of ‘translation’ of viral mRNA by affording
complete blockade in the initiation of the ensuing protein synthesis,
(b) Another AVP causes the inhibition of the phenomenon of ‘polypeptide elongation’,
and
(c) Still another AVP takes care of the process of destruction with regard to mRNA before
‘translation’.
Interferon : An Ideal Antiviral Substance : Various cardinal points are as stated
below :
• Prevailing ‘low concentrations’ at which interferon affords inhibition of viral multiplication
are found to be absolutely nontoxic to the uninfected cells.
• Interferon possesses essentially a good number of beneficial characteristic properties.
• Interferon is distinguishably effective for only short span.
• Interferon plays a pivotal and vital role in such critical infections which happen to be quite
acute and transient in nature, for instance : influenza and common colds.
Drawback : Interferon has a serious drawback, as it has practically little effect upon the viral
multiplication in cells that are already infected.
Interferon Based on Recombinant DNA Technology : In the recent past ‘interferon’
has acquired an enormous recognition and importance by virtue of its potential as an antineoplastic
agent, and, therefore, enabled its production in a commercial scale globally on a top public-health
priority. Obviously, the interferons specifically produced by means of the recombinant DNA technology
are usually termed as recombinant interferons [rINFs]. The rINFs have gained an overwhelming
global acceptability, popularity, and utility due to two extremely important reasons, namely : (a) high
purity, and (b) abundant availability.
Usefulness of rINFs : Since 1981, several usefulness of rINFs have been duly demonstrated
and observed, such as :
Antineoplastic activity – Large dosage regimens of rINFs may exhibit not so appreciable overall
effects against certain typical neoplasms (tumours), whereas absolute negative effect on others.
However, the scanty results based on the exhaustive clinical trials with regard to the usage of
rINFs towards anticancer profile may be justifiably attributed to the following factual observations,
such as :
several variants of interferons vis-a-vis definitive antineoplastic properties,
rINFs in cojunction with other known chemotherapeutic agents might possibly enhance
the overall antineoplastic activity,
quite significant and encouraging results are duly achievable by making use of a combination
of :
rINFs + doxorubicin*
or rINFs + cimetidine**
subjects who actually failed to respond reasonably well earlier to either particular chemotherapy
or follow up treatment with interferon distinctly showed remarkable improvement
when again resorted to the ‘original chemotherapy’.
Classical Recombinant Interferons [rIFNs] : There are quite a few classical
recombinant interferons [rIFNs] have been meticulously designed and screened pharmacologically to
establish their enormous usefulness in the therapeutic armamentarium. A few such rIFNs shall now be
treated briefly in the sections that follows :
[A] Interferon-α [Syn : Alfa-interferon ; Leukocyte interferon ; Lymphoblastoid interferon ;]
Interferon-α is a glycopeptide produced by a genetic engineering techniques based on the human
sequence. It does affect several stages of viral infections, but primarily inhibits the viral-protein translation.
It is invariably employed to prevent and combat the hepatitis B and C infections. In usual
practice the drug is administered either via subcutaneous (SC) route or intramuscular (IM) route.
However, it gets rapidly inactivated but generally the overall effects outlast the ensuing plasma
concentration.
Toxicities – include neurotoxicity, flu-like syndrome, and bone-marrow suppression.
Drug interactions – may ultimately result from its ability to minimize the specific hepatic syndrome
P450-mediated metabolism.
[B] Interferon Alfa-2A, Recombinant [Syn : IFA-α A ; R0-22-8181 ; Canferon ; Laroferon ; Roferon-
A ;]
Interferon alfa-2A refers to the recombinant HuIFN-α produced in E. coli, and made up of
165 amino acids
Characteristic Pharmacologic Activities : These are as follows :
(1) Enhances class I histocompatibility molecules strategically located on lymphocytes.
(2) Increases the production of ILs-1 and -2 that critically mediates most of the therapeutic and
toxic effects.
(3) Regulates precisely the antibody responses.
(4) Increases NK cell activities.
(5) Particularly inhibits the neoplasm-cell growth via its distinct ability to inhibit appreciably
the protein synthesis.
(6) Being antiproliferative in nature it may exert its immunosuppressive activity.
(7) Action on the NK cells happens to be the most vital for its antineoplastic action.
(8) Approved for use in hairy-cell leukemia and AIDS-related Kaposi’s sarcoma.
(9) Drug of first choice for the treatment of renal-cell carcinoma.
(10) Preliminary clinical trials ascertained virtually its promising efficacy against quite a few
typical disease conditions as : ovarian carcinoma, non-Hodgkin’s lymphoma, and metastatic
carcinoid tumour.
(11) Besides, it exhibits marked and pronouned antiviral activity against the RNA viruses.
(12) Effective in the treatment of varicella in immunocompromised children, non-A and non-
B hepatitis, genital warts, rhinoviral colds, possible opportunistic bacterial infections
in renal and transplant recipients.
(13) Increases the targetting process associated with monoclonal antibody (MAB)-tethered
cytotoxic drugs to the neoplasm cells.
[C] Interferon Alfa-2B, Recombinant [Syn : IFNα2 ; Introna; Intron A ; Viraferon ; Seh-30500 ;
YM-14090 ;] ;
The recombinant HuIFNα is produced in E. coli.
Therapeutic Applications : are as stated under :
(1) Approved for use in several disease conditions as : hairy-cell leukemia, AIDS-related
Kaposi’s sarcoma, myclogenous leukemia, melanoma, chronic hepatitis, and
condylomata acuminata.
(2) Most of its actions are very much similar to those of rIFN-αA.