by Academician Yevgeny VORONIN, Member of the Russian Agricultural Academy, Rector of the Moscow State Academy of Veterinary Medicine and Biotechnology (named after K. Skryabin)

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The ailments affecting the youngsters of most farm animals and inflicting appreciable economic harm on the state are chiefly caused by infections. The scale of this damage is second only to the losses of cattle produced by mastitis in cows.

Participants in the International Congress on homed cattle held in Spain in 1988 came to the conclusion that diarrhea in calves is caused by the enteropathogenic colon bacillus, Salmonella, Proteus, Klebsiella, staphylococci, citrobacterium, pseudomonades (pseudomonas),certain varieties of fungi and also by rota- and coronaviruses. It has also been established that simultaneously engaged in the etiology of this disease are no less than 2 to 3 causative agents and even more. In order to identify any of these as causative agents the microbe count per gram of feces should be greater than 10 ⁶ , and they should also possess adhesive and toxicogenic properties and be pathogenic for white mice.

At the same time our studies over many years have revealed that some gradual changes take place in what we call the etiological microbial picture in cases of diarrhea in calves. The place of prominence today is held by microbes of the Proteus group followed by Klebsiella, staphylococci, pseudomonades and, finally the enteropathogenic colon bacillus and Salmonella. It is therefore not surprising that as often as not diagnostic veterinary labs conducting this kind of analysis do not confirm diarrhea in the affected cattle because they fail to detect in them sufficient volumes of colibacilli and Salmonella, while also traditionally ignoring the rest of the microflora. Now, what is the reason for this change in the causative agents?

The reason for this situation is in the largely uncontrolled and massive use of antibiotics and vaccines which have "pushed back" colibacteriosis and salmonellosis. And tests of the sensitivity to these preparations of Proteus and Klebsiella microbes, citrobacteria, pseudomonades and staphylococci have demonstrated their absolute resistance to them.

We know that research scientists have always been trying to discover those "magic bullets" which could protect both people and their cattle from infections. Their efforts and achievements can be divided into three periods.

The first was crowned by the development of vaccines. In 1881, the French bacteriologist and immunologist Louis Pasteur, who was an Honorary Foreign Member of the Russian St. Petersburg Academy of Sciences, substantiated the principle of using vaccines as a barrier against infection. The principle of action of live attenuated vaccines and their preparations is now common knowledge. And the first theory of immunity was formulated in 1883 by the Russian scientist and Nobel laureate Ilya Mechnikov. These two events meant a virtual revolution in medicine and in veterinary science. With the help of vaccines people have been able to protect themselves from the scourge of various infections (suffice it to recall the role of vaccines in doing away with smallpox).

But more than a hundred years of research have failed to give us effective vaccines against malaria and parasitic infections, venereal diseases, staphylococcic infections, diarrheas and also respiratory diseases of young animals. True, medical scientists can weaken the pathogen, kill it or produce this or that antigen. And yet for genetic reasons neither animals nor man are capable of developing stable immunity against these diseases.

Which means that having recovered from such an infection they can contact it again within a short span of time. That is why specialists call them (so far) "unconquered infections".

The year 1929 was marked by the advent of antibiotics into veterinary medicine - the discovery of penicillin by the Scottish bacteriologist and immunologist, Sir Alexander Fleming, a Nobel laureate. That was the long-awaited "magic bullet" on which humankind had pinned so much hope. The success of the very first injections of the new drug really shook the world, and the common feeling back in the 1940s and 1950s was that diseases caused by microbial pathogens would soon be wiped out. These happy expectations, however, were soon dashed by the stem reality. Very soon there appeared clones of pathogenic microbes resistant to antibiotics. And they proved to be even more dangerous to both man and animals. And the "arms race" is still in progress now, with medical scientists developing new antibiotics capable of wiping out the respective microbes, but for not more than two years only. And one of the most deplorable facts of this ongoing battle is the ability of these preparations to accumulate in the body of patients. What is even worse, emphasis on antibiotics leads to dysbacteriosis, followed by immunodeficiency in man and animals.

That does not mean, of course, that the use of antibiotics is called into question. Giving them up would be a return to the tragic past

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when medicine and veterinary science were powerless against infections. But the future of antibiotics therapy is also in doubt if doctors do not get appropriate immunological solutions to these problems. And here we come to the third stage of our search for the "magic bullet".

The thing is that for a whole number of years now experts have been puzzled by the question of why potentially pathogenic microbes which are so common in the environment cause outbursts of diarrhea and losses of young livestock on a large scale.

Immunological examinations of newborn calves have revealed that most of them suffer from a deficiency of the B-system of immunity expressed in reduced levels of С and A immunoglobulins, a reduced total count of lymphocytes, a low level of T- helpers ^* , a low phagocytic activity of neutrophils and a sharp reduction of B-lymphocytes ^** . This is often accompanied by deficiency of the phagocyte and complement systems ^*** . It was noted that B-system immunodeficiency in calves is always preceded by some stresses, traumas of cows, delayed yield of beestings and poor zoohygienic conditions of livestock maintenance. And naturally enough, when the immune B- system is weakened, the negative effect of potentially-pathogenic microflora begins to manifest itself.

At later periods (5 to 7 days after birth) younglings develop rota- and coronaroviral infections.

On the basis of the obtained data experts produced an algorithm of diarrhea: stress-immunodeficiency of the B-system + bacteria + viruses = diarrhea.

Developed on this basis has been a diagram of application of specific and nonspecific preparations for combatting the disease. And since, as has been pointed out, specialists often registered, together with enteropathogenic colon bacillus and Salmonella, also Proteus and Klebsiella infections, 14 strains were used for an associated inactivated vaccine against the four above pathogens. The vaccine is administered twice to pregnant cows at intervals of 12-14 days or once with T-activin (polypeptide, obtained by biotechnology from livestock thymus). Also developed against these infections is what we call a hyperimmune polyvalent serum for the treatment of younglings.

Thus at the first stage pregnant cows are administered the vaccine and through their colostrum the calf receives the necessary quantity of antibodies ^**** . After that, as a precaution against immunodeficiency the immunomodulators T-activin and B- activin (peptide obtained from pig bone marrow) are injected subcutaneously. This is administered once a day for three days in succession ^***** .

However, as proved by latest investigations, B-activin is similar to endorphins - natural narcotics produced in the organism of man and animals. In view of that and in order to prevent the penetration of potentially pathogenic microflora into the intestine of calves, lactobactoerin, bifidumbacterin, biosphorin-B and other probiotics are administered orally. This is done 3 times a day for 3 to 4 days in succession. Besides, a hyperimmune polyvalent serum is administered orally or intramuscularly.

Diarrhea is usually accompanied by acute intoxication. We have synthesized a new antitoxic preparation - fluorazol - which can evacuate exo- and endotoxins from the body.

The proposed scheme of diarrhea prevention in newborn calves makes it possible to keep healthy from 90 to 95 percent of the younglings.

Respiratory diseases are the second common cause of death of young animals. This occurs 12 to 14 days after the release of calves from a preventorium into what we call the first regime of maintenance (or else in the second regime). The etiological agents causing the ailment include viruses of paragrippe-3, infectious rhinotracheitis, adenoviruses, the respiratory-syncytial virus, etc. An important role in such cases belongs to associations of 2 to 3 viruses many of which (adenoviruses, the diarrhea virus) produce a strong immunodepressive effect. Stress resulting from a change in the maintenance conditions of young cattle, including new service staff, new rations, rank strife, vaccination and the like, precede the onset of an ailment. The reason for that is fairly simple - the new environment stimulates the release of adrenalin and corticosteroids which weaken the immune system. Years of studies have demonstrated that an outburst of respiratory disorders is preceded by a weakening of the T-system expressed in a considerable drop in the relative and absolute counts of T- lymphocytes in comparison with healthy animals of the same age and also of the phagocytic activity and the phagocytosis neutrophil index. The secondary outbreaks of respiratory disorders are caused as a rule by such bacteria as Chlamydia and Mycoplasma.

The obtained data have made it possible to also synthesize the algorithm of respiratory diseases: stress - immunodeficiency of the T-system + viruses + bacteria = respiratory disorder.

Accordingly we have proposed a system of prevention of respiratory disorders in calves. It consists in the following: while switching calves from one period of maintenance to the next one, the T-activin and B-activin immunomodulators should be injected subcutaneously once a day for 3 to 4 days in succession. Also, the polyvalent serum against paragrippe-3, infectious rhinotra-

^* T-helpers: a variety of T-lymphocytes responsible for humoral immunity - Ed.

^** See: I. Akmayev, "Interaction of Regulatory Systems", Science in Russia, No. 6, 1996. - Ed.

^*** Complement - a set of immune proteins present in fresh blood serum of animals and man. - Ed.

^**** Antibodies - conjugated proteins, the immunoglobulins of blood plasma, which are synthesized by lymphoid tissue cells under the effect of various antigens. - Ed .

^***** See: V. Pchelyakova, " Immunoprophylaxis to Ward Off Contingencies", Science in Russia, No. 2, 1993 - Ed.

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cheitis, adenoinfections and viral diarrhea should be injected intravenously. The second injection is given in two weeks' time. Calves of 60 days and older, depending on the maintenance conditions at a farm, also need live and inactivated vaccines against paragrippe-w, infectious rhinotracheitis, adenoinfections, viral diarrhea and so on.

The proposed system of drug administration for the prevention of respiratory disorders makes it possible to preserve up to 97 percent of young cattle. On this basis we have drawn the conclusion that the main and decisive factor in cases of diarrhea and respiratory disorders of young cattle is immunodeficiency which is conducive to pathogenic viral and bacterial microflora.

Interestingly, over the past 3 to 4 years there have been a number of publications in this and other countries on the uses of probiotics and immunomodulators for the treatment of different pathologies. At the World Veterinary Congress in Rio-de-Janeiro in 1991 a special section on immunodeficiencies and immunomodulators had six communications on its agenda. As for immunomodulators, they are tested in various countries on a limited number of animals, though in Russia their commercial production was launched in 1988, and they are used on a large scale on hundreds of livestock farms.

Now, what about the prospects of disease prevention and treatment of young livestock? In the first place steps must be taken for the improvement and introduction of diagnostic methods, like the immunoenzymatic analysis with the use of monoclonal antibodies. With this aim in view achievements of biotechnology should be used as the basis for the development of new systems which can diagnose, localize and prevent microbiological lesions.

The year 1985 saw an event which changed in a radical way the basic strategy of diagnostics of pathogens. Dr. Mallis of the United States used amplification of DNA fragments which became known as the polymerase chain reaction. Duplication of DNA fragments occurs in a matter of 3 to 5 minutes as a result of which it is possible to obtain from molecules isolated from a single cell tens and hundreds of millions of copies of a fragment which is of interest to us - just within 2 to 3 hours! In fact a system of DNA amplification has been developed this way. This method has paved the way to building some supersensitive diagnostic systems capable of detecting even one single bacterium or virus.

The introduction of the new system in livestock farming would obviously call for a common system of diagnostics of both especially dangerous and common infections.

All of these innovations and achievements will help improve methods of immunocorrection and immunoprevention as well as of treatment of young livestock, of cattle leucosis and parasitic diseases. And new immunomodulators will find broad applications in combination with inactivated vaccines. As demonstrated by recent studies, antibody titers in animals after the administration of vaccines together with immunomodulators are increased by 3 to 4 times as compared with the administration of vaccine alone. This being so, the future role of immunomodulators in veterinary medicine can hardly be overestimated.

The past century was a century of a scientific and technological revolution. And I feel like calling the new century that of a scientific and biological revolution.

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