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HOW-TO SESSION: LIFE STAGE MANAGEMENT Foal Immunity—Clinical Applications David W. Horohov, PhD Although foals have a functional immune system at birth, several aspects of it are immature. This leaves them susceptible to infectious agents. Enhancement of foal immunity can lessen the effect of infectious disease. Author’s address: Maxwell Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546-0099; e-mail: [email protected]. © 2016 AAEP. 1. Introduction The fetal immune system develops in a sterile and protected environment, and therefore lacks antigenic experience. Soon after birth, the newborn is exposed to the “hostile world” of bacteria, viruses, fungi, and parasites. The exposure to these microbes both challenges the health of neonates and drives the maturation of their immune responses. This initial immaturity of the immune response in foals is considered to be responsible for their susceptibility to viral and bacterial infection, such as Rhodococcus equi (R. equi). R. equi, remains one of the most important causes of high-morbidity respiratory disease in foals. As such, it is important to understand what part of the naivety of the neonatal immune response is responsible for this susceptibility given that this affects our efforts to reduce the effect of this and other infectious diseases.1 The immune response of the horse is composed of both innate and adaptive systems to defend against infections. A wide range of distinct cell types comprise the immune system, each of which plays an important role in both innate and adaptive immune responses. The lymphocytes engage in the central role in adaptive immunity given that they are the cells that determine the specificity of immunity-spe- NOTES 448 2016 Ⲑ Vol. 62 Ⲑ AAEP PROCEEDINGS cific antibody production, cytokine secretion, and cytotoxicity. It is their response that directs the effector limbs of the immune response, humoral immune response, and cell-mediated immune response. Other types of cells interact with lymphocytes either in the way of antigen presentation or mediation of immunologic functions. These cells include: cells that eliminate invaders and initiate adaptive immunity during innate immunity such as granulocytes (neutrophils, eosinophils, and basophils), cells that present antigens to lymphocyte such as dendritic cells and monocytes/macrophages. These latter cells represent an important bridge between the innate and adaptive immune responses. Although all of these cells are present in the neonatal foal, their functionality is impaired compared with adult cells. B Cells Prior to birth, B cells are immunologically competent, but their production of antibodies is limited in neonatal foals, although immunoglobulin production increases rapidly after birth.1 As such, passive immunity transferred via colostrum is critical given that immunoglobulins are rarely transferred to the fetus due to epitheliochorial placentation. The relative concentration of immunoglobulins in the colostrum is such that IgG (IgGb⬎IgGa⬎IgGT) ⬎IgA HOW-TO SESSION: (negligible within 12–24 h) ⬎IgM.2 Neonatal absorption of immunoglobulin occurs within 2 hours of birth and is mediated by unselective pinocytosis through specialized enterocytes. The maternal immunoglobulins can be detected in the foal’s circulation within 4 – 6 hours and peaks at 18 –24 hours. Thereafter, these maternal immunoglobulins decrease gradually in foals, and disappear after 1 month for IgA and IgM, and after 6 months for IgG subtypes. Production of antibodies by foal B cells can occur in utero and steadily increases following birth. Very young foals can respond to vaccination, although their ability it produce all sub-types of antibodies remains impaired until 2 months of age.2 This age-related impairment of sub-isotype production is due, in part, to the immaturity of the T cell response in young foals. T Cells Functional T lymphocytes are present in equine fetus by day 100 of gestation and are capable of responding to stimulation by day 140.3 After birth, T-cell populations undergo expansion, similar to that seen in B cells. The numerical increase in the number of circulating T cells is primarily due to an increase in the CD8⫹ T-cell population, given that the proportion of CD8 T cells increases nearly 5-fold by the fourth month of age, whereas CD4⫹ T cells remain fairly constant with age.4 This selective expansion is likely in response to the foal’s exposure to environmental microbes.5 This change in T-cell numbers is also associated with an alteration in their functionality as evidenced by their production of various cytokines. Cytokines are potent regulators of innate and adaptive immunity. The expression of key cytokines such as interferon gamma (IFN-␥), IL-4, IL-17, and IL-10 represent the functions of specific T-cell subsets including type 1 helper T (Th1), type 2 helper T (Th2), type 17 helper T (Th17) cells, and regulatory T cells (Treg), respectively.6,7 Decreased expression of these cytokines by peripheral T cells in neonatal foals compared with adult T cells suggests an overall impairment of T-cell function in foals. Among all of the cytokines, the reduced production of IFN-␥, an indicator of cell-mediated immune response, is considered an important contributor to the foal’s susceptibility to viral and intracellular bacterial infections.8 Antigen-Presenting Cells The activation of lymphocytes is primed and modulated by antigen-presenting cells (APC), which function as a bridge linking innate and adaptive immune response. The APC engulf, process, and present antigens to T cells. This antigen presentation to T cells is mediated via surface molecules and the secretion of various cytokines. This APC population is composed of monocytes, macrophages, and dendritic cells, the latter being specialized and highly efficient APC. Not surprisingly, the APC of LIFE STAGE MANAGEMENT young foals exhibited decreased expression of these accessory molecules and cytokines.9 Here again, the maturation of these cells into a more adult-like phenotype seems to occur in response to stimulation by environmental antigens. Respiratory Immunity The respiratory tract provides the second largest route of exposure to invading microbes. Unfortunately, the immune system of the respiratory tract in foals is functionally immature. In particular, the mucosa-associated lymphoid tissue (MALT), which plays an important role in the protection of the respiratory tract, is incomplete in foals.10 The number and competency of immune cells is impaired in foals compared with that of adult horses. In adult horses, MALT in the respiratory tract is composed of nasal-associated lymphoid tissue, pharyngeal tonsils, laryngeal (LALT), trachea-associated lymphoid tissue, and bronchus-associated-lymphoid tissue. The appearance of the MALT begins in the fetus and gradually develops until 2 years of age. The first appearance of isolated lymphoid nodules occurs in the fetus as early as 9 months’ gestation at the vestibule, nasal cavity, nasophaynx, and LALT. The number of nodules shows a marked increase after birth and reaches the adult level by 2 years of age. The nasopharyngeal tonsil forms the largest single mass of lymphoid tissue in the respiratory tract. However, bronchus-associated-lymphoid tissue is not present in the fetus and neonatal foal, and only found in older foals. In adult horses, organized lymphoid nodules and predominately unorganized infiltrates of closely packed lymphocytes are seen in small intrapulmonary bronchi and these structures are absent in the lungs of neonates. Such structures typically begin to appear by 8 –22 weeks of life. This age-associated distribution of mucosal lymphoid tissues reflects a gradual maturation of the respiratory immunity in foals. The association of the occurrence of the nodules at specific sites within the tract and the areas where inhaled antigens accumulate suggests an influence of environmental exposure on this development. Bronchial Alveolar Lavage Cells Not only does the distribution of respiratory lymphoid tissue in the foals exhibit an age-related development, but the maturity of the immune cells within the lung also follows an age-dependent development. Besides being located in MALT, lymphocytes are distributed diffusely throughout the lung in the walls of the airways, the mucus, parenchyma tissues, and alveolar spaces. Current understanding of foal lymphocyte function in the lung is based mostly on the analysis of bronchial alveolar lavage (BAL) samples. Although lymphocytes compose approximately 40% of the total BAL cells in adult horses, they represent 4 – 6% of the cells in BAL from neonatal foals, the remainder being macrophages and some granulocytes. Both the absolute AAEP PROCEEDINGS Ⲑ Vol. 62 Ⲑ 2016 449 HOW-TO SESSION: LIFE STAGE MANAGEMENT number and the frequency of lymphocytes in BAL fluid has been shown to increase over time. B cells in particular are initially virtually absent at birth, although IgG-, IgM-, and IgA-producing plasma cells appear 1 week after birth and the numbers of the cells reaches an adult level in foals by 12 weeks of age. A reduced number of T cells in the BAL is also seen in foals less than 6 weeks old. This reduced number of lymphocytes present in alveoli and the lack of available lymphocytes to participate in the immune response in foals less than 6 weeks old may have relevance for foals’ susceptibility to pulmonary infection. An impaired function of lung T cells is also evident in neonatal foals as they exhibit low expression of cytokine, particularly IFN␥. However, over time there is increased expression of this cytokine likely as the result of exposure to environmental antigens.5 Together, these deficiencies likely provide the opportunity for infections to occur. Environmental exposure to antigens likely drives the maturation of the immune system. This postnatal exposure leads to both the recruitment of cells into secondary lymphoid sites and can play a role in directing the immune response toward a specific cytokine response. Thus, early exposure to bacterial antigens is thought to favor the induction of Th1-type immunity and prevents the development of allergic and autoimmune diseases associated with Th2 immune responses. As such, the microbiome of the respiratory and gastrointestinal systems plays a key role in the overall development of immune competency in the neonate. Perturbations of these biomes may lead to alterations in subsequent immune responses favoring Th2 over Th1 responses. This contribution of the microbiome in influencing immune development likely represents the underlying mechanism of the “hygiene hypothesis.”11 However, a recent study found no association between the gastrointestinal microbiome of healthy foals and those infected with Rhodococcus equi.12 2. Clinical Application Given the immaturity of the foal’s immune system at birth, several steps can be taken to maximize its effectiveness. Maternal antibodies are an essential component of the initial immune repertoire of the foal.13 The importance of passive transfer and the need for the foal to acquire sufficient maternal antibodies cannot be overstated. A post-suckling plasma immunoglobulin concentration of 800 mg/dL should be considered the minimum acceptable level. The quality of maternal colostrum is another important consideration, referring to the amount of antibodies present to specific agents. A mare vaccination program, as recommended by the American Association of Equine Practitioners (www.aaep.org), should be followed to insure the presence of adequate amounts of specific antibodies in the colostrum. Natural exposure of mares to pathogens in 450 2016 Ⲑ Vol. 62 Ⲑ AAEP PROCEEDINGS the environment can likewise augment her ability to provide the foal with protection. Earlier vaccination of foals that have received insufficient passive transfer or whose mares were not adequately vaccinated should be considered. Although maternal antibodies may inhibit responses to some vaccines, there is little evidence to suggest a long-term negative effect.14,15 As such, it is better to vaccinate the foal earlier rather than risk the possibility of it being unprotected.15 In the case of R. equi, where no vaccine is available, the use of Rhodococcal-specific hyperimmune plasma should be considered for foals on endemic farms. Although this treatment will not prevent infection, a single treatment administered after birth can reduce the severity of clinical signs in foals that become infected.16 Variability in the apparent efficacy of hyperimmune plasma (HIP) in the field may be due in part to differences in obtained antibody levels obtained in treated foals.17 The reasons for this variability are unknown, although variations between products and different lots within a product line does occur.17 Other methods of nonspecifically stimulating T-cell immunity in foals will likely be unsuccessful until the foal reaches at least 1 month of age based on recent studies.18 The overall effectiveness of this approach in reducing R. equi infections in the young foal remains uncertain.19 Likewise, the effectiveness of these treatments in re-directing foal immune responses is also unknown. Acknowledgments The contributions of Drs. Lingshuang Sun and Macarena Sanz are gratefully acknowledged. Financial support for much of the work cited in this paper was provided by the Grayson Jockey Club Research Foundation, Bioniche, and the U.S. Department of Agriculture. Additional support was provided by the William Robert Mills endowment in the Department of Veterinary Science at the University of Kentucky. Declaration of Ethics The Author has adhered to the Principle of the Veterinary Medical Ethics of the AVMA. Conflict of Interest The Author has provided paid consultation on immunology-related topics to a number of pharmaceutical companies and other related businesses. References 1. Perkins GA, Wagner B. The development of equine immunity: Current knowledge on immunology in the young horse. Equine Vet J 2015;47:267–274. 2. Sheoran AS, Timoney JF, Holmes MA, et al. Immunoglobulin isotypes in sera and nasal mucosal secretions and their neonatal transfer and distribution in horses. Am J Vet Res 2000;61:1099 –1105. 3. Perryman LE, Wyatt CR, Magnuson NS, et al. T lymphocyte development and maturation in horses. Anim Genet 1988;19:343–348. 4. Flaminio MJ, Rush BR, Davis EG, et al. Characterization of peripheral blood and pulmonary leukocyte function in HOW-TO SESSION: 5. 6. 7. 8. 9. 10. 11. 12. healthy foals. Vet Immunol Immunopathol 2000;73:267– 285. Sun L, Adams AA, Page AE, et al. The effect of environment on interferon-gamma production in neonatal foals. Vet Immunol Immunopathol 2011;143:170 –175. Wagner B, Burton A, Ainsworth D. Interferon-gamma, interleukin-4 and interleukin-10 production by T helper cells reveals intact Th1 and regulatory T(R)1 cell activation and a delay of the Th2 cell response in equine neonates and foals. Vet Res 2010;41:47. Boyd NK, Cohen ND, Lim WS, et al. Temporal changes in cytokine expression of foals during the first month of life. Vet Immunol Immunopathol 2003;92:75– 85. Breathnach CC, Sturgill-Wright T, Stiltner JL, et al. Foals are interferon gamma-deficient at birth. Vet Immunol Immunopathol 2006;112:199 –209. Mérant C, Breathnach CC, Kohler K, et al. Young foal and adult horse monocyte-derived dendritic cells differ by their degree of phenotypic maturity. Vet Immunol Immunopathol 2009;131:1– 8. Mair T, Batten E, Stokes C, Bourne F. The distribution of mucosal lymphoid nodules in the equine respiratory tract. J Comp Pathol 1988;99:159 –168. Daley D. The evolution of the hygiene hypothesis: The role of early-life exposures to viruses and microbes and their relationship to asthma and allergic diseases. Curr Opin Allergy Clin Immunol 2014;14:390 –396. Whitfield-Cargile CM, Cohen ND, Suchodolski J, et al. Composition and diversity of the fecal microbiome and inferred fecal metagenome does not predict subsequent pneu- 13. 14. 15. 16. 17. 18. 19. LIFE STAGE MANAGEMENT monia caused by Rhodococcus equi in foals. PLoS One 2015; 10:e0136586. LeBlanc MM, Tran T, Baldwin JL, et al. Factors that influence passive transfer of immunoglobulins in foals. J Am Vet Med Assoc 1992;200:179 –183. Sturgill TL, Horohov DW. Vaccination response of young foals to keyhole limpet hemocyanin: Evidence of effective priming in the presence of maternal antibodies. J Equine Vet Sci 2010;30:359 –364. Davis EG, Bello NM, Bryan AJ, et al. Characterisation of immune responses in healthy foals when a multivalent vaccine protocol was initiated at age 90 or 180 days. Equine Vet J 2015;47:667– 674. Sanz MG, Loynachan A, Horohov DW. Rhodococcus equi hyperimmune plasma decreases pneumonia severity after a randomised experimental challenge of neonatal foals. Vet Rec 2016;178:261. Sanz MG, Oliveira AF, Page A, et al. Administration of commercial Rhodococcus equi specific hyperimmune plasma results in variable amounts of IgG against pathogenic bacteria in foals. Vet Rec 2014;175:485. Sturgill TL, Strong D, Rashid C, et al. Effect of Propionibacterium acnes– containing immunostimulant on interferongamma (IFN␥) production in the neonatal foal. Vet Immunol Immunopathol 2011;141:124 –127. Sturgill TL, Giguere S, Franklin RP, et al. Effects of inactivated parapoxvirus ovis on the cumulative incidence of pneumonia and cytokine secretion in foals on a farm with endemic infections caused by Rhodococcus equi. Vet Immunol Immunop 2011;140:237–243. AAEP PROCEEDINGS Ⲑ Vol. 62 Ⲑ 2016 451