Natural Resistance and Nonspecific Defense Mechanisms [or Defensive Mechanisms of Body]

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Chapter: Pharmaceutical Microbiology : Immune Systems

In a broader sense the ensuing interaction existing between a host (human body) and a microorganism designates an excellent unique dynamic phenomenon whereby each and every protagonist critically serves to maximize its overall survival.


NATURAL RESISTANCE AND NONSPECIFIC DEFENSE MECHANISMS [OR DEFENSIVE MECHANISMS OF BODY]

 

In a broader sense the ensuing interaction existing between a host (human body) and a microorganism designates an excellent unique dynamic phenomenon whereby each and every protagonist critically serves to maximize its overall survival. It has been duly observed that in certain typical instances, after a specific microbe gains its entry or comes in contact with a host, a distinct positive mutually beneficial relationship takes place which ultimately becomes integral to the final health of the host. In this manner, the microorganisms turn out to be the normal microbiota*. However, in other such cases, the particular microorganism causes, induces or produces apparent devastating and deleterious overall effects upon the host ; and, therefore, may finally even cause death of the host via a dreadful ailment.

 

Interestingly, the prevailing environment of a ‘host’ is heavily surrounded with microorganisms, and there lies an ample scope and opportunity to come in their contact every moment of the day. Nevertheless, quite a few of these microbes are pathogenic in nature (i.e., cause disease). Surprisingly, these pathogens are at times duly guarded and prevented from producing a disease due to the inherent competition offered by the normal microbiota. In reality, the invading pathogens are squarely kept away from the host by the ‘normal microbiota’ by using nutrients, resources, space, and may even yield such chemical substances which would repel them ultimately.

 

In addition to the above stated glaring scientific fact and evidences these ‘normal microbiota’ grossly prevent colonization of pathogens to a great extent ; and, thereby, most probably checking the disease (to the host) via ‘bacterial interference’.

 

Example : An excellent typical example is stated as under :

 

Lactobacilli – present strategically in the female genital tract (FGT) usually maintain a low pH (acidic), and thereby exclusively afford the colonization by the pathogenic microbes. Besides, the corynebacteria located critically upon the skin surface give rise to the formation of ‘fatty acids’ which ultimately inhibit the phenomenon of colonization by the pathogenic organisms.

 

Note : It is an excellent example of ‘amensalism’. (i.e., symbiosis wherein one population (or individual) gets affected adversely and the other is unaffected).

 

Interestingly, the ‘normal microbiota’ usually give rise to protection confined to a certain degree from the invading pathogens ; however, they may themselves turn into pathogenic in character and cause disease under certain particular circumstances. Thus, these ‘converted pathogens’ are invariably known as ‘opportunistic microorganisms’** or pathogens.

 

Based on the above statement of facts and critical observations one may conclude that on one hand pathogen makes use of all the opportune moments available at its disposal to cause and induct infection, the host’s body possesses a plethora of ‘defense mechanisms’ to encounter the infection. In fact, the observed intricacies prevailed upon by the host-pathogen relationship are not only numerous but also quite divergent in nature, which may be classified under the following three heads, such as :

 

(a) Natural Resistance,

 

(b) Internal Defense Mechanisms, and

 

(c) Nonspecific Defense Mechanisms.

 

The aforesaid three categories shall now be discussed separately in the sections that follows :

 

(1) Natural Resistance

 

It has been observed that the two cardinal aspects, namely : (a) physiological needs, and (b) meta-bolic requirements, of a pathogen are an absolute necessity in establishing precisely the extent vis-a-vis the range of potentially susceptible hosts. However, the naturally resistant hosts exert their action in two variant modes, such as :

 

·        miserably fail to cater for certain urgently required environmental factors by the microbes for their usual growth, and

 

·        essentially possess defense mechanisms to resist infection considerably.

 

Besides, there are some other factors pertaining to the host’s general health, socioeconomic sta-tus, level of nutrition potentiality, and certain intangible conditions viz., stress, mental agony, depres-sion etc.

 

Natural resistance essentially comprises of the following four vital and important aspects :

 

1. Species Resistance

 

In general, the fundamental physiologic characteristics of humans, namely : normal body tem-perature may give a positive clue whether or not a specific bacterium can be pathogenic in nature. Likewise, in host-specific e.g., human and bovine species, the tubercle bacillus is found to cross-infect both humans and cattle having almost an identifical body temperature.

 

Salient Features : The salient features of species resistance are as given under :

 

(1) inability of a bacterium to induct disease in the resistant species under the natural environ-ments,

 

(2) critical production in the specific resistant species of either a localized or a short-period infection caused solely due to an experimental inoculation vis-a-vis a progressive or gener-alized ailment in naturally susceptible species, and

 

(3) introduction of experimental disease particularly in the resistant species exclusively caused by massive doses of the microbes, usually in two different ways :

(a) under unnatural parameters, and

(b) by an unnatural route.

 

2. Racial Resistance

 

Exhaustive and intensive studies have amply proved that the very presence of a pathogen in the isolated races give rise to a gradual selection for resistant members, because the susceptible members die of progressive infection ultimately. It may be further expatiated by the following three glaring examples :

 

Examples :

 

(i) Incorporation of altogether ‘new pathogens’ e.g., tubercle bacillus, by the relatively resist-ant Europeans into an isolated American Indians population*, finally caused epidemics that almost destroyed a major proportion of the ensuing population.

 

(ii) African Blacks (Negros) invariably demonstrate a relatively high resistance to the tropical diseases, namely : malaria, yellow fever, and

 

(iii) Orientals do exhibit a much reduced susceptibility to syphilis.

 

3. Individual Resistance

 

It may be critically observed that there are certain individuals who apparently experience fewer or less severe infections in comparison to other subjects, irrespective of the fact that :

 

·        both of them essentially possess the same racial background, and

·        do have the same opportunity for ultimate exposure.

 

Causation : Individual resistance of this nature and kind is perhaps on account of :

 

·        natural in-built resistance factor, and

·        adaptive resistance factor.

 

Age Factor – is equally important, for instance :

 

·        aged people are more prone to such ailments as : Pneumonia – most probably due to a possible decline of the ‘immune functions’ with advancement in growing age.

 

·        children i.e., very young individuals are apparently more susceptible to such ‘children’s disease’ as : Chicken-pox, measlesjust prior to their having acquired enough in-built resistance/immunity that essentially follows both inapparent and overt contracted infections.

 

Genetic Factor Immunodeficiencies** found in some, individuals are caused solely due to ‘genetic defects’, that largely enhance the probability and susceptibility to disease.

 

Other Factors – include malnutrition, personal hygiene, and an individual’s attitude to sex pro-file ; hazards and nature of work-environment ; incidence of contacts with infected individuals, and an individual’s hormonal vis-a-vis endocrine balance – they all do affect the overall frequency as well as selectivity of some critical ailments.

 

4. External Defense Mechanisms

 

In fact, the external defense mechanisms do represent another cardinal and prominent factor in natural resistance ; however, they essentially involve the chemical barriers as well. Besides, two other predominant factors viz., (a) mechanical barriers, and (b) host secretions, essentially make up the body’s First-Line of Defense Mechanism against the invading microorganisms.

 

Mechanical Barriers – actually comprise of such materials as : intact (unbroken) skin and mucous membranes that are practically incapable of getting across to the infectious agents. However, the said two mechanical barriers viz., intact skin and mucous membranes do afford a substantial ‘effec-tive barrier’, whereas hair follicles, dilatation of sweat glands, or abrasions do allow the gainful entry for the microbes into the human body.

 

Examples : Various typical examples are as given under :

 

(1) Large segment of microbes are duly inhibited by such agents as :

·        low pH (acidity),

·        lactic acid present in sweat, and

·        fatty acids present in sweat.

 

(2) Mucous secretions caused by respiratory tract (RT), digestive tract (DT), urogenital tract (UT) plus other such tissues do form an integral protective covering of the respective mucous membranes thereby withholding and collecting several microorganisms until they may be either disposed of effectively or lose their infectivity adequately.

 

(3) Chemical Substances – Besides, the ensuing mechanical action caused by mucous, saliva, and tears in the critical removal of microorganisms, quite a few of these secretions do con-tain a number of chemical substances which critically cause inhibition or destruction of microorganisms.

 

Examples : A few typical examples are as stated under :

(a) Lysozyme – an enzyme invariably observed in several body fluids and secretions viz., blood, plasma, urine, saliva, cerebrospinal fluid, sweat, tears etc., that predominantly do exert an effective antimicrobial action on account of its inherent ability to lyse some particular Gram positive microbs by specifically affording the hydrolysis of peptidoglycan,

(b) Several other hormones and enzymes are capable of producing distinct chemical, physi ological, and mechanical effects that may ultimately cause minimization of susceptibility to reduction, and

(c) The prevailing inherent acidity or alkalinity of certain ‘body fluids’ possess an apparent deleterious effect upon several microbes, and helps to check and prevent the potential pathogens for gaining an easy access to the deeper tissues present in the body.

(d) Lactoferrin-Lactoferrin is an iron-containing red-coloured protein found in milk (viz., human and bovine) that essentially possesses known antibacterial characteristic features. It is also found in a plethora of body-secretions that specifically and profusely bathe the human mucosal surfaces, namely :

·        bronchial mucous ;

·        seminal fluids ;

·        hepatic bile ;

·        saliva ;

·        nasal discharges ;

·        tears ; and

·        pancreatic juice ;

·        urine.

Lactoferrin forms a vital and important constituent of the highly particular granules of the ‘polymorphonuclear leukocytes’*.

 

(5) Transferrin : It represents the serum counterpart of lactoferrin. In fact, both these typical proteins essentially possess high molecular weights ~ 78,000 daltons, besides having several metal-binding critical sites.

 

Mechanism : Transferrin (as well as Lactoferrin) critically undergoes ‘chelation’ with the bivalent ferrous iron [Fe2+] available in the environment, thereby restricting profusely the availability of ferrous ion (i.e., an essential metal nutrient) to the particular invading microbes.

 

2. Internal Defense Mechanisms

 

Internal defense mechanisms emphatically constitute the ‘second-line of defense’ comprising of the body’s internal mechanisms that may be critically mobilized against the highly specific invading bacteria.

 

Mechanisms : The internal defense mechanisms are of two different types, such as :

 

(a) Non specific in actione.g., phagocytosis, and

 

(b) Specifically aimed at the pathogense.g., sensitized cells, and antibodies.

 

Importantly, the above two different types are usually designated as nonspecific defense mecha-nisms and specific acquired immunity*.

 

However, it is pertinent to state here that while the infection is active the two aforesaid mecha-nisms virtually exert their action simultaneously in order to rid the body of the so called ‘invading microbes’. In fact, this very interrelationship, and the interrelationships prevailing between the defense mechanisms may be explicitely depicted in Fig. 9.4.


 

3. Nonspecific Defense Mechanisms

 

Mother nature has enabled the ‘human body’ so splendidly as to critically mobilize several factors that act nonspecifically against the possible wide spread invasion by the ‘foreign organisms’. Interestingly, such cardinal and vital factors essentially consist of the following four typical examples, namely :

 

·        complement system,

·        phagocytosis,

·        naturally occurring cytotoxic lymphocytes, and

·        interferon.

 

Each of the aforesaid factors shall now be treated individually in the sections that follows :

 

1. Complement System

 

Higher animal’s serum usually made up of a particular group of ‘eleven proteins’, which are highly specific in nature, and are widely referred to collectively as the so called complement system by virtue of the fact that its action complements predominantly to that of some prominent antibody-medi-ated reactions. In other words, the complement system critically enacts a pivotal role with respect to the overall generalized resistance against the infection caused by the ‘pathogens’ ; and, therefore, accounts for as the ‘principal mediator’ of the ensuing specific inflammatory response.

 

Mode of Action (Modus Operandi) : The various steps involved are as follows :

 

(1) When the very ‘First Protein’, belonging to cluster of elevan proteins, gets duly activated there exist distinctly a prominent ‘sequential cascade’ whereby the ‘active molecules’ duly come into being via the inactive precursors*.

 

(2) Some of the protein variants do get activated very much along the ‘sequential cascade’ that may function as mediators of a specific response, and eventually serves as activators of the next step.

 

Table 9.1 : Records certain of the functional activities of the Host Complement System present duly in the Host Defense against the infection.

 

Table 9.1 : Functional Activities of Host Complement System in Host Defense Vs. Infection


Complement Fixation (or Attachment) : In a broader perspective, the complement system is quite capable of attacking and killing the invading cells exclusively after the antibody gets bound to the cell membrane, thereby specifically initiating the very phenomenon of complement fixation (or at tachment), which has been explicitely illustrated in Fig. 9.5.

 

[Redrawn From : Vander AJ el al. Human Physiology : The Mechanism of Body Action, McGraw Hill. New York. 19701

Explanation : Explanation of Fig. 9.5 is as stated under :

(1) Complement system do possess many characteristic features.

(2) Recognition unit present in it predominantly respond to the specific ‘antibody molecules’ which have meticulously identified (recognized) an invading cell.

(3) Receptor sites do exist which critically combine with the available surface of the ‘foreign cell' on being duly activated.

(4) Activity of the ‘foreign cell’ should be adequately restricted right in time so as to reduce the damage eventually caused to the host’s own cells.

(5) The resulting accomplished ‘limitation’ is actually brought about proportionately by the help of two distinct functionalities, such as :

(a) spontaneous decay of activated complement, and

(b) interference afforded by inhibitors and destructive enzymes.

 

Mechanisms of Complement Action in Microbial Lysis : The eleven components duly present in a complement are named as per the following rules and guidelines, namely :

(1) Each and every component has been assigned a particular number strictly according to its discovery, and that number is usually preceded by the below letter ‘C’.

(2) Surprisingly, the very first four components fail to interact in the desired order of their discovery, but instead of the sequence Cl, C4, C2 and C3.

(3) The remainder of the components certainly and strictly react in the suitable numerical or¬der viz., C5, C6, C7, C8, and C9.

(4) However, Cl essentially comprise of three subcomponents viz., Clq, Clr, and Cis.

(5) Fragments of components, obtained as a consequence of cleavage by other components, acting invariably as enzymes are adequately assigned the lowercase letters a, b, c, d or e such as : C3a and C3b.

 

In fact, one may vividly expatiate the underlying mechanisms of component action in microbial lysis as depicted in Fig. 9.5, in a more elaborated fashion, as illustrated in Fig. 9.6 thereby exhibiting a cascade of events in relation to both complement activation and recognition, ultimately culminating in cell attack. Summararily, it represents as the classical or antibody-dependent pathway that prevalently need to be activated by specific antibody : C1, C4, C2 and C3.


[Adapted From : Pelczar MJ et al. : Microbiology, Tata McGraw Hill Publishing Co., LTD., New Delhi, 5th edn., 1993]

 

2. Phagocytosis

 

Phygocytosis may be defined as — ‘the engulfing of microorganisms or other cells and for-eign particles by phagocytes’.

 

Alternatively, phagocytosis (from the Greek words for eat and cell) referts to — ‘the phenom-enon of ingestion of a microorganism or any particulate matter by a cell’.

 

Interestingly, the human cells which critically carry out this ardent function are collectively known as phagocytes, such as : all types of WBCs, and derivatives of WBCs.

 

Actions of Phagocytic Cells : In this event of a contracted infection, both monocytes* and granulocytes** usually get migrated to the infected area. Interestingly, during this process of migration, the monocytes do get enlarged to such a dimension and size that they finally develop into the actively phagocytic macrophages.

 

Types of Macrophages : There are, in fact, two major categories of the macrophages, such as :

 

(a) Wandering Macrophages : Based on the glaring fact that these cells (monocytes) do have a tendency to leave the blood and subsequently migrate via the tissue cells to the desired infected areas, they are commonly known as wandering macrophages.

 

(b) Fixed Macrophages (or Histocytes) : A monocyte that has eventually become a resident in tissue. Fixed macrophages or histocytes are invariably located in certain specific tissues and organs of the body. In fact, they are found abundantly in various parts of a human body, for instance :

·        Bronchial tubes ;

·        Lungs (alveolar macrophages) ;

·        Bone marrow ;

·        Nervous system (microglial cells ) ;

·        Lymph nodes ;

·        Peritoneal cavity (surrounding abdominal organs) ;

·        Liver (Kupffer’s cells ) ;

·        Spleen ;

Importantly, the macrophage variants critically present in the body strategically constitute the mononuclear phagocytic (reticuloendothelial) system.

 

2.1. Functions of Phagocytes (or Phagocytic Cells) :


It has been duly observed that when an infection gets contracted one may apparently observe a distinct shift taking place predominantly in the particular types of WBC which runs across the blood stream. Thus, the following cardinal points may be noted, carefully :

 

Granulocytes – particularly the ‘neutrophils’ occur overwhelmingly in the initial phase of infection, at this point in time they are found to be extremely phagocytic in nature.

 

Distinct aforesaid dominance is evidently shown by the presence of their actual number in a differential WBC count.

 

With the progress of contracted infection, the macrophages also predominate – scavenge – phagocytize remaining live/dead/dying microorganisms.

 

Enhanced number of monocytes, that eventually develop into the corresponding macrophages, is adequately reflected in the WBC-differential count explicitely.

 

Blood and lymph containing bacteria when made to pass via various organs in the body having fixed macrophages, cells of the mononuclear phagocytic system ultimately get rid of the bacteria by phagocytosis.

 

Mononuclear phagocytic system also helps in the critical disposal of the worn-out blood cells.

 

Table 9.2 records the classification as well as a summary of phagocytic cells and their functions.

Table : 9.2 : Classification and Functions of Phagocytes


 

2.2. Mechanism of Phagocytosis :


In order to understand the exact and precise mechanism of phagocytosis, we may have to divide the phenomenon of phagocytosis, as illustrated in Fig. 9.6, into four cardinal phases, such as : chemotaxis, adherence, ingestion, and digestion. These four dis-tinct phases shall now be treated briefly in the sections that follows from [A] through [D] :

 

[A] Chemotaxis [Syn : Chemotropism] :

 

Chemotaxis may be defined as — ‘the movement of additional white blood cells to an area of inflammation in response to the release of chemical mediators by neutrophils, monocytes, and injured tissue’.

 

In other words, chemotaxis refers to the chemical attraction of the phagocytes to microbes.

 

Importantly, the various ‘chemotactic chemical susbtances’ which specifically attract the phagocytes happen to be such microbial products as components of :

·        white blood cells (WBCs),

·        damaged tissue cells, and

·        peptides derived from complement.

 

[B] Adherence :

 

Adherence refers to the act or condition of sticking to something. In fact, it represents the ensu-ing adherence of antigen-antibody complexes or cells coated with antibody or complement to cells bearing complement receptors or Fe receptors. It is indeed a sensitive detector of complement-fixing antibody.

 

Because, adherence is intimately related to phagocytosis, it represents the attachment of the later’s plasma membrane onto the critical surface of the bacterium or such other foreign material. Nevertheless, adherence may be hampered by the specific presence of relatively larger capsules or M protein*. Besides, in certain instances adherence takes place quite easily and conveniently, and the microbe gets phagocytized rapidly.


[Adapted From : Tortora et al : Microbiology : An Introduction, The Benjamin/Cummings Pub-lishing Co., Inc., New York, 5th edn., 1995]

 

[C] Ingestion :

 

In usual practice adherence is followed by ingestion. One may vividly notice that during the phenomenon of ingestion, the plasma membrane belonging to the phagocyte gets extended in the form of distinct projections usually termed as pseudopods which eventually engulf the bacterium. Thus, once the bacterium gets duly surrounded, the pseudopods meet and fuse ultimately, thereby surround-ing the bacterium with a particular ‘Sac’ known as phagocytic vesicle or phagosome.

 

[D] Digestion :

 

Digestion refers to the particular phase of phagocytosis, wherein the respective phagosome* gets detached from the plasma membrane and duly enters the cytoplasm. Later on, within the cytoplasm the phagosome meticulously gets in touch with the lysosomes** which essentially comprise of two important components, namely :

·        digestive enzymes, and

·        bactericidal substances.

 

Modus Operandi [or Mode of Action] : The various steps involved are as given below :

 

(1) Both phagosome and lysosome membranes upon contacting each other invariably gets fused to result into the formation of a ‘single larger structure’ termed as ‘phagolysosome’.

 

(2) Interestingly, the integral contents of the phagolysosome usually ‘kills’ most types of microorganisms within a span of 10–30 minutes. The most plausible and possible reason for such a marked and pronounced bactericidal effect is perhaps due to the specific contents of the lysosomes.

 

(3) Residual body : After completion of the process of digestion the actual contents of the phagolysosome are duly brought into the cell by ‘ingestion’ ; and, therefore the phagolysosome essentially and exclusively comprises of the indigestible material, which is usually known as the ‘residual body’.

 

(4) Residual body subsequently takes a step forward toward the cell boundary and critically discharges its ‘waste products’ very much outside the cell.

 

A Few Exceptions : These exceptions are as stated below :

 

(a) Toxins of certain microorganisms viz., toxin-producing Staphylococci plus the bacterium Actinobacillus (present in dental plaque, may actually exert a cidal effect upon the phagocytes.

 

(b) Some other microbes, for instance : Chlamydia, Leishmania, Mycobacterium, and Shigella together with the ‘malarial parasites’ may possibly dodge and evade the various compo-nents of the immune system by gaining an access into the phagocytes.

 

(c) Besides, the said microorganisms may virtually block the ultimate fusion between phagosome and lysosome, as well as the adequate process of acidification (with HCl) of the digestive enzymes.

 

3.3. Natural Killer Cells [NK Cells]

 

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, particu-larly (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.

 

3.4 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.

 

3.4.1. 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’.

 

3.4.2. Interferon : An Ideal Antiviral Substance : Various cardinal points are as stated below :

 

·        Prevailing ‘low concentrations’ at which interferon affords inhibition of viral multiplica-tion 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.

 

3.4.3. 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 combina-tion of :

rINFs + doxorubicin*

or rINFs + cimetidine**

 

·        subjects who actually failed to respond reasonably well earlier to either particular chemo-therapy or follow up treatment with interferon distinctly showed remarkable improve-ment when again resorted to the ‘original chemotherapy’.

 

3.4.4. 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 trans-lation.

 

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 syn-drome P450-mediated metabolism.

 

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 meta-static 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.

 

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