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Understanding Immunology- Is It Possible- How to use the Immune system to our advantage Chris Chase Department of Veterinary and Biomedical Sciences South Dakota State University, Brookings SD Immunity The immune system consists of three lines of defense systems: barriers, innate immunity and adaptive or acquired immunity (Figure 1) that work together to give cattle protection from disease. Figure 1 The barrier system is probably the most overlooked but it eliminates 99.9% of all infections. This system is very susceptible to dehydration and changes in microbial populations. The innate system is the first to be activated and responds almost immediately (Figure 2). The adaptive response follows up 10-14 days later in naïve animals. The cumulative effect of these hormones is to suppress the immune system and to direct the immune response away from the memory response to the short-term antibody immune response. Figure 2 Stress, Immunosuppression, Nutrition and Immunity There is ample evidence that both physical and psychological distress can suppress immune function in animals, leading to an increased incidence of infectious disease (Figure 3). Figure 3 Reiche et al. 2004. The Lancet Oncology 5:617-625. Excess heat or cold, crowding, mixing, dehydration, weaning, calving, limit-feeding, shipping, noise, and restraint are stressors that are often associated with intensive animal production and have been shown to influence immune function in cattle. Also, social status, genetics, age and the duration of stress (chronic vs. acute) have been shown to be important in the animal’s response to stress (Figure 4). Figure 4 Nutritional Influences on Immunity The immune system does not get a free ride when it comes to nutrition. The immune requires energy, protein, vitamins and trace minerals. Both malnutrition and overfeeding may result in impairment of immune function and increased susceptibility to disease due to a deficiency or excess of proteins or calories, or a relative imbalance in vitamin or trace mineral content. Animals under intensive production conditions typically have a completely controlled diet. Therefore, it is very important that the diet, especially the vitamin and trace mineral content, be optimally formulated. Key vitamins and minerals for optimal immune function include vitamins A, C, D E, and the B complex vitamins, chromium, cobalt, copper (Cu), zinc (Zn), magnesium (Mg), manganese (Mn), iron (Fe), and selenium (Se). Calves often face a challenge associated with low trace mineral levels. This is due to low dry matter intakes and stress, which causes excretion of trace minerals. Zinc is involved in protein synthesis and, thus, antibody formation, cell differentiation, and enzyme formation and function. Zinc also plays a major role in mucosa and skin integrity, the first line of defense of the immune system. Copper and manganese are directly involved with cell-mediated immunity and protein matrix formation during the healing process. Copper has been linked with the ability of isolated neutrophils to kill yeast and bacterial infections. Manganese plays a role in facilitating the "germ-killing" function of macrophages. The balance of these constituents is especially important since excess or deficiency in one component may influence the availability or requirement for another. Vaccine Principles Vaccination is an important component for the prevention and control of bovine bacterial and viral diseases. Intranasal vaccines have the advantages of inducing mucosal immunity, stimulating good immunity in young animals and are not being affected by maternal antibody. Maternal antibody interference to bovine viral diarrhea virus (BVDV) or infectious bovine rhinotracheitis (IBR) are less of a problem than it is for bovine respiratory syncytial virus (BRSV) but animals should receive their first parenteral dose at 1-3 months of age with subsequent boosters depending on the type of vaccine (inactivated vs. modified live) and re-vaccination 30 days prior to breeding. Adjuvanted MLV vaccines can overcome maternal interference. Another approach to assess the impact of maternal interference is to get a serum sample from ten to twenty percent of the calves (at 3-4 months of age) and measure BVDV, IBR and/or BRSV antibody titers to determine if maternal antibody titers are high. If they are high, then retesting could be done in 1-2 months later to determine if antibody levels are at levels low enough to provide a good vaccine response. Vaccines should contain both CP BVDV 1 and 2 even though there is some cross protection between Type I and Type II as the best protection comes from CP vaccines containing both Type I and II. NCP BVDV vaccines provide excellent cross protection with just a single type as does the Singer CP BVDV strain5. Vaccine Types Modified live vaccines (MLV) have been used because of the good antibody response, longer duration of immunity, fewer doses needed per animal and lower cost. These vaccines are administered intramuscular, intranasally or subcutaneously. MLV vaccines have drawbacks because they can contain adventitious agents and the MLV bovine viral diarrhea virus (BVDV) and infectious bovine rhinotracheitis virus (IBR) are immunosuppressive. Although the return to virulence in MLV viruses has been minimal, mutations will occur and there is some risk of new strains arising. The selective pressure from an animal’s immune response may lead to new phenotypes. MLV vaccines also fail to booster well vaccinated animals as active vaccine induced immunity neutralizes vaccine virus preventing the MLV from replicating and preventing a booster immune response. One of the more interesting developments has been the development of intranasal live bacterial vaccine containing M. hemolytica and P. multicida6. Inactivated vaccines contain chemically or physically treated bacteria, toxins and/or viruses so there is no danger of replication in the vaccinated animal of the pathogen or adventitious agents that maybe present in a MLV. Improved adjuvants have increased the scope and duration of inactivated virus immunity. They have several disadvantages including cost, and a more of doses required per animal. Inactivated vaccines generate cell-mediated responses18,19. Hypersensitivity reactions (allergic) also occur more often with inactivated vaccines. Interestingly there is ample evidence that inactivated vaccines can effectively boost MLV vaccines9,13,17. Timing of vaccination Vaccination at the time of arrival (and/or weaning) Vaccination programs are a routine practice in beef operations to protect cattle against bovine respiratory diseases (BRD). Numerous commercial vaccines for the prevention of BRD have been available since the 1950s. Current vaccine protocols recommend that calves be vaccinated prior to weaning or commingling, to provide protection against BRD. Unfortunately, many calves are not vaccinated prior to weaning or commingling into backgrounding lots, feedlots or pasture operations. These animals are at increased risk of viral infection and are predisposed to secondary bacterial pneumonia16. However the highly-stressed calf presents a unique problem, the vaccines may sometimes actually predispose the calves to more severe disease while on other occasions providing protection. The time from vaccination to onset of protection can play an important role in subsequent management of newly arrived cattle against BRD viral agents i.e. bovine herpesvirus 1 (BHV-1; IBR) bovine respiratory syncytial virus (BRSV) and bovine viral diarrhea virus (BVDV). Commercially available MLV vaccines administered to non-vaccinated low-stress calves at weaning or at arrival to feed yards will provide increased weight gains and protection to animals as early as 48 hr prior to an IBR exposure, at 5-7 days prior to a BVDV and 8 days prior to BRSV exposure. This protection is due to the innate immune response, which is activated within hours after exposure to modified-live vaccines or infectious virus. Frequency of vaccination No more than 1-2 doses of MLV or 2-3 doses of inactivated vaccines should be administered in young calves less than 4 months of age to develop good herd immunity against respiratory diseases. Interval between doses of vaccine In all animals following vaccination there is expansion in the populations of responding T- and B-cells. However, to have a complete and mature immune response, this T- and B-cell expansion must not only stop but also an active process of cell death (apoptosis) must also occur. This “waning process” allows “culling” T- or B-cells that may be poor responders or even cause autoimmunity to be removed by apoptosis. This whole process from vaccination to achieving mature immune response homeostasis takes at least 3 weeks. This fully developed mature primary response can then be boosted to get a true anamnestic secondary response. In many cases, cattle vaccine primary and booster doses are administered at two-week intervals. In young calves, this is done to provide an opportunity to make sure that the calves develop a primary response in the face of maternal immunity. The adjuvants that are used with most commercial vaccines provide superior immune development over older generation adjuvants like alum. Therefore, in most instances if primary vaccination occurs after 3 weeks of age, booster vaccination beyond three weeks and even longer will be efficacious. The dogma that revaccination must occur within two weeks of the primary vaccination is not true and the anamnestic response will be better if we wait longer Summary Management of the calve’s immune system is not a simple process. It is important that vaccinations be given at optimal times and that vaccination is not overused. Vaccination can never overcome poor management. Understanding Immunology- When It Comes to Immunity Can We Have Too Much of a Good Thing?? Chris Chase Department of Veterinary and Biomedical Sciences South Dakota State University, Brookings SD Immunity, negative energy balance, microflora and cytokine storm. The immune system is a major consumer of energy and in times of negative energy like seen in the newly weaned calf can be difficult times for the immune to respond. In addition, the mobilization of energy from adipose tissue (fat) results in infiltration of macrophages as activity of adipocytes (fat cells) results in inflammation. These macrophages are particularly sensitive to signals from gut bacteria including endotoxin from gram-negative bacteria. With changes diet that occur at weaning or at parturition for the dairy cow the microflora changes are considerable changing populations. This combination of adipose remodeling, macrophage activation and microflora can result in a cytokine storm (Figure 1). A cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors). It is an overreaction of the immune system. Both pro-inflammatory cytokines [such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1, and Interleukin-6] and anti-inflammatory cytokines (such as interleukin 10 and interleukin 1 receptor antagonist) are elevated in the serum of people or animals experiencing a cytokine storm. It is believed that cytokine storms were responsible for many of the human deaths during the 1918 influenza pandemic, which killed a disproportionate number of young adults. In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results also indicated this as the probable reason for many deaths during the SARS epidemic in 2003. Human deaths from the bird flu H5N1 usually involve cytokine storms as well. Recent reports of high mortality among healthy young adults in the 2009 swine flu outbreak has led to speculation that cytokine storms could be responsible for these deaths, since the Swine Flu results from the same influenza strain as the Spanish Flu of 1918. Figure 5Tisoncik JR et al. Microbiol. Mol Biol Rev. 2012; 76:16-32. Immunity in the stressed calf. In the stressed calf, there are several factors that will compromise immune function. There is the stress of transportation, dehydration, feed change (with the resulting negative energy balance), acidosis, and associated microbial changes in the gut. There is clear evidence that waiting at least 2 days and preferable as long as 2 weeks before vaccination will result in better immunity and less sickness in that adjustment period after the stress. The issues that were described above for the activation of a cytokine storm are present in the stressed calf. The good news is that the macrophage activation in the stressed calf occurs over a much shorter period, so once the calves are back on feed and the microbiota is stable, the opportunity for the cytokine storm lessens dramatically. Immunity in the postpartum period. The common practice of vaccinating during the fresh period (15-45 days in milk) is an immunological challenge for dairy cows due to the negative energy balance associated with the high-energy demands and the low dry matter intakes typically observed postpartum. The requirement of the immune system for energy becomes a secondary requirement compared to lactation Depression in postpartum leukocyte function has been correlated to shifts in leukocyte trafficking patterns. The alteration in the proportions of the peripheral blood lymphocyte subset has been monitored in dairy cows during the pre-partum and post-partum periods. The variation of T cells was significant during the peripartum period, particularly around parturition. B cell and MHC II + populations remained constant until after calving and then decreased, returning to the initial subset proportion by Week 16. A decrease in the total number of T lymphocytes and changes in the T subpopulation have been reported in peripheral blood. In our research, we found that production, mastitis and reproductive health were improved in cows vaccinated in the prepartum period as compared to cows vaccinated in the postpartum period. Approximately 30% of dairy cows suffer sub-clinical ketosis during the fresh period because of the negative energy balance. The pathogenesis of this phenomenon is explained by the metabolic changes that occur when nutrient intake, particularly energy, does not meet production demands. In high-producing cows this metabolic disorder usually occurs from a few days up to six weeks post-calving, with the highest incidence occurring at about three weeks post-partum. Most high-producing cows undergo sub-clinical ketosis in early lactation when they are unable to consume enough energy to meet demands. Cows in negative energy balance are utilizing body fat and protein stores because of a drop-in blood glucose concentration (glycemia). When fat molecules reach the liver, they are converted to ketones, and elevate ketone levels in the blood. High levels of blood ketone bodies in blood interfere with the production of T cells and impair the chemotactic response of leukocytes. There is a link between elevated ketone levels and the risk of mastitis. In addition, subclinical ketosis results in increased pro-inflammatory cytokine production enhancing the cytokine storm (Figure 1). Since sub-clinical ketosis is present in nearly 30% of fresh dairy cows suggests vaccination during this period is probably not the best approach and that vaccinating during the dry period might be a better alternative. Evidence also exists that cows selected for high milk production traits, have an unfavorable correlated response in the functional capacity of immune functions traits. There is sufficient genetic variation in these immunological traits among sires of high genetic merit for milk production. Another consequence of peripartum cows feed disorders is hepatic lipidosis, a consequence of the fat cow syndrome. Upon vaccination, over-conditioned cows have lower humoral and cellular response when compared with cows with a low liver triacylglycerol (TAG) at Day 14 after vaccination. Cows in the transition period often face a challenge associated with low trace mineral levels. This is due to low dry matter intakes and stress, which causes excretion of trace minerals. Of concern are deficiencies in zinc, copper, chromium, manganese, cobalt, and selenium. The influence of these minerals on immunity was discussed above. Summary Management of the dairy cow and calves’ immune system is not a simple process. Stressors and nutrition often compromise immunity