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Equine September/October 2007 (Vol 2, No 5)

Abstract Thoughts—Immunocompetency: The Long and Winding Road

by David J. Hurley, PhD, James N. Moore, DVM, PhD

    Abstract

    The increased vulnerability of foals to specific pathogens, such as Rhodococcus equi, is believed to reflect an innate immunodeficiency, the nature of which remains poorly understood. Previous studies have demonstrated that neonates of many species fail to mount potent Th1 responses. The current research investigates the ability of circulating and pulmonary lymphocytes of developing foals to produce interferon-g (IFN-g). Peripheral blood mononuclear cells (PBMCs) were prepared from up to 10 foals at regular intervals throughout the first 6 months of life. Bronchoalveolar lavage samples were collected at 1, 3, or 6 months of age from three groups of five foals. The cells collected by bronchoalveolar lavage and the PBMCs were stimulated in vitro, and IFN-g production was measured by intracellular staining. In addition, RNA was extracted from freshly isolated and in vitro"stimulated PBMCs and cells collected by bronchoalveolar lavage for quantitation of IFN-g gene expression by real-time polymerase chain reaction testing. Newborn foals exhibited a marked inability to express the IFN-g gene and produce IFN-g protein. This deficiency was observed in circulating and pulmonary lymphocytes. However, IFN-g gene expression and protein production increased steadily throughout the first 6 months of life, reaching adult levels within the first year of life. These findings suggest that foals are born with an inherent inability to mount a Th1-based cell-mediated immune response, which may contribute to their susceptibility to intracellular pathogens.

    This abstract has been adapted with permission. Copyright 2006 Elsevier BV. All rights reserved.

    Commentary

    When you think about it, pregnant mares and their fetuses face the "born ultimatum" every day—they either downplay their immune functions and survive or let them crank up and see who wins. While anyone with a nickel would bet on the mare, the fetus isn't just along for the ride. During gestation, the "killer" side of the immune responses of the fetus and mare are significantly blocked. While the mare still makes a variety of antibodies and provides an active defense against invaders, the part of her immune system that recognizes grafts and intracellular invaders is greatly "turned down," particularly late in pregnancy. As you might expect, this component of her immune system is most severely restricted in the reproductive tract but is also reduced on a systemic basis.

    Years ago, it was assumed that the fetus exited the womb lacking a functional immune system. This isn't entirely true, as the fetus develops a functional immune system well before birth. However, a close look at the fetus' immune system reveals that only antibodies (usually of the IgM class) are routinely produced before birth. This is a good thing. If the fetus could mount a strong cellular killing response, it would be a danger to itself and its mother. Similarly, if the mother developed maximal anticellular responses to foreign antigens, the father's "contribution" to the fetus would be in danger. In fact, the whole process of making the new generation would be in great jeopardy.

    While turning down one side of the fetus' immune system is smart when it is in the protected environment of the womb, a significant problem arises when the neonate moves into the cold, cruel, dirty, and dangerous outside world. This abrupt transition leaves the neonate incapable of mounting a strong response against some types of foreign antigens. Furthermore, the fact that the blockade against mounting anticellular defenses against intracellular antigens is not lifted immediately at birth leaves the neonate at increased risk for infection and disease.

    At birth, neonates of nearly all species have a very strong bias toward Th2 activation in mounting initial immune responses, resulting in the activation of clones of T helper cells and the production of antibodies. Unfortunately, this leaves the newborn foal susceptible to invasion and disease caused by intracellular pathogens. In the article highlighted in this column, Breathnach et al document the inability of foals to mount adult-like Th1, IFN-g-producing responses in the circulation and on mucosal surfaces (the lungs). In fact, these responses are diminished for at least 3 months and possibly as long as 12 months after birth. A similarly strong Th2 bias at birth has also been reported in swine1 and humans.2

    This altered immune balance has a big effect on management of the young animal. Transfer of antibodies (and cells) from the mother is important to the health of the neonate.3,4 Management of intracellular infections in the neonate appears to strongly depend on antibodies and the killing of infected cells by complement or Fc receptor" mediated activation of macrophages and neutrophils.5

    This defect in IFN-g production not only puts the foal at increased risk for infection but also probably influences the effectiveness of vaccines administered to foals during the first 6 months of life. Modern vaccines are designed to yield a balanced response of antibody production and development of memory cells. Therefore, one goal of many vaccines is to induce IFN-g-producing T cells, particularly cells designed to control bacterial and viral intracellular infections.6 Thus, the use of vaccines in young foals may yield different outcomes than those in weanlings and yearlings.

    Importantly, there is some hope for the effective development of protection against intracellular infection in foals. For example, Boyd et al7 found that the level of IFN-g mRNA in circulating leukocytes doubled over the first month of life, showing a steady increase from birth to 1 month of age. Furthermore, Lopez et al8 demonstrated that foals were primed for increased IFN-g production by DNA vaccination with the vapA gene of R. equi, and those authors did not feel that the DNA vaccine was fully optimized. We'll keep our eyes and ears open for more progress on this front.

    So if you wonder why some foals appear to have a particularly rough time getting through their first few months of life, the answer is that they aren't really in a fair fight. After all, they literally enter the ring with one "arm" (of their immune response) tied behind their backs.

    1. Nguyen TV, Yuan L, Azevedo MS, et al: Transfer of maternal cytokines to suckling piglets: In vivo and in vitro models with implications for immunomodulation of neonatal immunity. Vet Immunol Immunopathol 117(3-4):236-248, 2007.

    2. Bendelja K, Gagro A, Bace A, et al: Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry. Clin Exp Immunol 121(2):332-338, 2000.

    3. Donovan DC, Reber AJ, Gabbard J, et al: Effect of maternal cells transferred with colostrum on cellular responses to pathogen antigens in neonatal calves. Am J Vet Res 68(7):778-782, 2007.

    4. Reber AJ, Hippen AR, Hurley DJ: Ingestion of whole colostrum rapidly induces the capacity in newborn calves to stimulate and respond in one-way mixed leukocyte cultures. Am J Vet Res 66:1854-1860, 2005.

    5. Kensinger M, Eskew ML, Scheuchenzuber W, Zarkower A: Porcine effector mechanisms: Antibody-dependent cell-mediated cytotoxicity of pseudorabies-infected target cells. Vet Immunol Immunopathol 14(3):223-231, 1987.

    6. Reber AJ, Tanner M, Okinaga T, et al: Evaluation of multiple immune parameters during development of immunity after vaccination with modified live virus or killed bovine viral diarrhea virus vaccines. Comp Immunol Microbiol Infect Dis 29:61-77, 2006.

    7. Boyd NK, Cohen ND, Lim WS, et al: Temporal changes in cytokine expression of foals during the first month of life. Vet Immunol Immunopathol 92(1-2):75-85, 2003.

    8. Lopez AM, Hines MT, Palmer GH, et al: Analysis of anamnestic immune responses in adult horses and priming in neonates induced by a DNA vaccine expressing the vapA gene of Rhodococcus equi. Vaccine 21(25-26):3815-3825, 2003.

    References »

    NEXT: Comparative Anatomy of the Horse, Ox, and Dog: The Vertebral Column and Peripheral Nerves

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