Defence Mechanisms of the Udder, Part two: Enhancement of the defence mechanisms of the udder

There are many management and pharmacologic procedures that might increase the effectiveness of the non-specific defence mechanisms of the udder.

Though individual research workers have a tendency to emphasise one component of the defence mechanisms of the udder over another, in reality they may function in a mutually beneficial way to eliminate an invading mastitis causing organism (MCO, Smith et al 1977).

Increasing of the non-specific defence mechanisms of the udder

There are many management and pharmacologic procedures that might increase the effectiveness of the non-specific defence mechanisms of the udder. Nowadays, most of the efforts toward mastitis prevention have focused on management practices.

Selection.

Despite traditional disease control measures, losses attributable to mastitis continue to impede the dairy industry. An alternative approach to this problem is genetic mastitis resistance involving both immune and non-immune mechanisms. Mastitis resistance is the inherent capacity of a previously unexposed animal to resist disease when challenged by MCO (Adams and Templeton 1998).

Genetic variations in resistance to mastitis has been shown with regard to mastitis and high milk cell counts in cows (Hibbit et al 1995; Rupp and Boichard 2003) and should be considered as a complementary way to improve mastitis resistance in dairy cattle (Hibbit 1985; Rupp and Boichard 2003). Selection should aim to increase the overall level of genetic resistance at both herd and population levels by using selective breeding programmes and optimal combination of mastitis related traits and associated predictors, such as udder morphology (Adams and Templeton 1998; Cassel 1994; Rupp and Boichard 2003).

Up to the mid-90s, in most countries, breeding objectives focussed on production traits (mainly protein and fat yield), milk composition (protein and fat contents), and several morphological traits, particularly capacity and udder type. In many countries, frequency of clinical mastitis increased over time, at least in the Holstein population. This trend resulted from the inverse relationship between milk production and mastitis resistance (Rupp and Boichard 2003).The Scandinavian countries were an exception with a more diverse breeding objective including many functional traits and, particularly, mastitis resistance and lower SCC. In the last five years, the continuous and unfavourable trend for fertility and mastitis susceptibility has led most European dairy populations to update their breeding objective and to increase the weighing of non production traits (Rupp and Boichard 2003).

Milking speed is antagonistic to SCC: fast milking cows are generally found to have a large number of SCC in milk (Rupp and Boichard 2003), but a relationship between milking characteristics and the incidence of intramammary infection (IMI) is not universally accepted (Hibbitt et al 1995).

Selection against extremes of teat length are advisable for proper milking machine function. If teats are too long to allow complete collapse of the liner beneath the teat or to short to be compressed by the collapsed liner, problems may occur (Mein et al 2004).

The heritability of fatty acid composition in the keratin of the teat canal is fairly high and selection for resistant cows through genetic transmission may be advantageous (Nickerson 1985).Keratin from mastitis-resistant quarters contains high concentrations of lauric, myristic and palmitoleic acid; whereas stearic, linoleic and oleic acids are increased in susceptible quarters (Nickerson 1985).

The selection for mastitis resistance based on decreased SCC is now used in many countries. Due to the increased incidence of mastitis caused by environmental MCO, the question of whether SCC should be decreased to the lowest possible value or a critical threshold (Rupp and Boichard 2003) has been raised, because the cows with low SCC have been shown to be more susceptible to environmental mastitis.

Difference in mastitis incidence between breeds is marked. These genetic differences could be estimated in herds with different breeds. Dairy breeds originating from eastern France (Montbéliarde, Abondance) or central Europe (Simmental, Brown Swiss) have a lower SCC and clinical mastitis frequency than the Holstein. Within breed, genetic variability is also quite large (Rupp and Boichard 2003).

Nutrition.

The diet of a dairy herd plays an important role on cow productivity, general ability to resist disease and health. Nutritional relationships to host defence mechanisms have led to the idea of increasing the resistance of dairy cattle to mastitis through nutrition. Not only gross malnutrition, but also merely suboptimal levels of any one micronutrient is sufficient to affect mammary gland (MG) immunity adversely. Mastitis control programs should ensure that proper levels of all macro- and micro- nutrients are maintained in all cows at all times. The key to ensuring adequate levels of these important micronutrients is direct testing of animals at the herd level to delineate patterns in overall nutrient deficits (Sordillo et al. 1997). Provision of dietary supplements of the deficient vitamins or minerals in accordance with accepted doses is one practical means to enhance the inherent defence of the cow against invading MCO. However, supplementation sometimes works and sometimes does not. The reason for this is not known yet.

Deficiencies of the following vitamins and minerals have been shown to be related to increased incidence of clinical or sub-clinical mastitis, increased severity of infection, or elevated somatic cell counts: Se, Vitamin E, Vitamin A, b-carotene, copper, cobalt, and zinc (Hibbit 1985; Hibbit et al. 1995; Morgante et al. 1999; Oldham et al 1991; Paape et al. 2003; Scaletti et al. 2003; Smith et al. 1997; Sordillo et al. 1997; Woolford et al 1996).

Vitamin E and Se are essential micronutrients that share common biological activities and are integral components of the antioxidant defence of tissues and cells (Paape et al 2003; Smith et al. 1997). Both nutrients as well as Vitamin A, b-carotene, vitamin C, zinc, and copper function to maintain low tissue concentrations of the oxygen metabolic products (Smith et al. 1997). The importance of b-carotene, zinc and copper in mastitis control is less well documented, but all are important and deficiencies in any could lead to increased incidence of mastitis (Smith et al. 1997).

Dietary supplementation of mammals with Vitamin E and Se is important to maintain host defence mechanisms, including antibody production, cell proliferation, cytokine production, prostaglandin metabolism, and polymorphonuclear neutrophils (PMN) function (Hogan et al. 1993). As discussed previously, the PMN are a major defensive mechanism against infection in the bovine MG. One of the known consequences of Vitamin E and Se deficiency is impaired PMN activity. Vitamin E and the Se-containing enzyme, glutathione peroxidase, are antioxidants that protect PMN from the destructive action of toxic oxygen molecules necessary for intracellular kill of ingested MCO (Hogan et al. 1992; Hogan et al. 1993). Vitamin E and Se are important for optimal immune functions associated with T and B lymphocytes (Hogan et al. 1993) and results in a more rapid PMN influx into milk following IMM challenge by MCO, increased intracellular kill of ingested organisms by PMN (Hogan et al. 1992; Hogan et al. 1993; Paape et al 2003; Smith et al. 1997; Sordillo et al. 1997), reduced rates and duration of clinical mastitis (Hogan et al. 1993; Paape et al 2003; Smith et al. 1997; Sordillo et al. 1997; Weiss et al. 1990) and decreased SCC (Hogan et al. 1993; Jukola et al. 1996; Smith et al. 1997; Weiss et al. 1990). Therefore, herd management practices that result in optimal Vitamin E and Se status of dairy cows also optimise neutrophil responses and increase resistance to IMI (Hogan et al. 1993).

Selenium is probably the best characterisedmicronutrient with regard to immuno-regulatory effect (Sordillo et al. 1997). It is an essential micronutrient present in tissues throughout the body. Se is important physiologically because it is an integral component of the enzyme glutathione peroxidase(Hogan et al. 1993; Smith et al. 1997; Sordillo et al. 1997). During the metabolism of oxygen within cells, large quantities of superoxide and hydrogen peroxide are produced and these reactive oxygen species can severely damage membrane lipids, DNA, cellular proteins, and enzymes. The specific function of glutathione peroxidase is the conversion of hydrogen peroxide to water and lipid hydroperoxides to the corresponding alcohol (Smith et al. 1997). Tissue concentrations of Se are correlated with GSH-Px activity and are directly related to dietary intake (Hogan et al. 1993). Deficiencies in Se result in compromised PMN function, which is a primary effector cell inthe initial elimination of infections, at selenium concentrations considerably above those known to cause nutritional muscular dystrophy (Smith et al 1988).The Se-supplemented cows had more rapid SCC response following challenge, maintained lower bacterial colony-forming units per milliliter of milk, eliminated IMI more rapidly, and had less severe clinical signs than did unsupplemented cows.

Vitamin E supplementation of diets increased intracellular kill of S.aureus and E.coli by bovine blood PMN but had no effect on phagocytic index (Hogan et al. 1993). Vitamin E, which is similar to Se in its biological properties, is an important component of all cell membranes (Jukola et al. 1996; Smith et al 1997; Sordillo et al. 1997). However, deficiencies in both Se and Vitamin E generally place cows at higher risk to mastitis, than a deficiency of just one of them. Se and Vitamin E used separately are able to mitigate the severity of the clinical symptoms of mastitis and to shorten their effects; used together, they are even more efficacious. The effects of Vitamin E and Se supplementation on intracellular kill of MCO by PMN are not additive (Hogan et al. 1993). Vitamin E provides stability and inhibits autoxidation of polyunsaturated fatty acids in PMN membranes (Hogan et al. 1993; Hogan et al. 1992; Smith et al. 1997; Sordillo et al. 1997). Vitamin E is localised in cellular membranes in close proximity to oxidase enzymes that initiate the production of free radicals. Polyunsaturated fatty acids located in the vicinity of the oxidase enzymes are protected from peroxidation by Vitamin E. Vitamin E inhibits autoxidation of polyunsaturated fatty acids in PMN membranes and enhances their function (Hogan et al. 1992). Vitamin E also plays a regulatory role in the biosynthesis of various inflammatory mediators, is necessary for the integrity of integument and wound healing, and has shown immuno-stimulatory effects, both cellular and humoral. A major source of vitamin E for dairy cows is forages, but the concentration of a-tocopherol in forages decreases asplants mature. Substantial loss of Vitamin E also occurs when feedstuffs are processed and stored (Hogan et al. 1993).Another concern regarding the cow’s Vitamin E status is that its concentrations in blood plasma normally decline during the transitional period partially due to decreased feed intake (Hogan et al. 1992; Smith et al. 1997). Concentration of plasma a-tocopherol typically decreases 7 to 10 d prior to calving and remains low during the first 1 to 3 wk of lactation, even when the dietary Vitamin E offered to cows is constant throughout this period (Hogan et al. 1992; Hogan et al. 1993). Because of its positive role in immunity and the widespread potential for deficiency in farm animals, vitamin E supplementation could provide great benefit to the control of bovine mastitis. Parenteral administration of Vitamin E successfully elevated a-tocopherol concentrations in plasma and PMN during late gestation and early lactation periods (Hogan et al. 1993). Vitamin E has immuno-enhancing properties when incorporated into vaccines (Hogan et al. 1993; Smith et al. 1997). Positive attributes ascribed to Vitamin E in adjuvant systems include detoxification of reactive oxygen radicals generated at the sites of injection during antigen processing and presentation by immune cells (Smith et al. 1997).

Vitamin A (Vitamin A) and its precursor, b-carotene, have long been known for their effect on vision, normal cell growth, epithelial cells, and therefore mucosal surface integrity and stability (Sordillo et al. 1997). In the MCO killing after phagocytosis, toxic oxygen compounds are produced inside the cell. The cells are protected from these compounds by Vitamin E and b-carotene (Jukola et al. 1996).Both Vitamin A and b-carotene have been shown to have stimulatory effects on immune cell populations and have been correlated with a generally increased resistance to mastitis (Jukola et al. 1996; Sordillo et al. 1997). Vitamin A deficiency has been linked to increased glucocorticoid response to stress, which has an immunosuppressive effect. b-carotene can act independently as an oxygen radical scavenger and is incorporated into cell membranes as such (Sordillo et al. 1997). A sufficient intake of Vitamin A guarantees the normal function of epithelia, which might improve the defences of the MG against infections (Jukola et al. 1996). Supplementation with both of these nutrients improved the status of clinical mastitis over the provision of Vitamin A alone, indicating a protective role of b-carotene that is independent of its function as precursor to Vitamin A. (Sordillo et al. 1997).However some trials found that Vitamin A and b- carotene have no impact on mastitis resistance in dairy cattle (Oldham et al. 1991).

Copper (Cu) is an essential element in the antioxidant Cu-dependent enzyme superoxide dismutase and in the serum protein ceruloplasmin, which is recognised as an acute phase protein in cattle. These two proteins are important to immune function, partially because of their protection of cells from oxidative products released by phagocytosis and killing by leukocytes (Sordillo et al. 1997).Due to the large copper demand of the fetus, copper status of cows tends to be lowest at calving. In one of the trials (Scaletti et al. 2003), with E.coli challenge, the Cu-supplemented animals had lower microbial counts, lower SCC, lower clinical scores, and lower peak rectal temperature than responses in Cu-un-supplemented animals. The decreased clinical severity could be due to increased capability of PMN in supplemented animals to kill the invading E.coli (Scaletti et al. 2003; Sordillo et al. 1997).

The potential role of zinc (Zn) sequestration during acute mastitis is more obscure (Erskine and Bartlett 1993). Zinc is essential for the integrity of skin, the first physiologic barrier to infection (Sordillo et al. 1997).In addition to improved skin health and integrity, zinc also speeds wound healing. Another mode of action for zinc improving udder health is related to its role in keratin formation. Zinc is also a component of the antioxidant Zn-dependent superoxide dismutase and likely to have a stabilising, antioxidative role in cellular membranes and therefore protects those membranes from damage. Mobilisation of leukocytes, fever, increases in serum cortisol, increases in serum concentrations of proteins (such as fibrinogen, complement, haptoglobin, and ceruloplasmin), and transient decreases of serum iron (Fe) and Zn are acute phase events that have occurred in cows as a result of mastitis(Erskine and Bartlett 1993). Deficiencies in Zn predispose the cow to secondary infections, which can be reversed by supplementation (Sordillo et al. 1997). The problems associated with Zn insufficiencies can be exacerbated by high Ca diets, a common condition of cows during early stages of lactation (Sordillo et al. 1997).

Iron- Gram-negative bacteria require Fe for growth, and decreased Fe may be a host defence mechanism to limit bacterial growth (Erskine and Bartlett 1993). During the MCO killing oxygen radicals are released as a result of phagocytic function and from endotoxin-induced inflammatory mediators. Free radicals are potentially harmful to host cytosol and membrane systems and some defences to neutralise them exist. Iron is a catalyst for lipid peroxidation and radical formation. Therefore, Fe sequestration during acute Gram-negative mastitis plays an antioxidative role (Erskine and Bartlett 1993).

Enhancement of PMN activity.

The recruitment of circulating PMN from the blood to the site of infection and killing ability of cells, as well as type of cells present in milk, is essential for the defence of the bovine MG against invading MCO (Riollet et al. 2000).The promptness of PMN mobilisation can dramatically influence the outcome of infection. Nevertheless, milk is not a favourable medium for phagocytosis by PMN, and PMN can exert a deleterious effect on the inflamed tissue under certain circumstances (Rainard and Riollet 2003). There are many other parameters such as the activation status of the PMN, their essential antimicrobial activity, the presence of opsonising and toxins neutralising antibodies, which have to be taken into account (Rainard and Riollet 2003) when PMN activity is analysed.

To stimulate the early recruitment of PMN, there is a possible way which exploits the genetic regulation of the acute inflammatory reaction (Rainard and Riollet 2003). It is possible to increase the intensity of the recruitment of PMN by the MG in response to a particular antigen, by local or systemic immunisation, and all the observations are in favour of mediation by the T lymphocytes (Rainard and Riollet 2003; Sordillo et al. 1997). The increased phagocytic efficiency per PMN via specific antibodies, particularly opsonins, may decrease the number of milk PMN needed to protect the MG against new IMIs.

Concurrent disease.

Increased incidence of diseases such as hypocalcaemia, ketosis, and displaced abomasums are associated with increased incidences of clinical mastitis due to decreased cows’ resistance and increased recumbency leading to higher exposure to environmental MCO. Thus preventing the occurrence of these diseases should help to lower the new mastitis cases.

Maintaining the integrity of the anatomic barriers prevents MCO the opportunity to invade unprotected tissue. Teat lesions are important in the epidemiology of mastitis, so their prevention reduces the risk of mastitis. Teat sores and cracks provide sites where MCO can multiply. They also lower the effectiveness of milking and under-milking occur. Incomplete milk-out increases the incidence of clinical mastitis or slows the resolution of clinical signs in quarters that are already infected (Bramley et al 1992; McDonald 1971). The large numbers of MCO and toxins left in the gland after milking impair local defence mechanisms leading to an exacerbation of mammary inflammation (Bramley et al 1992). Correct milking procedures, properly functioning milking equipment and the use of emollients with post-milking disinfection, are some of the procedures involved in the prevention of teat lesions.

Pharmaceutical preparations

1. Non-antibiotic preparations

Non-antibiotic approaches to the control of bovine mastitis could occur through enhancement or manipulation of the natural defence factors in the mammary gland. As concern over the possible overuse of antimicrobials increases, attention has focused on reduction of their usage and trying to find some alternatives (Berry and Hillerton 2002). There is also an increasing interest in organic dairy production; it is a growing niche market that specifies that antibiotics not be used as prophylactics (Berry and Hillerton 2002).

Teat sealants. They provide a non-antibiotic approach to protecting uninfected cows from environmental MCO during the dry period (Green et al 2002). Teat sealants are inert compounds that physically prevent MCO from entering the MG through the teat end, an intervention that mimics the natural defence mechanism of a keratin plug, closing each teat canal at drying-off (Godden et al. 2003).

One management tool that may be used to prevent new IMI during the dry period is an external teat sealant. Various types of external teat seals have been available for some time to limit exposure of the teats to MCO invasion. Once applied, these products dry to generate latex, acrylic, or other polymer-based film over the teat that prevents entry of MCO into the teat canal. They have had only limited success in reducing IMI during the dry period, largely due to poor persistence on the teat (Berry and Hillerton 2002; Godden et al. 2003).

An alternate management tool may be the use of an internal teat seal. This inert viscous paste is infused into the quarter at time of dry off forming an immediate physical barrier in the distal portion of the teat cistern to prevent bacteria from ascending through the teat canal. Insoluble in milk, it has no antimicrobial properties and no residue or food safety risks. The majority of the internal teat seal product is stripped out at first milking after calving, with some residual product removed in the subsequent several milkings after calving (Godden et al. 2003; Green et al 2002).

Teat sealants will benefit potentially all cows, but it will be of particular benefit to those cows that have teat canals of wide diameter or less effective mechanisms for closure of the teat orifice, commonly called cows with “open teat canals”. Such cows are therefore vulnerable to infection (Berry and Hillerton 2002; Green et al. 2002) - particularly in the early dry period before the keratin plugs have formed in the teat canals and around calving when they have been lost from many teats. The benefits could be significant as typically 20% of quarters may not have an adequate keratin plug after 30 days after drying-off and 5% of teats never form one (Green et al. 2002). An internal teat seal may be useful as an alternative to dry cow treatment (DCT) for the prevention of new IMI during the dry period, when infused into uninfected quarters at dry off (Godden et al. 2003).

Cytokine immunotherapy.The possibility of enhancing resistance level of the mammary gland with some cytokines as IL-2, has received considerable research attention. Recent studies have shown that intramammary administration of some cytokines such as bovine IL-2 can enhance cellular and humoral immune responses against S.aureus and coliforms. Prophylactic administration of IL-2 has been shown to protect the mammary gland from subsequent intramammary challenge with S.aureus. (Sordillo et al. 1991; Sordillo et al. 1997). The use of cytokines by IMM administration routinely is not yet developed. However, research into the role of cytokines in bovine mastitis is in the beginning stages. Further developments in these areas are necessary before experimental findings can be transferred to field conditions (Sordillo et al. 1997).

Bovine lactoferrin.There is some experimental data suggesting that application of bovine Lf in the early non-lactating period might increase the cure rate through the induction of non-specific immunity in the host (Erskine et al 1997; Kai et al 2002; Kutila et al 2003; Kutila et al 2004).

Increasing the specific resistance factors of the udder

There are two opinions on the role of immunological intervention in mastitis control programmes. The first believes that it is not possible to generate protective immunity in the MG and that control measures will have to be directed towards management, therapeutic strategies and genetic selection. The second opinion voices that vaccination has a role in a mastitis control programme. This latter view is derived from an improved knowledge of the bovine immune system and from research reports which indicate that heightened resistance to certain MCO can be generated. It is necessary to state that there are many unsolved problems in bovine mammary immunity and that there are also conflicting results and unsubstantiated reports (Hibbitt et al 1995; Kenny et al 1995). The MCO that account for over 99 per cent of bovine clinical mastitis have one common feature. This is the lack of a commercial vaccine to prevent disease in humans caused by the same causative organisms or strains (Kenny et al 1995).

A sound understanding of the problem requires knowledge of the nature of the organisms causing mastitis and their antigenic variation. For example there are many variants of S.aureus and a vaccine developed against one strain may not give protection against another. There is the issue of where and when to administer the vaccine, for example systemically or locally, during the dry period or during lactation. There are issues associated with the type of response enhancement of IgG may not give the same protection as enhancement of IgA or a cell response.

Vaccination.

Vaccination programs are designed to potentiate the immune system of the host toward a unique, specific antigen (Sordillo et al. 1997). For mastitis vaccines, eliciting a prompt recruitment of PMNs to the site of infection can stimulate the production of specific antibody.

Immunisation can enhance PMN recruitment through the release of inflammatory mediators by localised antigen-specific lymphoid populations (Hibbit et al 1995; Sordillo et al. 1997). Specific antibodies are required for the opsonisation of MCO and the promotion of phagocytosis by mammary gland populations of PMNs. In addition to serving as opsonins, antibodies may neutralise organisms’ toxins, interfere with adherence mechanisms of organisms and induce cell lysis of the invading MCO. Immunisation protocols that are capable of potentiating these essential bactericidalcomponents should contribute to the effective control of mastitis.

Mastitis vaccines are expected to eliminate chronic IMI, prevent the establishment of new IMI, and reduce the frequency and severity of clinical disease (Sordillo et al. 1997). Vaccines that are currently available apparently do not consistently reduce the incidence of new IMI or eliminate chronic mastitis. However, several recently available vaccines have effectively reduced the incidence and severity of clinical mastitis (Sordillo et al. 1997).

Considerable progress has been made over the last several years in the development of an effective mastitis vaccine against coliform mastitis (Sordillo et al. 1997). To protect against coliform mastitis it is important to stimulate antibody-production with maximal antibacterial and opsonic effect. Initial studies showed that cattle with low pre-existing serum titres against common Gram-negative core antigens were more susceptible to clinical coliform mastitis than were cows with higher titres. Gram-negative core antigens have immunologic homology across organism species. Typically, these antigens are masked by the immuno-dominant O polysaccharide. Animals immunised with killed mutant organism, E. coli J5, are able to produce antibodies to the core region and are partially protected from challenge with heterologous live organisms. Experimental challenge models of E. coli mastitis have indicated that vaccination with J5 bacterins decreases clinical severity but does not prevent infection (Smith et al 1999), reduces the concentration of E. coli in milk, and is beneficial for multiparous cows as well as primigravid heifers (Smith et al 1999). Despite the potential benefits, these vaccines cannot overcome poor environmental conditions. The practical application of coliform mastitis vaccines is as a supplement to traditional methods of mastitis control based on good management and nutritional practices (Sordillo et al. 1997).

Numerous attempts have been made to ameliorate or to prevent S. aureus mastitis through vaccination programs. Many of the earlier studies used systemically injected bacterins derived from in vitro grown cultures. Increased milk antibody titres were effective in lessening the severity of disease but had no effect in preventing new IMI (Radostits et al 1994). Newer trials are with vaccines against anti-phagocytic properties of S. aureus. Experimental trials are promising (Sordillo et al. 1997).

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Author

Kiro R.  Petrovski

Kiro R. Petrovski
3 articles

Senior research officer, Institute of Veterinary, Animal and Biomedical Sciences, Massey University, New Zealand

A native of the Republic of Macedonia in Europe, Kiro R Petrovski began working with dairy cows at age 11. With a lifelong interest in animals and animal health, he completed his primary, secondary and tertiary education in Macedonia, then graduated from the Veterinary Faculty Skopje in 1997. Following graduation, he worked in a mixed animal practice and a dairy farm in Macedonia until mid 1999 when he moved to New Zealand. He is currently working at theSchool of Animal and Veterinary Sciences at the University of Adelaide. 

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