Consequences of Stress

The importance of observation and fast reaction are emphasized by these two large eyes, larger even than the brain itself.
Many fanciers no doubt have noticed the reaction of their young birds upon seeing a bird of prey for the very first time. There is no hesitation to their reaction. What I find even more surprising is that they take evasive action depending on the silhouette of the predator in question. The response to some birds of prey is that the young ones try to escape by flying kamikaze style while the silhouette of a different one causes the young ones to hit the ground and try to find a hiding place.
Even the silhouette of a crow may be similar enough to that of an accipiter and cause the youngsters to react by bolting. After many benign encounters with crows pigeons gradually learn to be at ease in their presence.
Let us refresh our memory about the "fight or flight" response:
Impulses from the retina travel via the optic nerves to the visual cortex to be relayed to the cerebral cortex for analysis. Although this process is exceedingly fast, it may be too slow for a peregrine falcon, to name just one threat. Impulses from the retina travel also directly through subcortical regions to the amygdala, the emotional part of the brain which can start a cascade of events a fraction of a second faster than that through the cortical pathway and a fraction of a second can make the difference between becoming lunch for a bird of prey or being able to parent many more offspring and thus pass on one's successful genetic material to future generations.
The fastest direct pathway from the retina to the amygdala appears to be hard wired and does not appear to depend on learning.
How else could one explain the reaction of the young birds to the silhouette of a bird of prey which they have never encountered before?
So what's so special about this, you may ask. A pigeon sees a predator and tries to escape. Big Deal! And you would be right thinking that unless one examines all the intricacies of the process. I hope that I can show you that the "fight or flight" response is not only responsible for our pigeons to survive the attack of birds of prey but is also responsible for pigeons losing form after weeks of successful racing.
Let us take a closer look at the cascade of events: A second player enters the stage, the Hypothalamic - Pituitary - Adrenal axis which is a major neuroendocrine system. The hypothalamus secretes corticotropin releasing hormone and arginine vasopressin which stimulate the anterior lobe of the pituitary gland to release adrenocorticotropic hormone or ACTH.
ACTH causes the adrenal cortex to release glucocorticoids, primarily cortisol which enhances metabolism in a number of ways: Cortisol increases blood sugar through these actions. It also causes a rise in blood pressure and suppresses the immune system by suppressing inflammation. Inflammation is suppressed by preventing phospholipid release, decreasing eosinophil action and various other mechanisms.
In summary the overall effect is an animal that can run and fly faster with more endurance, see better due to the dilation of the pupils, hear more acutely and think faster than it could before the cascade of reactions. Excess waste may be voided and food present in the stomach or crop may be vomited to make this animal lighter.
However, all bodily functions not needed for the immediate survival were shut down such as digestion, reproduction, and immunity. And this is where chronic stress or stress of long duration begins to have a deleterious effect leading to high blood pressure, type 2 diabetis, both of which may result in arteriosclerosis leading in turn to heart disease and stroke. We are lucky that our birds don't live long enough for these degenerative diseases to take hold but the decrease in immunity due to exposure to chronic or prolonged stress does affect them to their detriment.
Please note the taste buds and opening to the silavary glands flanking the anterior choana, note the tonsils to the side of the infundibular cleft leading to the pharyngotympanic tubes that are homologous with the Eustachian tubes. Also note signs of inflammation in the middle section of the choana where it is closed, signs such as redness and swelling.
Looking at this mandible one notices immediately the collection of fluid in the entrance to the esophagus, fluid that is to neutralize the irritants produced by many micro-organisms. Although we cannot see the micro-organisms with our unaided eyes, we can see the effects of them on the mucous membranes. The laryngeal mound surrounding the glottis which opens into the trachea can be seen to carry many prominent blood vessels and appears to be completely red in other areas - again indicating the inflammatory response.
Chronic and/or prolonged stress will result in inflammation of the tissues of the oropharynx. Initially such signs are very subtle. There may be just a bit of reddening due to the tiny blood vessels becoming more pronounced. Perhaps there are some excess fluids produced which is the bird's attempt to dilute the toxins due to an increased number of micro-organisms present. Taking a sample and looking at it under the microscope will show that there are many more bacteria present than when the bird was in better condition. Culturing these organisms will usually reveal nothing new. These are usually not some new exotic bacteria the birds picked up during the races but what one usually finds is that the normal flora has increased in numbers. This increased number of bacteria are fed upon by the flagellated protozoans Trichomonas gallinae. These in turn find their living conditions now improved and multiply leading to canker.
Going to the other end and taking a fecal sample often confirms the state of affairs one finds in the mouth. The number of normal inhabitants like Escherichia coli and cocci have increased tremendously and one may even find some budding yeast cells, organisms normally absent in health.
It would appear that the bird's own immune system keeps the micro-organisms normally present in the mouth and the digestive system in check and does not allow them to cause clinical disease but the stress of racing with perhaps the added training tosses causes the release of glucocorticoids such as cortisone which in turn lowers immunity sufficiently for the normal flora to cause disease.

What is the solution?

  1. Administer antibiotics, and if so to all birds in the loft the same amount?
  2. We can try to decrease stress as much as possible
  3. We can look for ways to boost the immune system
  4. A combination of any or all of the above?
It is obviously important to react before the bird's performance has declined, i.e. react when one sees the first sign of the blood vessels of the laryngeal mound becoming more prominent - when one notices an increase in Trichonomas organisms in the crop smear or cocci and E. coli in fecal smears. The administration of antibiotics will have side effects which may depress the form even further. Antibiotics will deplete the intestinal flora of micro-organisms which in turn will make it easier for fungi and yeasts to colonize the intestine and this type of infection is very difficult to treat. Using iodine containing products may prevent colonization by yeasts and fungi. Using a very specific antibiotic selected on hand of sensitivity tests will allow us to use a minimal amount with the highest efficiency.
The reduction of stress should be our aim during any of our activities with pigeons although the sport of racing pigeons is inevitably linked with stress and is not different than the situation with human athletes.
Trying to boost the immune system has been wishful thinking until very recently although physicians and scientists have often seen desirable side effects of pox vaccinations. The resistance to infection against the pox virus is referred to in this context as immunity while the desirable "side effects" such as immunity against other infections will be referred to as paramunity.
X indicates a link. We can see from the above that although vaccination with Baypamun, an inactivated sheep pox virus responsible for "orf", leads to non-specific paramunity in a wide variety of animals who are normally not a host of this inactivated virus, paramunity can be elicited with other vaccines as well. The last point above shows that chicken deposit antibodies in the yolk just as efficiently as mammals do in the colostrum.
Although it should not come as a surprise I was nevertheless astounded by how much stress young horses, calves and pigs experience from weaning, transport and commingling. This reminded me of the time when I received young pigeons for the Alberta Classic Young Bird Derby and the subsequent health challenges. In this context it is regrettable that Baypamun® is not yet available in Canada. Still, the above shows that:
  1. There is another tool for fighting infections and keeping our birds healthy besides using antibiotics.
  2. Similar to the situation with almost all micro-organisms, the complete eradication of Chlamydia and Hexamita, for example, from one's loft, although possible, may not be desirable. If bacterial strains were eradicated, how would these birds and their offspring develop resistance to these micro-organisms which they would eventually come in contact with during flying competitions and shows?
Each of our pigeons is endowed with an immune system which may be stronger or weaker than the immune system of another bird. A micro-organism capable of causing disease in one pigeon may not be able to do so in another pigeon even if confronted with the same concentration of the micro-organism in question. Our pigeons do not only differ genetically in their resistance to infection they also differ in their resistance due to different stress levels they may be exposed to at some time since the cascade of stress hormones inhibits the immune response. Like it or not, we need to learn to live with micro-organisms and perhaps even use them to our advantage for strengthening not only our own defences but also the defences of our birds.
From the above you will likely get the impression that I favour to make the pigeon strong enough so that by itself it can fight any and all infections that it may encounter rather than me trying to keep these pesky microbes away - through the use of poisons that do harm also to the pigeon or through keeping the environment sterile by constant scraping and using a flame thrower periodically. Still, the use of antibiotics is indicated occasionally and is another weapon at our disposal.
It is my understanding that Bayer AG sold the patent for Baypamun® recently (it is the year 2005 now) to the drug company Pfitzer for a lot of money. One can consequently no longer buy Baypamun® itself or even this vaccine under a different name. Why then did I wet your appetite for this vaccine and this method of protecting the birds?
Please remember that most pox vaccines are very stimulating for the immune system. Why not use the pigeon pox vaccine itself? Or paratyphoid vaccine?
Yes, I already can hear some people with dire warnings about possible mutations, et cetera, et cetera, but I am glad that the medical profession did not have similar reservations about using the small-pox vaccine for human beings as they were successful in wiping this plaque from the face of this earth!
Evolution will continue until mankind is no more and will continue thereafter as long as there is life on this planet. Viruses will mutate but our immune systems as well as the immune systems of all living species will adapt. Perhaps some individuals will not survive - perhaps some species will not survive - but this is in the nature of evolution - one of the most beautiful sytems Nature has devised.

Update #1:


Pfizer is marketing the new version of "Baypamum": http://www.pfizerah.com/product_overview.asp?drug=ZS&country=US&lang=EN&species=EQ
ZYLEXIS™
Parapox Ovis Virus Immunomodulator
Description

An immunomodulator consisting of inactivated (killed) parapox ovis virus, Zylexis aids in the reduction of upper respiratory disease associated with EHV-1 and EHV-4 that can be expensive to treat, and may compromise the health of other horses, resulting in lost training or competition time.

Advantages

  • Equine herpesvirus (EHV) types 1 & 4 latently infects 80% of all horses

    • EHV-1 has been demonstrated to cause respiratory disease including pneumonia, abortion and stillbirth in pregnant mares, and neurologic symptoms.

    • EHV-4 has been demonstrated to cause respiratory disease in young and stressed horses.

  • Equine herpesvirus is easily reactivated by common stressors such as environmental changes, training, competition and trailering.

  • Reactivation causes a high viral load that can contribute to sickness, respiratory signs, and sometimes results in pneumonia.

  • These infections can be expensive to treat, may compromise the health of other horses in the barn and may result in lost training/competition time for valuable show horses.

  • Zylexis has been safely and effectively used in horses in Germany since 1998.

  • Safe for use in healthy horses including foals four months of age and older.


Indications

For use in healthy horses four months of age or older as an aid in reducing upper respiratory disease caused by equine herpesvirus types 1 and 4.



Update #2:

(The original article can be found here: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-736X1999000300001&lng=&nrm=iso&tlng= )

REVIEW ARTICLE

A new concept in prophylaxis and therapy: paramunization by poxvirus inducers1

 

Anton Mayr 2 and Barbara Mayr2

 

 

ABSTRACT.- Mayr A. & Mayr B. 1999. A new concept in prophylaxis and therapy: para-munization by poxvirus inducers. Pesquisa Veterinária Brasileira 19(3/4):91-98. Lehrstuhl für Mikrobiologie und Seuchenlehre der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München, Veterinärstraße 13, D-80539 München, Germany.

The so-called primitive, innate or paraspecific immune system is the phylogenetically older part of the complex immune system. It enables the organism to immediately attack various foreign substances, infectious pathogens, toxins and transformed cells of the organism itself. ,,Paramunity" is defined as an optimal regulated and activated, antigen-nonspecific defence, acquired through continuous active and succesful confrontation with endogenous and exogenous noxes or by means of ,,paramunization" with so called ,,paramunity inducers". Paramunity inducers based on different pox virus species (e.g. Baypamun®, Duphapind®, Conpind) have turned out to be effective and safe when applied with human beings as well as with animals. Pox virus inducers activate phagocytosis and NK-cells in addition to regulation of various cytokines, notably interferon a and g, IL 1, 2, CSF and TNF which comprise the network of the complex paraspecific immune system.
The results of experimental work as well as practical use in veterinary medicine have shown that paramunization by pox inducers goes far beyond the common understanding of so-called ,,immuno-therapy". They are ,,bioregulators", because they have 1. a regulatory effect on a disturbed immune system in the sense of an optimal homoeostasis, and 2. simultaneously a regulatory effect between the immune, nervous, circulatory and hormone system. Therefore, the use of paramunization by pox inducers opens a new way of prophylaxis and therapy, not only with regard to infections, but also with regard to different other indications.
INDEX TERMS: Paramunization, paramunity inducer, pox viruses, therapy, prophylaxis.

 

 

INTRODUCTION

The terms ,,paramunity" and ,,paramunization" are new and thus open to discussion. The terms embrace certain new prophylactic and therapeutic measures covered by a single principle. This is both appropriate and necessary, since there are a number of new diseases which can only be partly combated by the methods of classical medicine: infectious factorial diseases, mixed infections, chronic and recurrent diseases, therapy-resistent bacterial and viral infectious diseases, tumors, immune diseases and lowered resistance of an organism by immune-suppressive noxae or disregulation of the immune system with the known pathological consequences.

For this reason, more attention has been paid to the influence of endogenous unspecific defence potentials as a prophylactic and therapeutic concept over the past few years. Suppressives have been used for a long time to suppress immunological reactions, for example in transplantation medicine. However, the purposeful regulation and activation of endogenous unspecific defence mechanisms, especially in the antigen-nonspecific areas, is a new prophylactic and therapeutic principle.

The immune system of warm-blooded animals, especially of mammals and birds, consists of an antigen-specific part and an antigen-nonspecific part (Fig. 1). The two parts are cross-linked and so form an uniform organic system. The antigen-specific mechanisms are responsible for building up immunity, while the antigen-nonspecific mechanisms are responsible for building up paramunity. Accordingly, for both historical and functional reasons the antigen-nonspecific part of the defence is known as the paraspecific (innate, primitive) immune system. Up until the present, immunology research has been mainly concerned with the antigen-specific part of the immune system, i.e. with how immunity is formed. The utilization of this defence potential led for example to the development of active and passive immunization. In contrast, the exploitation of the paraspecific activities of the immune system for prevention and therapy is still in its early stages. The paraspecific immune system makes it possible for the organism to mount an immediate defence when confronted by the most diverse foreign substances, infectious pathogens, toxins and transformed cells of the organism itself. There are patterns of close functional interplay between the paraspecific and the specific activities of the immune system, generally involving a flow of information from the paraspecific mechanisms, which react first, to the specific activities of the immune system.

 

 

Since Edward Jenner introduced protective immunization against smallpox in 1798 using a vaccine obtained from animals (cattle or horses) and based on the vaccinia virus, empirically obtained results have been reported showing that protective immunization against smallpox resulted in those vaccinated recovering surprisingly rapidly, without complications, from other infections and diseases, especially chronic and relapsing complaints, from which they happened to be suffering at the time of vaccination (Baxby 1981, Mayr 1993). In particular this applies to herpes infections of varying genesis, papilloma, chronic eczemas and pathological conditions of the ears, nose and throat. As well as this, however, it was noted, that those immunized showed a generally raised short-term level of resistance to acute ambient infections. Similar phenomena have been noted after protective immunization against various forms of animal pox. It was deduced from these findings that poxviruses or certain structural components of these viruses can positively influence the organisms ability to resist infections and tumours, on a nonspecific level. Because these nonspecific healing processes commence immediately after vaccination and develop 5 to 7 days before the specific immunity conferred by vaccination develops, as well as parallel to thereto, A.Mayr (1978) designated these nonspecific consequences of a prophylactic immunization as ,,paraspecific". Accordingly, medicaments produced specifically to exploit such paraspecific effects are known as ,,paramunity inducer". The condition which results of treatment by paramunity inducers is called ,,paramunity".

 

DEFINITIONS AND FUNDAMENTALS

The paraspecific immune system is a physiological process in the daily struggle of an organism against endogenous and exogenous noxious influences. It goes into action immediately, reacts in a correspondingly non-specific manner, and may be defined as a ,,primary check" of the native immune system. It's task is to bind pathogens, then to inactivate and remove them, or at the very least to prevent them from exerting any effect damaging to the organism until specific immune reactions (antibodies, immune cells) are present. The unspecific immune system possesses regulatory functions for the immune system as a whole.

The paraspecific immune system is irreplaceable not only for the lower organisms but also for the highly developed vertebrates. Primary congenital defects in this phylogenically old (innate) immune system lead to life-threatening situations. Fortunately enough, there are at present only a few examples, one of which being the Chediak-Steinbrinck-Higashi syndrome in man, which is characterized by granulocyte defects and dysfunctions of the natural killer cells (NK cells) and is usually fatal by the age of 10 (Padgett et al. 1970). Transient secondary defects, on the other hand, have a higher incidence, for example in the complement system, causing impairment of phagocytosis and promoting the activation of infections with opportunistic pathogens (Büttner 1993, Finlay & Falkow 1989, Rumyantsev 1992, Warner et al. 1988, Welsh et al. 1991).

As a result of a continuous grappling with the most exogenous and endogenous noxious influences, the organism develops an enhanced antigen-nonspecific defence, and this defence is known as paramunity.

Paramunity is the state of a well regulated and optimally functioning nonspecific defence system, combined with an enhanced defence, of limited duration, against a large number of different causative agents, antigens and other noxious influences. Just as ,,immunity" is understood to be acquired specific protection against one particular infectious disease, ,,paramunity" is the acquired nonpathogen-specific and nonantigen-specific protection of an individual. This may be accompanied by an enhancement of phagocytosis rate, the function of spontaneous cell-mediated cytotoxicity (NK cells) and the activity of other lymphoreticular cells. At the same time, certain cytokines are released, and these interact both with the cellular elements and among each other. This interactions may be of both a stimulating and a suppressive nature (repressor mechanisms). The aim is to relieve dysfunctions, to rapidly raise the defence level of individual which is not pathogen- or antigen-specific, to eliminate any immunosuppression or immunological weakness that has arisen through the effects of stress or otherwise (i.e. through medication). This closely enmeshed biosystem of immunity, which reacts in stages, and involves receptor, effector and target cells, is furthermore closely bound up with the hormonal and nervous systems (Fig. 2).

 

 

Paramunity is exploited by paramunization. Paramunization is set in train 1.) as the result of a physiological process in the daily struggle of an organism against endogenous and exogenous noxious influences, and 2.) by the use of medication with paramunity inducers. The paramunization is an imitation of natural reactions under controlled conditions with much higher efficacy and safety (Mayr 1997).

Paramunity inducers are biological products similiar to vaccines which have a paraspecific effect and which are non-immunizing. Paramunity inducers must meet strict requirements of nonharmfullness and efficacy, which sharply differentiates them from what are called immune stimulants. The most important criteria are given in Table 1.

 

 

At present these requirements are fullfilled only by paramunity inducer made from pox viruses. Poxvirus paramunity inducer consist of attenuated (avirulent) and inactivated pox viruses, virus components, i.e. subunits, especially derived from the envelope of pox viruses. In contrast to vaccines poxvirus inducers do not directly interact with the antigen-specific part of the immune system, but with the non-specific i.e. paraspecific part of the immune system. The result is an optimal regulation of the highly complex immune system through activation of macrophages, NK-cells and lymphoreticular cells as well as through the production, release and interaction of many cytokines (cytokine cascade), such as interferon, interleukin (IL-1, IL-2, IL-12) CSF, TNF and several others (Fig. 3).

 

 

More than 20 interacting protein complexes within the viral envelope, such as the adsorption protein, the fusion protein and various further structural proteins are responsible for the paramunizing effect. Meanwhile some of these proteins could be isolated and the corresponding parts of the DNA could be expressed in a suitable system. Each protein component by its own has only a very low efficacy detectable in ,,in vitro"-systems, and only marginal effects in ,,in vivo"-experiments (Czerny & Mahnel 1990, Büttner et al. 1995). For the required complex efficacy and for the safety of humans and animals, however, the non-immunizing protein complexes in the envelope of the intact virus particles are necessary, true to the cybernetic idea that ,,the total is more than the sum of its parts". The reason for the complex efficacy is the so-called ,,system-theory" based on the interactions and connections of the single parts.

Paramunity inducers made from pox viruses are novel drugs which contain non-immunizing, intact connected antigenic structures of attenuated and inactivated strains of pox viruses and which are intended for paramunization in man and animals. In contrast to the antigen-specific vaccination the paramunization can be used for prophylaxis and also for therapy to prevent or regulate dysfunctions of the immune system in order to optimise the non-specific acquired resistance. The paramunization supports, for example, the stimulation of TH-1 subpopulations, and thereby prevents the production of TH-2 subpopulations which are known to be involved in the induction of the immediate hypersensitivity (antibody-mediated allergy).

The pox paramunity inducers are metabolised immediately and do not leave residues. The duration of efficacy is short (about up to 12 days). A possible minimal antibody production detectable by way of ELISA tests emerging after repeated and continuous application does not interfere with the efficacy of the drug.

In veterinary medicine, paramunity inducers have been produced from purified, attenuated and inactivated avipox and parapox viruses. These paramunity inducers are registered in the European countries as Duphapind® and and Duphamun® (PIND-AVI) and as Baypamun® (PIND-ORF) for virtually all species of farm and domestic animals. Paramunity inducer PIND-AVI is prepared from attenuated avipox virus, strain HP 1, and paramunity inducer PIND-ORF is prepared from an attenuated parapox virus, strain D 1701. The attenuated viruses are rendered inactive in a manner known per se, e.g. by g-radiation or chemical means such as treatment with b-propiolactone.

Pox inducers can be used as drugs, prepared from a single pox virus, as well as preparations made from different poxvirus species, e.g. avian and parapox viruses or other combinations (multipotent paramunity inducers, e.g. Conpind; Europ.Patent No.0669133; Dtsch.Patent No.4405841). It was unexpectedly found that combining pox virus components in the multipotent paramunity inducers does not result in a decrease in, let alone loss of, the respective paramunizing activities of the individual poxvirus components. Instead it was seen that combining the poxvirus compoments derived from various poxvirus strains or species in the multipotent paramunity inducers brings about not only an additive or supplementary effect, but a potentiation of the respective paramunizing action. Experiments have shown that the action of the multipotent paramunity inducers combined from poxvirus compenents far exceeds their respective individual actions. This phenomenon could not have been predicted, and in terms of their potency and their paramunization-related activities it enhances the paramunity inducers as compared with conventional preparations from a single component. Another finding is that the multipotent paramunity inducers have virtually no immunogenic properties, but do have very strong paramunization properties, as a result of which they can safely be administered on a repeated or continuous basis.

There exists a competitive situation between the epitopes of the structural proteins of the poxviruses responsible for paramunization and those responsible for immunization. The steeper the decline in activity on the part of the epitopes responsible for antigen-specific immunization, the bigger is the increase in paraspecific activity. This is attested by the following two observations:

1. Attenuation over several hundred passages in cell cultures causes the immunizing properties of poxviruses to decrease, whilst the paraspecific activities not only increase but in the case of certain pox strains only appear after attenuation.

2. Inactivation of the poxviruses suited to preparation of the paramunity inducers, preferably by irradiation, or by chemical treatment, e.g. with g-propiolactone under specific conditions, causes the poxviruses to lose their immunizing properties whereas their paramunizing activities increase.

The combinations of poxvirus components with different activities in a single drug are suited for use as multipotent paramunity inducers in both human and veterinary medicine.

The term ,,poxvirus component" covers a large number of viral structures derived from poxviruses with paramunizing properties, for example viable (i.e. capable of multiplication) or inactivated, attenuated poxviruses, individual viral polypeptides obtained by biochemical or immunochemical methods from cultures that have been infected with the poxviruses or recombinant viral polypeptides (Table 2 ).

 

 

   

PRECLINICAL STUDIES

The above described poxvirus paramunity inducers Duphapind®, Baypamun® and Conpind were tested in different test models for their efficacy and safety (Mayr & Mayr 1995, Mayr 1997).

The investigations on the ,,systemic level" (parenteral application of pox-inducers to man and animals) have proved the preparations to be harmless and surprisingly effective with regard to certain indications. The efficacy was demonstrated for example in viral challenge infections in mice (reduction of mortality), bacterial wound infections (rapid healing), radiation-induced murine osteosarcoma and various other murine carcinoma (reduction of tumour growth and metastasis), radiation-induced immunosuppression in mice (recovery of the immune system). Above that pox inducers prevent the transport-induced increase of cortisol level in horses, increase the levels of interferon a in periphereal blood (man, piglets, mice), prime leucocytes (pig) and have a regulative effect on the ,,rolling" of leucocytes after endotoxin-challenge (leucocyte/endothel interaction in mice) (Schmitt 1995). The clinical data correlate to laboratory parameters apt to serve as proof for the efficacy. The challenge models (VSV, Aujeszky) verify a dosis- efficacy relationship.

The evaluation of the efficacy of the pox inducers in isolated blood- and liver-cells respectively cell cultures (cellular ,,in vitro" level) provide a unified picture: increase of the phagocytosis (uptake and respiratory burst (FACS), clearance and phagocytosis of Ps.aeruginosa in isolated perfused livers of germ-free rats), the thymidin metabolism in liver cells, the NK-cells (spontaneous natural cytotoxicity) and stimulation of lymphatic cells (lymphoma, hybridoma) to release cytokines.

The investigations in the ,,cytokine release" illustrate that pox inducers promote the release respectively the production of diverse cytokines important for the regulation of the immune system. This has been proved for interferon a and g, the interleukines 1, 2 and 12 as well as for CSF and TNF.

To conclude, a regulative effect is ascribed to the poxvirus inducers in the network of paraspecific defence in regard to stimulating as well as inhibiting effects. The endogenous medication by way of pox inducers (paramunization) is diametrically opposed to the exogenous application of cytokines.

The described investigations confirm that results of ,,in vitro" or "ex vivo-in vitro" tests allow extrapolations as to the clinical efficacy of pox inducers for both therapy and prophylaxis. As matter of general principles, it is true for biopreparations as well that the preclinical demonstration of efficacy cannot be automatically equated with the prophylactic and therapeutic effect. For the inducers obtained from attenuated poxvirus strains, however, the preclinical demonstrations of efficacy are clinically relevant according to the broad spectrum of all the test results so far obtained. The clinical relevance, or the evaluation of the results of in vitro and ex vivo-in vitro investigations for assessing the clinical efficacy of pox inducers, is scientifically valuable and can be experimentally proved. The most important concepts for comparison are the following:

- homologous results in vitro, ex vivo-in vitro and clinically (prophylaxis, therapy) in farm animals, pets and humans;

- homology of cellular (phagocytosis, NK activity) and soluble components (interferon, interleukins, tumor necrosis factor, colony stimulating factor) in humans and animals;

- homology of both phylogenetic and ontogenetic development of both the complex paraspecific and antigen-specific immune systems;

- equal efficiency and safety in humans, pets, farm animals and experimental animals;

- paraspecific efficacy demonstrable for all genera of pox viruses;

- homology of immunological, endocrine and nervous control mechanisms (compound system);

- historical reports from the age of smallpox vaccinations since Edward Jenner 1796.

 

CLINICAL STUDIES

The pox inducers Duphamun®, Duphapind® and Baypamun® have been registered in Europe for many years. They were succesfully used on a wide variety of pets and farm animals with different indications. The abundance of publications on this topic make a general review in this place impossible. The following examples in Table 3 and 4 will prove the correctness of the above mentioned concept in regard of the extrapolation of in vitro and ex vivo-in vitro obtained results for the clinical efficacy of pox inducers.

 

 

 

 

   

CONCLUSIONS

Indications

The experience in practice has demonstrated that paramunization with poxvirus inducers is a new concept in as well prophylaxis as therapy. The most important indications for prophylactic use are:

- rapid activation of the neonate paraspecific part of the immune system;

- before expected stress situations (avoidance of stress-induced damages);

- before hospitalization;

- when there is acute danger of infection;

- prevention of vaccination complications;

- reducing the danger of tumours and/or metastasization;

- in support of bioregulation;

- raising the life expectancy;

- regulation of homeostasis in interplay with the hormonal, circulatory, metabolic and nervous systems.

Paramunity inducers obtained from poxviruses are particularly suitable for therapeutic use in the follwing instances:

- immune weakness;

- virus diseases (e.g. herpes diseases), therapy-resistant bacterial diseases, infectious factorial diseases, intoxications (especially endotoxicoses);

- chronic and relapsing infections;

- tumours (substitutal therapy);

- convalescence;

- chemotherapy and antibiotic treatment;

- liver diseases of differing etiology;

- chronic skin diseases;

- immunopathogenic secondary diseases.

Bioregulatory activity

The results of as well experimental work as practical use in veterinary medicine have shown that treatment with pox inducers goes far beyond the common understanding of so-called "immunotherapy". They are "bioregulators", because pox inducers have a regulatory effect on a disturbed immune system not only in the sense of increasing or stimulating reduced or suppressed activities but also in the sense of decreasing pathologically enhanced immunoparameters to the optimal physiological range. For understanding the regulatory effect of pox inducers in the sense of bioregulation which takes place between the immune, hormon, metabolic, circulatory and nervous systems, it x inducers. This may, for example, occur because the number or activity of specific effector cells (e.g. macrophages, leukocytes, T-cells, NK-cells) rises or drops, or the production of cellular and humoral mediators (e.g.IL 1, 2, interferons, TNF etc.) increases or decreases. Each organism reacts differently and individually depending on the functional state of its defence system at the beginning of the treatment with the pox inducer. For example, after the treatment of the patient with pox inducers the number of leucocytes may increase, while on the other hand the number of NK-cells in their activity remains the same or even decreases. For the compensation of dysregulations of the immune system it is not necessary that all immunological parameters be stimulated or suppressed simultaneously, since only existing deficiencies or excessive values are equilibrated. The individualisation into the physiological standard range by the treatment with pox inducers is therefore a completely new finding. Since an intervention of pox inducers in the individual defence system also simultaneously has a regulatory effect on the nervous, hormone, (circulatory and metabolism) systems, pox inducers should not be defined as immuno-regulators, rather it is suggested that they be considered bioregulators. Such a bioregulator which is harmless even when used in high overdoses, which does not influence the physiological normal values" of the immune system and which has a regulatory effect in the case of dysfunction in the sense of a physiological normalisation, i.e. stabilising or restoring the immune system in its entire functionality, so far does not exist in medicine.

Application and dosage

Therefore, pox inducers are particularly useful for the prophylactic and metaphylactic application in patients having a dysregulated immune system, for example in case of immunodefects of different genesis, such as after an immunosuppressive therapy, in case of immunosuppressive primary disease, or by exogenic influences, like stress situations, unusual strains, long journeys, acute infections in the environment. For the prophylactic paramunization normally 2 to 3 injections of a pox inducer preparation are sufficient given on consecutive days shortly before expected strain. Metaphylactic or therapeutic doses of pox inducers should be given at least 3 days or until a clear decline of clinical symptoms. After serious illnesses, in particular after infectious diseases, convalescence should be supported by 2 to 3 injections per week of a pox inducer until complete rehabilitation.

Limitations of paraspecific immune system. The limits of the paraspecific immune system and thus of paramunization are found in genetic defects such as the Chediak-Steinbrinck-Higashi-syndrome (see above). When there is a total primary absence of, or some form of transient secondary damage to, the paraspecific immune system, the organism, in contrast to a deficiency in the formation of antibodies or immune cells, has no chance. Transgenic animals, such as nude mice, which possess no T- or B-lymphocytes, can quite well live in a germ-laden environment if their nonspecific immune system is functioning (Welsh et al. 1991); if the system is absent, their chances of survival are virtually nil. Corresponding to this, the success of a paramunization as well depends entirely on the residual "responsiveness" of the paraspecific immune mechanisms.

For the substitution of defined immune deficiencies the avaible methods are exogenic medication with cytokines or adoptive cell transfer. It is hoped that this will open up new paths for medical indications or principles of treatment. Thus, for example, the exogenic use of recombined interleukin 2 preparations is of particular benefit to patients with melanoma and renal carcinoma, in whom the primary disease can at least be kept under control for a certain time with this treatment method. Meanwhile, however, even here there is an increase in the number of reports of serious side effects, as with the administration of exogenic interferon. Generally speaking the clinical use of individual cytokines is accompanied by more or less toxic effects, and it harbours the danger of upsetting existing endogenous regulatory mechanisms. As far as is known at present, the least dangerous method is the exogenic administration of cytokines G-CSF and GM-CSF (colony stimulating factors) and of interleukin 2 and 3 individually or in combination. By contrast, interleukin 1,6 and 8, TNF and interferon should be used with great caution.

This page was last up-dated on May 14, 2007

Below are your comments:
Friday December 9, 2005
Bjorn Bjornson
Victoria, B.C.
24.68.236.186
Thanks Karl for a well researched and informative article. I`ll be spending some time digesting it`s content. Bjorn.

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