key: cord-009385-mcfnhscj authors: BLECHA, FRANK; CHARLEY, BERNARD title: Rationale for Using Immunopotentiators in Domestic Food Animals date: 2012-11-05 journal: Adv Vet Sci Comp Med DOI: 10.1016/b978-0-12-039235-3.50007-1 sha: doc_id: 9385 cord_uid: mcfnhscj nan to losses due to death, economic losses caused by bovine respiratory disease include reduced growth performance and increased treatment costs. These losses emphasize the need for alternative or comple mentary therapeutic approaches, such as immunomodulators, that may be well suited for the multifactorial etiology involved in the disease. In economical terms, mastitis is the most devastating disease affect ing dairy cows. In the United States, losses attributed to mastitis ap proach $2 billion each year; 70% of this economic loss is due to a reduced milk yield as a result of subclinical mastitis (National Mastitis Council, 1987) . Similarly, a French epidemiological survey found that mastitis was by far the most frequent pathology affecting dairy cows (Barnouin et al., 1986) . Vaccination against bacteria that cause intramammary infections has been attempted as a means of decreasing mastitis. However, even in studies that have shown beneficial effects of immuni zation against mastitis, vaccination did not prevent new intramam mary infections (Pankey et al., 1985) . Antibiotic therapy is used in the control of mastitis. However, because Staphylococcus aureus mastitis responds poorly to antibiotic therapy and because of the problem of antibiotic residues in milk, the effectiveness of antibiotic therapy in mastitis prevention and treatment is limited. These specific examples emphasize the need to continue to search for more effective ways to minimize the impact of disease on animal pro duction. Augmentation of the animal's immune response with the in tent of increasing resistance to disease-causing organisms should de crease the economic loss due to disease in food animal production. Immunomodulation may provide an effective means of enhancing the ability of domestic food animals to withstand disease. When one considers the possibility of enhancing an animal's immune response, a question that must be addressed is whether specific or nonspecific immunomodulation is desired or required. Specific immuno modulation involves the potentiation of the host's immune system toward a unique, specific antigen. Vaccination programs are perhaps the best example of producing specific immunity in domestic food animals. Nonspecific immunomodulation generally is an attempt to heighten immunologic capabilities at a time when an animal may be exposed to one or several pathogens and/or be immunocompromised. Both of these concepts will be discussed further. The distinction between adjuvants and specific immunomodulators is blurred and may be only a matter of semantics. Classical and new adjuvants offer the capability of enhancing specific immunity and are discussed in great detail in Chapter 5 of this volume. However, some substances that are not generally thought of as adjuvants, such as the interleukins and interferons, also induce a state of specific immuno modulation. For example, peripheral blood mononuclear cells from cat tle injected with recombinant bovine interleukin-2 display enhanced cytolytic capabilities against bovine herpesvirus-infected target cells (Reddy et al., 1989a) . However, protection against a bovine herpesvirus challenge was observed only in animals that received a vaccination against the virus in conjunction with injections of interleukin-2. Thus, in this case both nonspecific and specific immunomodulation was produced in cattle that were administered interleukin-2, but only specific immunomodulation resulted in protection against a viral chal lenge. Theoretically, the capability of potentiating the host's immune re sponse at a time when it might be immature, compromised, or overcome with pathogens should enhance the animal's ability to resist disease. This is the rationale for nonspecifically augmenting an animal's im mune response. Nonspecific immunomodulation has potential in at least 3 different conditions: (1) during the neonatal period when the immune system may not be fully developed; (2) during periods of stressinduced immunosuppression; and (3) during virus-or bacteria-induced immunosuppression. Because of a very efficient placental barrier, pig, horse, and ruminant fetuses are generally very well protected from in utero antigenic stim uli. Therefore, although fully immunocompetent at birth, domestic food animal newborns differ from other mammalian neonates in being im munologically "virgin" (Kim, 1975; Salmon, 1984) and the development of totally effective immune defenses requires 2 to 3 weeks. During this critical neonatal period the young animal is highly susceptible to mi crobial infections. Postnatal development of immune functions has been most exten sively studied in the pig (Sterzl and Silverstein, 1967; Kim, 1975) . Most immune parameters that have been studied appeared to be very low at birth and reached adult values at about 1 month of age. Thus, the percentage of Τ and Β lymphocytes in peripheral blood, as estimated by Ε-rosettes and anti-Ig immunofluorescence techniques, was shown to increase from 3 to 4% at birth to adult values by 35 days of age (Reyero et al., 1978) . A similar age-related increase has been described for serum concentrations of the third component of complement (C3) in pigs (Tyler et al., 1988) . Because of the high incidence and economic impact of respiratory and intestinal infections in young domestic animals, it is important to review studies related to the postnatal development of the mucosaassociated immune system in the pig. At birth, the intestinal, nasal, and tracheobronchial mucosa are devoid of plasma cells. Plasma cells first appear in the respiratory tract at 6-7 days of age and reach adult values at 3 -4 weeks of age. This postnatal development was described for cells containing IgA as well as IgM and IgG (Bradley et al., 1976) (Chu et al., 1979; Pabst et al., 1988) . Inside the lung, residing at the air-tissue interface and directly exposed to inhaled microorganisms or air pollutants, the alveolar mac rophage functions as the primary defense against respiratory infections (Hocking and Golde, 1979) . Functional properties of alveolar macro phages, including their immunological and antiinfectious features, have been studied in domestic food animals (Khadom et al., 1985; Charley, 1985) . Rothlein et al. (1981) have studied the postnatal devel opment of alveolar macrophages in Minnesota miniature swine. These researchers showed that lavage fluids from the lungs of newborn piglets were devoid of macrophages. However, within 2 to 3 days after birth, macrophages gradually appear inside the lung airspaces and adult values are reached at 2 weeks of age. Furthermore, macrophages col lected from piglets less than 1 week old showed immature function, i.e., lower phagocytic capacity and enzyme content than adult cells. The postnatal development of lung macrophages appears to depend upon nonspecific antigenic stimulation since germ-free piglets have a much lower number of alveolar macrophages than specific-pathogen-free pig lets (Rothlein et al., 1981) . Additionally, alveolar macrophages from young piglets have been shown to be more permissive to pseudorabies virus, yielding higher virus progeny titers, than cells from older animals (Iglesias et al., 1989) . A last example of an immune defect occurring during the neonatal period is given by studies on porcine natural killer (NK) cells. Natural killer cell activity in the peripheral blood of newborn pigs is much lower (often undetectable) than the activity of adult cells. This NK cell defect has been observed regardless of the target cell system used: hu man tumor cells (Huh et al., 1981) , virus-infected cells (Cepica and Derbyshire, 1984a; Yang and Schultz, 1986), or porcine tumor B-cells (Onizuka et al., 1987) . Of particular interest are the observations that postnatal development of NK cells activity, which requires 2 -3 weeks in specific-pathogen-free miniature swine (Huh et al., 1981) and in conventionally reared Large-White pigs , is de layed in germ-free miniature piglets (Huh et al., 1981) . These data imply that microbial flora play a role in the maturation process of NK cell activity in neonates. , 1984a) . This observation has led to the hypothesis that a NK cell defect could in part explain the great suscep tibility of piglets to coronavirus-induced transmissible gastroenteritis. Indeed, adoptive transfer of adult pig leukocytes established functional NK cell activity in recipient piglets and reduced their susceptibility to a TGEV challenge (Cepica and Derbyshire, 1984b) . The examples described above illustrate the existence of several different immune defects (see Table I ) in neonatal domestic food animals. This lower functional immune status during the neonatal period could explain some of the neonates' susceptibility to infectious diseases, especially intestinal infections. Thus, the potential exists to increase the neonates' immune functions by using immunomodulators. A few studies have been conducted exploring means of enhancing the young animals' immune functions. For example, newborn piglets' NK cell activity was shown to be responsive in vitro to interferon (Charley et al., 1985) , and in vivo to poly I : C (Lesnick and Derbyshire, 1988) or bacterial extracts (Kim, 1984) . Additionally, isoprinosine has been shown to enhance the immunocompromised immune status of artifi cially reared neonatal pigs (Hennessy et al., 1987) . In the following chapters several immunomodulating strategies will be reviewed and should help to define possible immunotherapeutic approaches to en hance young domestic food animals' resistance to disease. (Loan, 1984; Filion et al., 1984) . The idea that stressed animals are more susceptible to disease generally relies on the assumption that alterations in immunocompetence have occurred (Table II) . Indeed, some researchers have suggested that changes in immune function may be a useful indicator of stress in domestic food animals (Kelley, 1985; Siegel, 1985) . Over the last decade several review articles have been written on the topic of stress and immunity in farm animals (Kelley, 1980 (Kelley, , 1982 (Kelley, , 1984 (Kelley, ,1985 Observation Reference Blecha and Minocha (1983) 1988; Albani-Vangili, 1985; Siegel, 1985; Blecha, 1988a; Griffin, 1989 ). If stress-induced changes in host immunity predisposes animals to disease, then methods of modulating the immune response in stressed animals should increase disease resistance (Blecha, 1988b) . When one attempts to intervene in an animal's response to a stressor, several different approaches can be envisioned (Fig. 1) . Perhaps the best means of reducing the impact of stress on animal health is by providing a less stressful environment. However, deciding which envi ronment or management condition is the least stressful is not a simple or easy task (Curtis et al., 1989; McGlone and Hellman, 1988) . Thus, several environments and management conditions have been evalu ated for their influence on immune function Blecha et al., 1984 Blecha et al., ,1985 Blecha et al., ,1986 McGlone and Blecha, 1987; Minton etal, 1988) and for their impact on the physiology of the animal (Dantzer and Mormede, 1983) . Another approach has been investigated as a method of reducing the influence of stress on susceptibility to disease: blocking the physiologic response to the stressor. The association between stress, neuroendo- crine responses, and alterations in immune function or disease sus ceptibility has been recognized for several years (Munck et al., 1984; Kelley, 1988; Griffin, 1989) . When increased concentrations of glucocorticoids have been associated with lower immune responses, administration of drugs that block the synthesis of corticosterone, such as metyrapone, resulted in an abrogation of the stress-induced immu nosuppression (Blecha et al., 1982) . Recently, adrenal blocking chemicals (metyrapone and dichlorodiphenyldichlorethane) have been shown to increase the resistance of stressed chickens to viral and respi ratory infections (Gross, 1989) . Finally, when stress-induced immuno suppression has occurred, neurohormones, such as melatonin (Maestroni et al., 1988) , immunomodulating drugs (Hennessy et al., 1987; Blecha, 1988b; Komori et al., 1987) , and cytokines (Conlon et al., 1985) have been used to "up-regulate" or restore the immune response. It is likely that a combination of the approaches indicated above will pro vide the best means of reducing stress-induced disease problems in domestic food animals. C. PATHOGEN-INDUCED IMMUNOSUPPRESSION Animals exposed to infectious disease often show depressed immune function. This is the case for several parasitic, bacterial, and viral infections. Pathogenic bacteria have been shown to affect immune re sponsiveness of infected animals. Thus, Pasteurella hemolytica or Hae mophilus pleur^pneumoniae, which both cause acute pneumonia in cattle and pigs, have been reported to exert toxic effects on lung macro phages and to alter macrophage phagocytic functions (Markham and Wilkie, 1980; Bendixen et al., 1981) . During bacteria-induced mastitis, suppressed responses in lymphocyte proliferation and neutrophil phagocytic functions have been reported (Nonnecke and Harp, 1988; Reddy et al., 1989b) . Immunosuppression of the host is also a frequent consequence of viral infections. Several examples of virus-related im munosuppression are well documented in domestic food animals (Table III) , including viral diseases of great economic importance such as infectious bovine rhinotracheitis (bovine herpesvirus type-1) and pseudorabies, which cause severe pneumonia and death in cattle and pigs, respectively. As a consequence of virus-induced alteration of im mune function, animals become very susceptible to secondary bacterial infections. The detrimental effects of these virus-bacteria synergistic interactions are of particular importance in the case of respiratory infections. Thus, following an initial viral multiplication in the lung, pathogenic bacteria proliferate, inducing the development of more se- In the production of domestic food animals several situations exist where disease decreases production efficiency. Some of these diseases are exacerbated by a lowered or compromised immune response of the host. If immunomodulators can be used to augment immune function at critical periods during the production of food animals, such as the neonatal period, and prior to or during exposure to stressors or patho genic organisms, then the economic loss caused by infectious disease should be reduced. vere and acute lung lesions (Jakab, 1982; Babiuk et al., 1988) . If pathogen-induced immunosuppression can be moderated by immunomodulating substances, then the prospects for domestic food animals to withstand disease should be increased. Stimulation of defense mecha nisms, especially lung immune defenses, will likely require activation of local lymphoid cells such as alveolar macrophages (Charley, 1986) . Targeting of immunomodulators to the critical organs will require special delivery systems, such as encapsulation in liposomes (Fogler et al., 1980) , which should be considered in the field of domestic food animal immunoenhancement. Stress e immunita. Obiettivi Vet The relative frequencies and distribution of immunoglobulin-bearing cells in the intestinal mucosa of neonatal and weaned pigs and their significance in the development of secretory immunity Bovine respiratory disease: Pathogenesis and control by interferon Viral-bacterial synergistic interaction in respiratory disease Enquêt e éco-pathologique continue Toxicity of Haemophilus pleuropneumoniae for porcine lung macrophages, peripheral blood monocytes, and testicular cells Viral infections in domestic animals as models for studies of viral immunology and pathogenesis Stress et immunité chez l'animal Immunomodulation: A means of disease prevention in stressed live stock Cold stress reduces the acquisition of colostral immunoglobulin in piglets Suppressed lymphocyte blastogenic responses and enhanced in vitro growth of infectious bovine rhinotracheitis virus in stressed feeder calves Adrenal involvement in the expression of delayed-type hypersensitivity to DNFB in stressed mice Weaning pigs at an early age decreases cellular immunity Shipping suppresses lymphocyte blasto genic responses in Angus and Brahman x Angus feeder calves Immunologic reactions of pigs regrouped at or near weaning Decreased mononuclear cell re sponse to mitogens in artificially reared neonatal pigs Influence of isoprinosine on bovine herpesvirus type-1 infection in cattle The respiratory tract immune system in the pig. I. 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Influence of the journey duration Physiological functions of glucocorticoids in stress and their relation to pharmacological actions The effects of road transportation on peripheral blood lymphocyte subpopulations, lymphocyte blastogenesis and neutro phil function in calves Current Concepts of Bovine Mastitis Experimentelle untersuchungen zur wirkung einer chronischen aerogenen schadgasbelastung des saugferkels mit ammoniak unterschiedlicher konzentrationen. II. Die reaktion zellularer und humoraler infectionsabwehrmechanismen NH 3 -exponieter saugferkel unter den bedingungen einer experimentallen Pasteurella-multocidainfektion mit und ohne thermo-motorische belasturg Effects of Staphylococcus aureus on bovine mononuclear leukocyte proliferation and viability: Modulation by phagocytic leuko cytes Nonspecific cell-mediated cytotoxicity of peripheral blood lymphocytes derived from suckling piglets Postnatal development and lymphocyte production of jejunal and ileal Peyer's patches in normal and gnotobiotic pigs Evaluation of protein A and commercial bacterin as vaccines against Staphylococcus aureus mastitis by experimental challenge Bovine recombinant interleukin-2 augments immunity and resistance to bovine herpesvirus infection Bovine recombinant granulocyte-macrophage colony-stimulating factor aug ments functions of neutrophils from mastitic cows Heat-and cold-stress suppresses in vivo and in vitro cellular immune responses of chickens Development of peripheral Β and Τ lymphocytes in piglets Suppression of neutrophil and lymphocyte function induced by a vaccinal strain of bovine viral diarrhea virus with and without the administration of ACTH Development of alveolar macrophages in specific pathogen-free and germ-free Minnesota miniature swine Effect s o f ambien t temperature s o n induction o f transmissibl e gastroenteriti s i n feede r pigs Immunologica l response s a s indicator s o f stress . 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