Research - Immune Function

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Immune Function

The natural environment contains a large variety of infectious microbial agents - bacteria, viruses, and fungi. If left unchecked and allowed to multiply, pathogenic species will eventually kill the host. In normal healthy animals most infections are of limited duration and cause little if any permanent damage. This is due to the immune system - a natural defence mechanism that helps ward-off or combat infectious agents.

The immunoglobulins have an integral role in this defence system in that they form antibodies. The most prevalent immunoglobulin in all species of animals is IgG. In human trials it has been demonstrated that specific antibodies exist in bovine milk which are effective against both enteropathogenic and enterogenic organisms.

The Immune Response

Antibodies

Passive Immunity

Passive Local Protection

Immuno-Supplementation

Bovine IgG s

Safety of Bovine Immunoglobulins

Efficacy: - Antibody Activity, Specificity, and Titre

Pathogen

Stability

References

The Immune Response

The immune response is a defence mechanism by which the body fights infection. It is divided into two functional systems, the innate immune system and the adaptive immune system. The innate system is the first line of defence by which the host combats infectious agents and pathogenic microbes. This is a non-specific response, which proves effective against most infective agents. In case this primary response is not affective and the invading microbe is lead to proliferate the adaptive immune system comes into action. The adaptive immune system produces a specific response in the form of antibodies to the infective agent that normally proves effective in neutralising that agent. In the case of the innate system resistance (immunity) is not improved by repeated infection. The adaptive immune response involves memory and gives rise to resistance to repeated exposure to the same infective agent. Childhood diseases such as mumps, measles, and chickenpox produce life-long immunity following an infection.

Most infectious agents enter the body proper via the epithelial surfaces of either the upper respiratory, digestive or genito-urinary tract. Once infectious agents have penetrated the body a variety of physical and chemical defence mechanisms come into play to help protect these tissues from most infections. This involves a specialised set of cells called leukocytes (white blood cells) and their products that have evolved to help combat infection and disease. Leukocytes fall into two broad categories of cell types: phagocytes and lymphocytes. Phagocytes form part of the innate immune system and provide non-specific immunity. Included in this category are neutrophils, basophils, eosinophils, monocytes, and macrophages. Lymphocytes form the adaptive immune system and provide specific immunity.

There are two types of lymphocytes B cells and T cells. The B cells are differentiated in the bone marrow and found mainly in the lymph nodes and spleen. They are the cells that make antibodies (immunoglobulins). The T cells are differentiated in the thymus and fulfill two major functions. They regulate the activity of the B cells and directly attack infectious agents.

Antibodies

Antibodies belong to the specialised group of bio-active proteins called immunoglobulins (Ig's).They are glycoproteins and are present in serum and other tissue fluids, including the milk, of all mammals. Antibodies are produced in response to the host being exposed to immunogenic foreign (antigens) substances such as infectious microbes. They are an important element in the adaptive immune response in that they are directed specifically to the antigen that induced their formation and that they impart memory. In this manner the body is effectively prepared to repel any later invasion by the same organism.

Antibodies are produced by activated B cell lymphocytes (plasma cells). Each plasma cell secretes one class of antibody and all the antibody produced by a single plasma cell is of the same specificity. There are five classes of immunoglobulin that are recognised in mammals IgG, IgA, IgM, IgE, and IgD. The most prevalent class of immunoglobulin in all species of animals is IgG. The function of these molecules is to bind to invading organisms and to activate specific actions that help rid the body of disease causing agents. They function in cell killing, inflammation, and prevention of bacterial and viral attachment.

Passive Immunity

During embryonic development the unborn animals immune system is not sufficiently developed to ward off potentially harmful microbes. Fortunately the foetus is protected from harmful environmental factors by its position in the womb; normally potentially harmful agents will not pass the placental barrier. At birth the newborn without a complement of antibodies would find its environment very hostile, being quite susceptible to infection from invading organisms.

To alleviate this potentially lethal situation a very interesting phenomenon, known as passive immunisation, has evolved. The maternal blood contains a full complement of antibodies to various antigens to which the mother has been exposed to during her lifetime. In humans and apes the mother passively immunises her young in utero by passage of antibodies through the placenta. In animals where the maternal antibodies do not pass the placental barrier (cattle, pigs, and sheep) the young are passively immunised immediately after birth by way of colostrum. In these species the maternal antibodies present in the colostrum are absorbed directly through the gut in the first few days after birth.

In the case of newborn cattle, pigs and sheep being deprived colostrum; a significant increase in mortality rate is observed (1,2). In a study conducted by the Invermay Agricultural Center it was shown that the post-treatment mortality of triplet lambs was significantly increased from 7.4 % to 19.4%. The association of high neonatal mortality rates and the successful transfer of colostrum has been reported (1, 2, 3, 4, 5).

IgG is the form in which antibodies occur most abundantly. In all species of mammals IgG is passed from the mother to its young, although the actual mechanism of transmission varies species to species. In humans and apes it has been shown that IgG and its compliment of antibodies pass across the placental barrier from mother to foetus during the second two-thirds of gestation. This passage appears to be selective in that IgG is transferred but not the other immunoglobulins (IgA, IgM, IgE, IgD). Albumin is also transferred but to a lesser degree. Other plasma proteins are not transferred across the placental barrier. In cattle it appears that the same type of selection occurs in absorption of antibody through the gut in that there is a preferential passage of IgG and not IgA, IgM, IgD or IgE.

Passive Local Protection

In humans, passive transmission of maternal antibodies occurs prior to birth and is in utero. After birth the antibodies present in human milk function in local passive protection. In cattle, pigs, and sheep passive transmission of maternal antibodies occurs in the first 20-48 hours after birth by way of the colostrum. During this time they absorb intact antibodies via the newborns digestive tract. After these first few days the direct absorption of intact antibodies ceases and any antibodies present in the colostrum and milk then function in local passive protection of the gastrointestinal (GI) tract.

The importance of this passive local protection is evidenced in the newborn calf where diarrhoea and other enteric infections (scours) can prove fatal (6). It has been reported that the best source of nourishment for the infant mammal is mother's milk (7). This has largely been attributed to not only the nutritional benefits of milk but also to the presence of milk immunoglobulins providing local passive protection to the GI tract.

Immuno-Supplementation

Local protection in the form of immuno-supplementation with bovine milk antibodies has been shown to be an effective means of providing local protection to the GI tract against disease. Bovine immunoglobulin in the form of specific antibody has been shown to be effective against various enteric diseases. In trials it has been successfully shown that specific antibodies in bovine milk are effective against both enteropathogenic and enterotoxigenic Escherichia coli, cryptosporidium, rotavirus, and Shigella flexneri (8, 9, 10, 11, 12, 13, 14).

Bovine IgG s

The cow is an ideal source of natural occurring antibodies. Though all species of mammals have antibodies to various pathogenic microbes, the established supply and volume of cow's milk available, make this species an ideal candidate as a source of the natural antibodies.

Safety of Bovine Immunoglobulins

The manufacture and use of dairy products, and their associated safety and nutritional benefits is well known. One of the best sources of bovine colostrum is from the early milk of pasture fed, non-immunised healthy New Zealand cows. New Zealand milk products are renowned world-wide for their quality and consistency in both manufacture and supply. Thorough quality management of the entire manufacturing process, from collection of the milk, through to packaging and storage, ensures the colostrum is delivered in perfect condition, certified to be fit for human consumption. Testing laboratories and all manufacturing facilities are certified by international quality auditors to ISO 9001 standards.

Efficacy: - Antibody Activity, Specificity, and Titre

The antibody activity, antibody specificity, and relative antibody titre (quantity) of the colostrum products may be determined by way of enzyme linked immunosorbent assay (ELISA). Utilising this technique specific antibodies to the following microorganisms have been identified:

Pathogen

Stability

An important consideration is the stability of antibodies in the digestive tract. In a study conducted to ascertain the stability of bovine immunoglobulins to proteolytic digestion it was revealed that antibodies which possess specific activity can pass through the gastrointestinal tract of infants without being completely destroyed (7). This indicates that the specific action of antibodies in the gastrointestinal tract is not adversely affected and that biological activity is retained.

References

1. Brambell, F. W. R. (1969). In The Transmission of Passive Immunity From Mother to Young. Vol. 18. Am. Elsevier Publishing Co., New York.

2. Penhale, W. J., Logan, E. F., Selman, I. E., Fisher, E. W. and McEwan, A. D. (1973). Observations on the adsorption of colostral immunoglobulins by neonatal calf and their significance in colibacillosis. Ann. Rech. Vet. 4: 223-229.

3. Smith, T. and Little, R. B. (1922). The significance of colostrum to the newborn calf. J. Exp. Med. 36: 181-186.

4. McEwan, A. D., Fisher, E. W. and Selman, I. E. (1970). Observations on the immunoglobulin level of neonatal calves and their relationship to disease. J. Comp. Path. 80: 259-263.

5. McGuire, T. C., Pfeiffer, N. E., Weikel, J. M. and Bartsch, R. G. (1976). Failure of colostral immunoglobulin transfer in calves dying from infectious disease. J. Am. Vet. Med. Assn. 169: 713-716.

6. Pahud, J. J., Hilbert, H., Schwartz, K., Amster, H., and Smiley, M. (1981): Bovine milk antibodies in the treatment of enteric infections and their ability to eliminate virulence factors from pathogenic E. coli. In: The Ruminant Immune System, edited by J. E. Butler, pp 591-600. Plenum, New York.

7. Hilpert, H., Gerber, H., Amster, H., Pahud, J. J., Ballabriga, A., Arcalis, L., Farriaux, J. P. de Peyer, E., and Nussle', D. (1977): Bovine milk immunoglobulins (Ig) and their possible utilisation in industrially prepared infant's milk formulae. In: Food and Immunology, Swedish Nutritional Foundation Symposium XIII, edited by L. Hambraeus, L. A. Hanson, and H. McFarlane, pp 182-196. Almquist and Wiksell, Stockholm.

8. Mietens, C., Keinhorst, H., Hilpert, H., Gerber, H., Amster, H. and Pahud, J. J. (1979). Treatment of infantile E. coli gastroenteritis with specific bovine anti-E. coli milk immunoglobulins. Eur. J. Ped. 132: 239-52.

9. Tacket, C. O., Losonsky, G., Link, H., Hoang, Y., Guesry, P., Hipert, H. and Levine, M. M. (1988). Protection by milk immunoglobulin concentrate against oral challenge with enterogenic Escherichia coli. Eng. J. Med., 318: 1240-1.

10. Tzipori, C. O., Binion, S. B., Bostwick, E., Losonsky, G., Roy, M. J., and Edelman, R. (1986). Remission of diarrhoea due to cryptosporidosis in an immunodeficient child treated with hyperimmune bovine colostrum. Brit. Med. J., 293: 1276-7.

11. Ebina, T., Sato, A., Umezu, K. Ishida, N., Ohyama, S., Oizumi, A. Kitaoka, S., Suzuki, H., and Kunno, T. (1985). Prevention of rotavirus infection by oral administration of cow colostrum containing antihuman rotavirus antibody. Med. Microbiol. Immunol., 174: 177-85.

12. Brussow, H., Hipert, H., Walther, J., Sidoti, J., Meitens, C., and Bachman, P. (1987). Bovine milk immunoglobulins for passive immunity to infantile rotavirus gastroenteritus. J. Clin. Microbiol. 25: 982-6.

13. Hilpert, H., Brussow, H., Meitens, C., Sidoti, J., Lerner, L., Werchau, H. (1987). Use of bovine milk concentrate containing antibody to rotavirus to treat rotavirus gastroenteritis in infants. J. Infect. Dis., 156: 158-66.

14. Tacket, C. O., Binion, S. B., Bostwick, E., Losonsky, G., Roy, M. J., Edelman, R. (1992). Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge. Amer. J. Trop. Med. Hyg., 47: 276-83.