Dysregulation of the immune system occurs during critical phases of production such as the transitioning period.
Dysregulation of the immune system occurs during critical phases of production such as the transitioning period.

Good animal husbandry, which includes attention to nutrition, minimizing the exposure of cattle to multiple concurrent stressors, and attention to biosecurity, can improve both innate and adaptive immune functions.

“Some people overlook these not very ‘sexy’ strategies in their ongoing search for the latest silver bullet that can protect cattle from all disease, all the time, regardless of inadequate management,” say Amelia Woolums, DVM, PhD, Dipl. ACVIM, Dipl. ACVM, University of Georgia. “Nutritional deficiency and prolonged stress have both been shown to impair innate immune functions as well as adaptive immune functions, so preventing these problems is important to support both arms of the immune response.”

It’s interesting, Woolums says, that short-term stress can actually improve innate immune responses. A recent study showed that neutrophil function in bulls increased over baseline at 48 hours after a short (four hour) transport (Hulbert et al, Vet Immunol Immunopathol 2011; 143:66-74). “So from the perspective of the immune response, not all stress is bad,” she adds. “Persistent or chronic stress is generally a problem, but short-term stress is not always a problem.”

Proper nutrition is needed for all aspects of performance and the immune system is a key homeostatic mechanism to keep the body healthy, says Marcus Kehrli, Jr., DVM, PhD, National Animal Disease Center, Ames, Iowa. “Simply put, in the absence of proper nutrition, the immune system will not perform optimally. However, very little research has been done to define basic nutritional requirements of cattle to support immune function; especially lacking is science defining the nutrient requirements of transition cows.”

Because nutritional deficiency can impair innate immune responses, some believe that supplementing nutrients (such as vitamins or minerals) in excess can improve response. Woolums says numerous studies have looked at the impact of various nutrients and feed supplements on immune response, and the bottom line is that nutrient supplementation in excess of maintenance requirements does not consistently improve immunity, although there are specific examples of certain vitamins or minerals associated with improved immunity.

Regarding vaccines, Woolums says it’s interesting to note that adjuvants, which are often included in vaccines to improve the host immune response, likely work at least in part by activating the innate immune response. “For example, it’s been shown that alum, which is an adjuvant commonly used in human and veterinary vaccines, interacts with receptors inside of cells which activate innate immune pathways, and this interaction is what leads to the adjuvant effect induced by alum.”

“Immunologists recognize that we can enhance selected aspects of innate immunity but there might be risks associated with doing this in healthy animals with normal functioning immune systems,” Kehrli says. “You can certainly have too much of a good thing. However, use of immune modulators is a viable approach to restoring a derailed immune system back to normal and ideally this should be achieved without causing any damage to the host through an over-exuberant immune system.”

Toward this end, scientists have studied the ability of selected cytokines such as interferons and interleukins, as immune modulators administered to cattle whose immune systems are compromised, as a way to help them combat infectious diseases. “What we have learned is that many of these cytokines (or regulatory molecules of the immune system) are highly potent and there can sometimes be a very narrow therapeutic dose range before toxic effects are observed,” Kehrli explains. “We don’t currently have products available that meet this need, but I am confident scientists will eventually find immune restoratives to help compensate for a dysregulated immune system during critical phases of production such as the transition cow.”

Weaning, which can be a source of stress, was also recently shown to be associated with decreased neutrophil function in dairy calves (Hulbert et al, J Dairy Sci 2011;94;2545-2556).

Measuring innate immunity

How do you measure innate immunity? Chris Chase, DVM, PhD, Dipl. ACVM, South Dakota State University, says one of the proteins that can be measured is haptoglobulin, an acute phase protein. “Unfortunately, it is always increased after the fact so it really doesn’t tell you what shape the innate immune response is in,” he says. “Alpha interferon is another protein that is measured, but again it is after the fact.”

Woolums says we can measure the neutrophil count in blood (via a CBC) or milk (with SCC, measuring neutrophils). “Neutrophil counts in these body fluids are widely used as a measure of how well, or not well, the cow is doing in terms of infection/inflammation,” she says.

Recently, researchers looked at whether measurement of innate immune factors such as defensins or cathelicidins could be measured in milk to serve as a surrogate measure of somatic cell count (SCC). “This might eventually be a cow-side test that could improve diagnosis of mastitis,” Woolums notes. “However, we do already have the California Mastitis Test, which is a cow-side test that provides a semi-quantitative measure of SCC.”

Kehrli adds that it is also important to understand that numbers of cells alone is not entirely informative and, in fact, could be highly misleading given there are situations where leukocyte numbers may be high but they are not functional.

If a tissue sample test was available, Kehrli says realistically the tissue would need to be readily accessible and blood comes the closest to fulfilling this criteria. “Secondly, I would argue the diagnostic test needs to be a comprehensive immune capacity panel that takes a snapshot of both the innate and adaptive immune systems, including cellular and non-cellular components of each system.”

We must take into account the production periods where animals are naturally stressed (e.g., parturition and weaning) or production cycle phases where our management practices (e.g., commingling and transport stress) would predictably impair immune function. “We know there are genetic differences in the duration and magnitude of immune suppression in periparturient cows,” Kehrli says. “But practical ways to include immune performance in a selection index are only a distant thought even to those of us conducting research in this area.”

Relationship with antibiotics

Antibiotics have significantly lowered mortality rates of many bacterial diseases, suggesting that antibiotics fill a void where both innate and adaptive immunity are failing to optimally protect against mortality. “Furthermore, some classes of antibiotics are known to accumulate inside phagocytic cells of the innate immune system and in so doing help the phagocytic cell more efficiently kill an ingested bacteria,” Kehrli explains.

Antibiotics are certainly helpful as evidenced by the fact that antibiotic treatment can sometimes be life-saving for individuals with bacterial infections. However, the innate immune response is also critical for antibiotics to be useful, as evidenced by the fact that animals with defects in innate immune function, such as defects in neutrophil function, develop repeated bacterial infections that cannot be effectively controlled long-term with antibiotics. “So I would say that antibiotics and the innate immune system work hand-in-hand to fight off bacterial infection,” Woolums says.

Today there is abundant evidence that cross-talk between the innate and adaptive immune systems is vital to a successful vaccination program to prevent disease. “We already know quite a bit about the effects of various physiological stressors on neutrophil and lymphocyte functional activities, as well as the reduced ability of an immune-suppressed animal to respond to vaccination,” Kehrli notes.

“However, we don’t know all of the underlying causes of poor responses to vaccines and what contribution dysregulation of the innate immune system makes in these situations,” he adds. “Hence, it is critical that we invest in research to provide a better understanding of what components of the innate immune system are necessary for effective vaccine responses and how we might enhance any weak links so that we can better design vaccines to achieve protective immunity when vaccinating animals whose immune systems may be less than fully functional.”

Mastitis and bovine respiratory disease are examples of diseases caused by many different pathogens, and continued research is needed in these areas. “A multi-etiology disease often suggests an underlying impairment of innate immunity contributing to its development,” Kehrli says. “The importance and need for basic research in these areas is abundantly clear to livestock producers and veterinarians who help produce the most affordable, safe and sustainable food supply in the world.”


Immunity and the transition cow

Proper immune function, like all systems of the body is dependent on proper nutrition – and nowhere is this more evident than in the transition dairy cow that is faced with numerous challenges. Much of the research on innate immunity in bovine medicine is focusing on the role of the innate immune response in defense of the mammary gland.

Nutritional deficiency and chronic stress can certainly impair innate immune responses. Amelia Woolums, DVM, PhD, Dipl. ACVIM, Dipl. ACVM, says hypocalcemia during the transition period in dairy cows, for example, has been shown to be associated with depressed neutrophil function (Kehrli and Goff, J Dairy Sci 1989;72:1188-1196).

Epidemiological data going back decades has identified greater disease incidence in transition cows that experience ketosis and/or milk fever (e.g., higher incidence of mastitis and metritis), adds Marcus Kehrli, Jr., DVM, PhD. “Given the immune system requires a wide array of nutrients to make cells, enzymes, cytokines, antibacterial peptides, antibodies and other soluble glycoproteins of the innate immune system, it only makes common sense that if we short-change the transition cow nutritionally, it will only further enhance her susceptibility to a myriad of infectious diseases – particularly in the first few weeks of lactation.

“Therefore it is absolutely critical that we manage transition cow diets to minimize the effects of both clinical and subclinical hypocalcemia and ketosis. In addition, we know the importance of a proper balance of vitamin E and selenium to support optimal neutrophil function and defense against mastitis.”