It is generally understood that a healthy, well-immunized dairy or beef cow on a good plane of nutrition will produce high-quality colostrum. But the last four to five weeks of gestation is probably the most critical as that’s when most of the antibody to be transferred to the calf gets made by the cow, and is then brought from the circulatory system to the mammary gland. The cow must transfer a high level of nutritional values and essentially all the protective and priming immune components that she can offer for the systemic development of her calf in this one meal.
David Hurley, PhD, an immunologist at the University of Georgia College of Veterinary Medicine explains that many of these factors are transported from the circulation to the mammary gland, and others are produced in immune cell foci that are directly associated with the mammary gland.
“In either case, the mother is preparing to transfer protective and priming molecules that reflect the ‘dangers’ she has recently or is currently facing in her environment,” Hurley says. “The biology of late pregnancy changes the pattern of the immune response toward a high level of antibody and cytokine production than would be typical for a cow under other physiological conditions.”
Hurley adds that the thick placenta of the cow does not allow antibody, most growth factors or cytokines, or cells to cross to the fetus during gestational development. Thus, colostrum is the “lump sum” delivery of the maternal side of immune protection and immune triggers for development for the calf.
Derailing immunity factors
The effects of late pregnancy toward enhanced development of the lactation-related tissues and enhanced recruitment of cells, cytokines, growth factors and antibody from the circulation also prime the mammary gland for delivery of the calf, but this mammary development and enhanced immune response to environmental danger come at a considerable energy cost.
“Nutrition and stress at this time can have big effects on the production of colostrum and may lead to poorer colostrum quality as well as reduced quantity. Each can have an impact. Exposure to environmental pathogens and vaccines each impact the diversity of antibodies and cells in colostrum.” Thus, cows that do not receive enough protein and energy in late lactation (at times seen in the dry lot on the dairy or when beef cows deliver following a diet of low protein content hay in late winter) may have trouble providing for proper mammary development, a high level of immune response and the production of an optimal volume of rich colostrum. Reduced levels of protein and in total caloric intake have both been demonstrated to dramatically reduce the level of immune response in mammals.
The stress associated with late pregnancy and the high levels of stress-related hormones that are part of the process of delivery both limit the intake of feed, the activation of the immune system and anabolic metabolism. “In the last week before birth, much of the work to develop quality colostrum must have already been done,” Hurley says. “Induction of social, weather or other stress during the last 4–5 weeks of pregnancy can expand the window that leads to compromise in the development of colostrum in the late-pregnant cow.” Moving of late pregnant cows, change in their diets, and change in the grouping of cows during the last month can have a negative effect on the quantity and quality of
colostrum that is produced.
Hurley says immune stress, such as viral disease in cows, can have an impact on the level and diversity of antibody produced and exported to the mammary gland. “Timing of disease is important to the quantity and quality of colostrum.” Other health issues such as mastitis can also have a deleterious effect. “Inflammation in the mammary gland will change the dynamics of antibody and cell recruitment and often lead to increased exposure to pathogens present in colostrum,” Hurley adds. “This can lead to problems with the calf. It is likely to have an impact for several weeks, particularly if it is peri-partum mastitis, like Streptococcus uberis or Streptococcus aureus.”
Timely vaccination about 6–8 weeks prior to calving (or earlier in the pregnancy for some antigens) may help expand the pool of circulating antibodies and memory cells needed to transfer immune protection and priming to the calf, Hurley says. However, trying to catch up on cow health by vaccinating late in pregnancy or vaccinating stressed or malnourished cows may adversely affect colostrum quantity or quality.
Immune system at birth
The neonatal calf is born with all the components of the immune system that may be found in the adult circulating in its blood. In most cases these components have never been exposed to challenge from the danger that pathogens represent. “The immune system of the neonatal calf is very naïve,” Hurley explains. “It can be induced to mount responses that reflect what an adult would do under specific conditions, but the calf is not yet very good at the immune response process.”
The calf has a limited number of critical antigen presenting cells, few macrophages in the tissue, poorly developed secondary lymphoid tissues (like the lymph nodes) that are needed to provide a focused response by lymphocytes to make antibody or activated T-cells, and no memory lymphocytes to provide enhanced responses. The neonatal calf tends to respond to a high level of pathogen exposure by developing significant disease, and in some cases where a rapid response is required, even a low level of exposure to a pathogen can be a significant problem.
To allow the neonatal calf to survive, a multi-component process must occur that protects the calf in the short-term, expands the level of immune response in the intermediate-term and allows for strong development of an immune response network for long-term protection, Hurley says. This process is dependent on both the immune components transferred from the mother and the interaction of the calf with microbial flora it gradually becomes exposed to from the environment, including the mother
Components of colostrum
Antibody (particularly IgG1) transferred in colostrum is a critical element in arming the innate immune cells and molecules that circulate in the neonate toward the recognition of dangerous invaders early in life. “The IgG1 antibody readily crosses the gut during the first 24–48 hours depending on mostly when the first feeding occurs, by using special antibody transport receptors found on the neo-natal intestinal cells,” Hurley explains (see Handling of Colostrum and its Effect on the Neonate case study).
“We have not been able to demonstrate transfer of maternal leukocytes after about 24 hours in calves,” Hurley adds. Antibody from the mother, both IgG1 and IgA, appear to modulate the interaction in the gut of the neonate with microbes from the environment. “We do have good evidence of a salutary effect of continued milk ingestion on the health of the developing calf, which is easy to see when one looks at the incidence of disease in beef and dairy calves.”
IgG1 is the “perfect” component for the job of immediate protection in the neonate because: 1) it easily enters the circulation of the neonate, 2) it easily moves from the circulation to the tissues of the neonate, 3) it tends to have both strong binding affinity and binding avidity for many types of pathogens (it is the primary product of the pregnancy immune bias in the late gestation cow), and 4) many of the innate immune cells and molecules (such as monocytes, granulocytes and complement) are readily activated by IgG1-antigen complexes. “For these reasons, mother and neonate, working together can rapidly respond to and clear microbial invaders that enter the tissues of the neonate,” he says. “Further, antibody delivered by the mother was held in the mammary gland in very high concentration — the highest observed in nature. This leads to the aggregation of antibody molecules prior to transfer.”
These aggregates are transferred across the gut into to the circulation. The aggregates appear to have several additional functions in improving immune activity within the neonate. They appear to bind to monocytes and cause them to become “primed” to leave the circulation and enter the tissues. When this occurs, these long-lived monocytes differentiate into macrophages that provide sensing of dangerous pathogens and arming of local defenses. They also appear to interact with neutrophils present in the circulation at birth and to induce them to undergo apoptosis. This process releases cytokines that recruit the production of new and more neutrophils.
“This appears to be important because fetal neutrophils appear to be limited in function,” Hurley says. “We observed that neutrophils from the circulation of neonates respond weakly prior to the ingestion of colostrum, but much more strongly 24 hours after the ingestion of colostrum. They are fewer in number than in the adult, but a big increase in the percent of circulating neutrophils and their absolute number is observed after the ingestion of colostrum until the calf is about 2 weeks old. Thus, maternal antibody seems to play a direct role in immune competence of the neonate.”
The cells, cytokines and growth factors transferred to the neonate have a less clearly defined role in the immune development of the immune system. It has been demonstrated that maternal cells circulate in the blood of the neonate after ingestion of colostrum. “We know that the circulation of these cells begins within four hours of ingestion, peaks at 24 hours after ingestion, and cannot be readily observed after 36 hours after ingestion,” Hurley notes. “It has also been observed that labeled maternal cells can be found in secondary lymphoid tissues two days to three weeks after ingestion, but these observations are limited in number. Second, we know that after the ingestion of colostrum we observe a rapid and dramatic reduction in the percentage and absolute number of circulating lymphocytes in the neonatal calf that lasts for a period of about two to three weeks.” At birth the percentage of circulating lymphocytes in the neonatal calf is similar to or higher than observed in the mature cow.
It is hard to find lymph nodes in the neonate calf at birth and even for the first few days after birth. It appears that antibody, cells and cytokines/growth factors from the mother, and stimulation initiated by microbial colonization, work together to promote the population of lymph nodes with lymphocytes. Further, the cells from colostrum “kick start” the maturation of antigen presenting cells necessary to start adaptive immune responses.
“It appears that there is a connection between the lymphocytes rapidly leaving the circulation and the population of the lymph nodes in the neonatal calf,” Hurley says. “This takes a day or two to be observed in some of our testing and about two to three weeks before it is clear on the macroscopic scale of the lymph node structure on necropsy.”
Hurley adds that colostrum-deprived calves, kept under conditions to minimize their exposure to environmental microbes, do not rapidly develop lymph nodes or other secondary lymphoid structures. They also retain a naïve response to pathogens and are highly susceptible to induced disease. These findings may indicate that maternal cells play critical roles in the development of the tissues required for establishment of adaptive immune responses and appear to do so by “encouraging” the movement of neonatal lymphocytes from the circulation to the secondary lymphoid tissues.
Maternal cells have also been shown to shorten the time required for neonatal antigen presenting cells to become functional. It has been demonstrated that calves deprived of maternal cells took at least a week longer to develop the capacity to present antigen in cell mediated response model. The combination of enhanced antigen presenting cell activity and enhanced development of the secondary lymphoid tissue provides the basis for a productive adaptive immune response network capable of protecting the neonatal calf. “This may be a critical function in immune development,” Hurley says.
Hurley notes that piglet and lamb studies indicate that maternal cytokines may also serve to enhance the response network in the secondary lymphoid tissues of the neonatal calf. “These immune factors appear to control the ‘vigor and focus’ of the neonatal immune response during the first few weeks of life while the calf is sorting out its cues from the environment.”
Maternal cells may also transfer “immune memory” directly to the calf in the form of T-cells. “There is evidence of transfer of T-cells across the gut of the neonate from colostrum. In addition, it has been shown for bovine viral diarrhea virus that enhanced response to viral antigen during the brief window that maternal cells circulate in the neonate can be measured in the blood of the neonate in a culture model of antigen specific response. It is not clear from these studies if these cells function by expanding and protecting the neonate from infection or if they function by being activated to produce cytokines that amplify the neonatal response in the secondary lymphoid tissues.”
In the past decade, a number of studies looking at microbial colonization of neonatal mucosal tissues and immunity have been conducted, and have indicated a number of things. First, many different microbes are capable of influencing the development of the neonatal immune system. Second, if the exposure of the neonate to these microbes is limited and colonization occurs, they can impact immune development in the absence of colostrum.
Third, the relationship between these microbes and components transferred in colostrum has not yet been studied. “We have also learned from working with gnotobiotic models that typical secondary lymphoid development is either severely delayed or absent in these colostrum-deprived animals that have severely limited exposure to microbes,” Hurley says.
He adds that we have also learned that the interaction between pathogens and cattle is a fluid, development-dependent process. “We have learned that E. coli infections are often significant problems in young calves, however, K99 E. coli is a much bigger problem in calves less than a week old than in older calves, and many enterotoxogenic E. coli can be a problem in younger calves.” Some respiratory and enteric viral agents cause less severe disease in calves near birth than in calves of about 1 month in age. And, calves that continue to suckle (beef calves) have a different pattern of neonatal disease than those that are forced-weaned within about one day of birth (dairy calves). “This suggests that there is a complex pattern of interaction between maternal immune transfer to the gut and neonatal interaction with environmental pathogens.”
Overall, there is no one, single, absolute optimal method to handle transfer of immunity for all operations. In the typical beef operation, making sure that the cows have minimal stress and good nutrition prior to delivery has a good chance of optimizing immune transfer through colostrum and continued milk feeding of their calves. Seldom do pasteurization or freezing of colostrum become an issue in the beef herd.
In contrast, in the dairy herd, Johne’s disease transmission, milk production concerns, weaning practices, and freezing colostrum are all economic as well as health questions that must be addressed. “At present, they appear best addressed by a ‘success monitoring’ approach,” Hurley says. “If the economic goals and overall health of the dairy herd is at desired levels, then the approach is right. Even if all these economic goals are not met, it may not be possible to solve the problem at the level of colostrum, as the dairy is a complex system and much impact in colostrum may occur due to an upstream problem.”