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ANIMAL HEALTH SYMPOSIUM |
* Department of Animal Sciences, University of Illinois, Urbana 61801; and
and
Department of Animal and Food Sciences, Texas Tech University, Lubbock, TX 79409
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Abstract |
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 Top Abstract INTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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Key Words: immune system • social status • stress • T helper cells
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INTRODUCTION |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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The response of the immune system is one of the mechanisms that organisms have developed to defend against environmental challenges. The most common theory is that stress suppresses components of the immune system, thus enhancing susceptibility of an animal to disease. Some studies have shown that the immune system is enhanced by stress, whereas others have shown no effect of stress on immunity. How the immune system responds precisely to stress remains a mystery, primarily because of the complexity of the immune and stress systems and other factors (i.e., age, genetics, social status) that influence the stress responsiveness of an animal.
This review will consider the effects of environmental stress on the immune system of swine and cattle and will attempt to clarify some of the contradictory findings about the effects of stress on the immune system. To address this topic, what is known about the immediate response of the brain and the adrenal gland under stress will be briefly discussed. Next, the paper will briefly describe immunity and glucocorticoids, specifically the interaction among T helper cell subsets, glucocorticoids, and stress. The effects that circulating stress mediators, in conjunction with other environmental and genetic factors, have on the responses of the immune system to environmental stressors will then be examined. Finally, the paper will hypothesize that the shift in the balance between cellular (T helper 1) and humoral (T helper 2) immunity in response to stress determines disease susceptibility in livestock.
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THE BRAIN AND ADRENAL RESPONSE TO STRESS |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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; Fulford and Harbuz, 2005; Levine, 2005). The activation of the HPA axis leads to production and secretion of corticotropin releasing factor (CRF) or corticotropin releasing hormone, primarily from the PVN of the hypothalamus via the median eminence and into the hypothalamic-hypophyseal portal system (Swanson and Sawchenko, 1980; Swanson et al., 1980). Endocrine cells in the anterior pituitary respond to CRF by synthesizing and secreting proopiomelanocortin or its products [ß-endorphin, adrenocorticoptropin hormone (ACTH), and melanocyte stimulating hormone]. Pituitary ACTH travels through the blood to the adrenal cortex, where cells of the zona fasciculata secrete glucocorticoids (Fulford and Harbuz, 2005), with cortisol being the primary glucocorticoid in swine and cattle (Minton, 1994). The glucocorticoids provide negative feedback to the PVN to inhibit CRF and catecholamine synthesis (Minton, 1994; Fulford and Harbuz, 2005). Minton (1994) argued that catecholamines may play a more pivotal role in farm animal stress responses than previously thought.
Glucocorticoids effectively inhibit the neuroendocrine stress response. Corticotropin releasing factor from the PVN activates norepinephrine neurons and neuron tracts in the locus coeruleus (LC). The LC also contains CRF neurons that activate catecholamine neurons. When not stressed, CRF secretion within the LC is restrained by basal levels of glucocorticoids (Valentino and Van Bockstaele, 2005).
Different stressors activate at least 5 pathways that converge on the various regions of the PVN and stimulate the release of CRF (Sawchenko, 1991). Furthermore, stressors may have very different effects on glucocorticoid and catecholamine secretions (Kovacs et al., 2005). For example, dehydration activates only the magnocellular region of the PVN (the site of vasopressin secretion), whereas restraint and most acute stressors activate only the medial PVN, which is the site of greatest CRF secretion within the PVN (Kovacs et al., 2005).
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IMMUNITY AND GLUCOCORTICOIDS |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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Moreover, primarily based on classical rodent literature, the accepted dogma is that activated CD4+ T cells commit early to a pathway of differentiation that results in the formation of 2 distinct subsets called T helper1 (Th1) or T helper2 (Th2) cells (reviewed in Mosmann and Coffman, 1989). Differentiation of either subset is established during priming of naïve CD4+ T cells, and a variety of factors can influence this differentiation process in the early phase of the immune process, including cytokines, receptors on the cell surface, antigen dose, nature of the antigen, and direct cell-to-cell interaction with the antigen presenting cell (Constant and Bottomly, 1997; Kidd, 2003). The nature of the innate immune response to an antigen or pathogen dictates whether the subsequent adaptive CD4+ T cell response will be mainly Th1 or Th2 (Janeway and Medzhitov, 2002). These 2 distinct subsets of T helper cells are responsible for different functions of host defense and are distinguished by the spectrum of cytokines they secrete.
The key cytokines are interferon-
(IFN) and IL-4, which are central to stimulatory and inhibitory roles of a Th subset (Coffman, 2006). Thus, IFN and IL-4 do not directly inhibit differentiated Th1 or Th2 cells; instead they inhibit by blocking the differentiation of these subsets from naïve precursors. Essentially, IFN has been shown to inhibit Th2, whereas IL-4 and IL-10 inhibit Th1 (Coffman, 2006). It has also been reported that IL-12 favors Th1 and has no effect on Th2 (Constant and Bottomly, 1997). However, it should be emphasized that none of the cytokines specific to 1 particular subset are exclusive products of Th cells because other leukocytes can contribute to Th1- or Th2-type responses (Mosmann and Sad, 1996).
Cytokines released upon activation of the immune system stimulate the HPA axis and increase peripheral levels of glucocorticoids. Most evidence implies that glucocorticoids suppress the synthesis and release of cytokines. Glucocorticoids have been shown to inhibit a plethora of cytokines, including but not limited to IL-4, IL-5, IL-6, IL-12, IFN, and tumor necrosis factor-
(Wiegers and Reul, 1998; Richards et al., 2001; Sapolsky et al., 2001). However, not all cytokines are suppressed by glucocorticoids; IL-10 secretion is increased by glucocorticoids (Blotta et al., 1997; Richards et al., 2001), whereas others (i.e., IL-1, IL-4, and IL-6) act synergistically with glucocorticoids (Wiegers et al., 2005). The effects of glucocorticoids on IL-4 production are controversial because IL-4 has been shown to be enhanced or inhibited by glucocorticoids in human lymphocytes (Wu et al., 1991; Blotta et al., 1997). Also, IL-4 is enhanced by IL-12, but glucocorticoids inhibit IL-12 (Wu et al., 1998; Elenkov et al., 2000). The inhibition of cytokines by glucocorticoids most likely provides a protection mechanism that prevents overshooting of the immune defenses. In general, glucocorticoids inhibit proinflammatory cytokine synthesis or induce the cytokines that have immunosuppressive potential (Wiegers et al., 2005).
Glucocorticoids may cause a shift from a Th1 immune-driven response to a Th2 response (Wiegers et al., 2005). A potential mechanism by which glucocorticoids affect the Th1/Th2 balance may be through the inhibition of the production of, and responsiveness to, IL-12 (DeKruyff et al., 1998; Elenkov et al., 2000). Catecholamines also inhibit IL-12 and enhance IL-10 production (Elenkov et al., 1996). Thus, glucocorticoids and catecholamines, through their effects on Th1 and Th2 cytokine secretion, may cause suppression of cellular immunity and cause a shift toward Th2-mediated humoral immunity (Elenkov, 2002).
Even though glucocorticoids have been reported to bias cytokines toward a Th2 phenotype, this has been disputed. Physiologic concentrations of cortisol were ineffective in suppressing IL-10 or IL-12p70 in human whole blood cultures (Visser et al., 1998). In contrast, human dendritic cells treated with cortisol produced less IFN and greater IL-10 and IL-5 (de Jong et al., 1999). Recently, Skjolaas et al. (2002) reported that cortisol was suppressive to Th1 and Th2 cytokines in pig splenocytes. These data indicate that IFN is less sensitive to cortisol suppression than IL-10 and that IL-2 may be resistant to cortisol (Skjolaas et al., 2002; Skjolaas and Minton, 2002).
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STRESS EFFECTS ON IMMUNITY |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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; Blecha and Baker, 1986; Salak et al., 1993). In vivo activation of glucocorticoid release via ACTH injection reduced mitogen-induced lymphocyte proliferation, IL-2 production, and antibody production in cattle and pigs (Blecha and Baker, 1986; Wallgren et al., 1994), whereas natural killer cell (NK) cytotoxicity was enhanced in pigs (McGlone et al., 1991). Intramuscular injection of short-acting dexamethasone followed by long-acting dexamethasone 37 h later induced leukocytosis, increased the neutrophil-to-lymphocyte ratio, and CD4+ cells and chemotaxis, whereas CD8+ cells were decreased (Anderson et al., 1999). Mitogen-induced lymphocyte proliferation and serum immunoglobulin-M (IgM) were also suppressed by dexamethasone treatment, but IFN and NK cell activity were not affected (Anderson et al., 1999). In steers, an injection of a high dose of dexamethasone profoundly increased the number of circulating neutrophils but inhibited neutrophil cell surface marker expression (Weber et al., 2001). The number of apoptotic cells increased, whereas the number of proliferating cells decreased in calves receiving dexamethasone injections twice daily for 4 d (Norrman et al., 2003), thus leading to an increase in the ratio of apoptotic cells to proliferating cells. In these same calves, T-cells were increased, whereas B-cells were decreased.
Activation of the HPA axis by administering exogenous ACTH, cortisol, or by blocking cortisol synthesis has been used to investigate the effects of cortisol on immune function. In pigs, administration of an intravenous bolus of ACTH caused an increased NK activity and IL-2-stimulated NK activity (McGlone et al., 1991), whereas an ACTH injection suppressed neutrophil cellular function in Japanese Black steers (Ishizaki and Kariya, 1999). A pharmacologically induced, 3-fold increase in plasma cortisol concentration via cortisol injection had no effect on NK cytotoxicity, but an infusion of 400 µg of cortisol resulted in reduced NK activity at 1 h postinjection but not at 2 h (Salak-Johnson et al., 1996). Blocking cortisol synthesis by feeding metyrapone to pigs resulted in low plasma cortisol concentrations and reduced NK cytotoxicity at all time points (Salak-Johnson et al., 1996).
Central injection of CRF has been shown to decrease NK cell activity in rodents (Irwin et al., 1990), but in pigs NK activity was only marginally reduced, whereas neutrophil chemotaxis was significantly suppressed (Salak-Johnson et al., 1997) by central CRF injection. Administration of central CRF resulted in reduced concanavalin-A (ConA)-induced proliferation in pigs (Johnson et al., 1994) but had no effect on phytohemagglutinin (PHA)-induced proliferation (Salak-Johnson et al., 1997).
Acute and Chronic Stressors
Acute and chronic stressors tend to affect the immune responses differently, whereby chronic stress most often leads to suppression of the immune system. In pigs, exposure to acute heat and shipping stressors had no effects on various immune measures (McGlone et al., 1993; Hicks et al., 1998), but acute transportation stress did reduce chemiluminescence response of alveolar macrophages and increase the ratio of CD4+ to CD8+ cells in cattle (Ishizaki et al., 2005). Acute cold stress caused an increase in porcine NK cytotoxicity (Hicks et al., 1998), whereas NK cytotoxicity was both increased and decreased in pigs subjected to acute restraint stress (Wrona et al., 2001). Specifically, NK was enhanced during the early phase (0 to 1 h) and reduced during the late (3 to 4 h) phase of the stressor (Wrona et al., 2001). Pigs weaned at less than 5 wk of age have decreased cellular immunity, specifically reduced PHA responses and lymphocyte proliferation (Blecha et al., 1983). Recently, Davis et al. (2006) reported that the age at which a pig is weaned has no effect on mitogen-induced lymphocyte proliferation. In contrast, abrupt weaning and disruption of the social group in calves did affect immune responsiveness of these animals (Hickey et al., 2003). More specifically, weaning and social disruption resulted in suppressed IFN response to keyhole limpet hemocyanin. Often, acute stress has limited suppressive effects on immune function.
Chronic stress has differential effects on various aspects of the immune system. Chronic heat stress had no effect on concanavalin-A or PHA-induced lymphocyte proliferation (Bonnette et al., 1990; Morrow-Tesch et al., 1994), but lipopolysacharride-induced proliferation was increased in pigs exposed to 14 d of heat and crowding stress (Sutherland et al., 2006). In pigs, prenatal stress and social isolation caused a reduction in lymphocyte proliferation (Tuchscherer et al., 2002; Kanitz et al., 2004). Moreover, 3 d of transportation stress reduced PHA-stimulated lymphocyte proliferation in steers (Stanger et al., 2005). Natural killer cytotoxicity was increased in pigs after 14 d of heat and crowding stress (Sutherland et al., 2006), whereas 4 d of cold stress reduced NK activity and total plasma IgG concentration (J. L. Salak-Johnson and S. R. Niekamp, University of Illinois, unpublished data). In contrast, 14 d of heat and crowding had no effect on total IgG concentration (Sutherland et al., 2006).
Pathogen Challenges
Pathogenic challenges have been shown to alter cytokines, endocrine responses, and other aspects of immunity. Pigs challenged with Salmonella typhimurium had greater haptoglobin and 1-acid glycoprotein but showed no effect on immunoglobulins (Turner et al., 2002). Immunoglobulin concentration was not affected in pigs that were mixed and challenged with pseudorabies virus vaccine (de Groot et al., 2001) or porcine reproductive and respiratory syndrome (PRRS) challenge (Sutherland et al., 2007). However, NK cytotoxicity was enhanced in PRRS-infected pigs, whereas macrophage phagocytosis was reduced (Sutherland et al., 2006).
Cytokines are influenced by various pathogenic challenges. Pigs subjected to mixing stress and vaccinated with pseudorabies virus had greater IFN than control pigs, but there was no effect on IL-10 (de Groot et al., 2001). However, IFN and IL-2 were elevated in pigs vaccinated against parasitic Taenia solium, but no differences were detected in IL-4 or IL-10 concentration (Diaz et al., 2003). In pigs 7 d after PRRS challenge, IL-10 was increased, but there was no effect on IFN (Sutherland et al., 2007). Pigs challenged with Toxoplasma gondii had elevated TNF, IFN, IL-4, and IL-15 (Dawson et al., 2005). In cattle challenged with Ostertagia ostertagi, IL-4, IL-10, and IL-13 were all elevated, whereas IFN and IL-12 were reduced (Claerebout et al., 2005), but vaccination had no effect on the cytokine profile. Moreover, sheep selected for enhanced resistance during a challenge with Trichostrongylus colubriformis had greater expression of IL-5, IL-13, and tumor necrosis factor, but not of IL-4, IL-10, or IFN than did those susceptible to the disease (Pernthaner et al., 2005).
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OTHER FACTORS AFFECTING STRESS AND IMMUNITY |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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Social Status
Social status often plays a more significant role in an animal’s response to a stressor than the stressor itself. Pigs identified as dominant had greater NK cytotoxicity than did socially intermediate or submissive pigs in response to acute shipping (McGlone et al., 1993; Hicks et al., 1998). Heat stress reduced NK cytotoxicity among intermediate pigs compared with other social ranks (Hicks et al., 1998). Cytotoxicity of NK cells was greater among dominant and intermediate pigs subjected to acute cold stress, but acute heat reduced NK cytotoxicity in the intermediate pigs (Hicks et al., 1998). Dominant pigs had greater NK cytotoxicity, phagocytosis, and leukocyte populations after 14 d of heat and crowding (Sutherland et al., 2007), whereas NK cells and the percentage of immature alveolar macrophages were greater in submissive pigs inoculated with PRRS virus than in the dominant pigs (Sutherland et al., 2007). Dominant pigs challenged with Aujeszky disease had a greater lymphocyte proliferative response to purified Aujeszky antigen than did submissive pigs (Hessing et al., 1994). Moreover, it appears that the immune responses of dominant pigs that are mixed are more seriously affected than subordinates that are mixed (de Groot et al., 2001). Intermediate pigs had greater lymphocyte proliferation responses than did pigs of other social ranks after acute shipping stress (Hicks et al., 1998), but intermediate pigs exposed to chronic heat stress had reduced responses (Morrow-Tesch et al., 1994). Among pigs subjected to mixing stress, lymphocyte proliferation and total IgG were both greater in dominant pigs than in subordinates (Tuchscherer et al., 1998). However, social status had no effect on lymphocyte proliferation, chemotaxis, or IgG concentration in pigs that were exposed to 14 d of heat and crowding (Sutherland et al., 2007).
Genetics
Genetics affects the immune response of an animal. A study with cattle showed that Angus cattle had a greater PHA response than did Braham x Angus crosses (Blecha et al., 1984). Others have shown that IgG concentration was different between Angus and Hereford cattle (Muggli et al., 1987), and Angus cattle had greater immune response than did Simmental cattle (Engle et al., 1999). Genetic differences in breeds of pigs have been reported in response to antigens or vaccines for sheep red blood cells, E. coli, and other factors (Meeker et al., 1987). Differences in NK cytotoxicity and the lymphocyte proliferative responses have been reported in 2 commercial lines of pigs (Reed and McGlone, 2000). More recently, studies by Sutherland et al. (2005, 2006) reported several breed effects on various immune components (i.e., neutrophil phagocytosis and NK cytotoxicity).
The stress responsiveness of an animal has also been shown to be affected by genetics. Blecha et al. (1984) reported that Angus and Braham x Angus cattle responded immunologically differently to shipping stress; lymphocyte proliferation was reduced in both breeds, but total leukocytes and skin-test response to PHA were greater in Angus steers than in Braham x Angus steers. Angus calves had greater total IgG and IgM titers against pig red blood cells and lymphocyte proliferation in response to PHA compared with Simmental calves (Engle et al., 1999). In 2 commercial lines of pigs, the environment in which they were kept influenced their immune status; both genetic lines had similar chemotaxis indoors, but outdoors chemotaxis differed between the 2 lines (Reed and McGlone, 2000). Large White pigs had greater poststress ACTH levels after exposure to a novel environment than did Meishan pigs, but no immune measures were evaluated (Desautes et al., 1999). Others have investigated the immune competence of 2 Australian breeds of pigs to a bacterial challenge; specific cell populations were different between the breeds (Nguyen et al., 1998). Recently, studies by Sutherland et al. (2005, 2006) showed numerous breed effects on various immune components (i.e., neutrophil phagocytosis and NK cytotoxicity), but there were no breed x stressor effects on immune status of several breeds of pigs exposed to 14 d of heat stress and crowding (Sutherland et al., 2006).
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STRESS SHIFTS THE TH1/TH2 BALANCE |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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). This model holds that stress hormones influence the production of Th1 and Th2 cytokines, which determines the type of immune response that prevails (Elenkov et al., 1999). Cytokines provide the link between the innate and adaptive immune systems and help maintain T-cell homeostasis during infection (Bot et al., 2004). The hallmark cytokine of Th2 immunity is IL-4. If IL-4 is overexpressed, it negatively interferes with the immune defense mechanisms, thus decreasing the recruitment, expansion, or activity of major effector cells such as the Th1 cells (Bot et al., 2004). During a viral infection, a strong bias toward Th2 responses may interfere with viral clearance. However, if the opposite scenario occurs (i.e., elevated Th1 and reduced Th2 immunity), normal viral clearance can occur (Bot et al., 2004). It is possible that certain stressors may disrupt this balance by interfering directly or indirectly with the mechanistic immune processes. A balanced Th1/Th2 response may be favored in some cases of disease challenge to achieve a compromise between defense mechanisms and immune homeostasis.
Interleukin-12 or IFN- produced by cells of the innate immune systems act on corresponding receptors expressed by differentiating T cells (Hanlon et al., 2002; Trinchieri, 2003). The T cells may redirect the process from Th2 toward Th1 cells. Thus, if stress disrupts the balance between Th1 and Th2, then disease is the outcome. We can examine the impact stress has on the Th1/Th2 balance from recent studies based on cytokine profiles and immune function. Mixing stress in conjunction with pseudorabies vaccine may result in a shift toward Th1 based on IFN levels (de Groot, et al., 2001), whereas pigs challenged with Toxoplasma gondii had elevated Th1 and Th2 cytokines; thus at the time of sampling these animals were still in a balanced Th1/Th2 response (Dawson et al., 2005). Moreover, in cattle challenged with Ostertagia ostertagi, the cytokine profile appeared to be skewed toward Th2, which would be the appropriate response for parasitic challenge (Claerebout et al., 2005). In contrast, in pigs vaccinated against parasitic Taenia solium, there was no effect on Th2 cytokines, and thus the vaccine did not skew the immune system toward a Th2 response (Diaz et al., 2003).
Furthermore, other stressors that affect immune measures may also skew the Th1/Th2 balance. Based on immune characteristics, 4 d of cold stress appeared to shift the Th1/Th2 balance toward a Th1 response (J. L. Salak-Johnson and S. R. Niekamp, unpublished data), whereas 14 d of heat/crowding resulted in a Th1 response based on enhanced NK in stressed pigs (Sutherland et al., 2006). Acute restraint stress may disrupt the Th1/Th2 balance temporarily as a homeostatic mechanism (Wrona et al., 2001). More specifically, 1 h of restraint stress may skew the balance toward a Th1 response, but by 4 h poststress the response is skewed toward Th2 (Wrona et al., 2001). Moreover, it is possible that pigs weaned at 28 d of age become skewed toward a Th2 response, whereas pigs weaned at 14 d of age appear to be shifted toward a Th1 response or have a balanced Th1/Th2 response based on their cytokine and immune profile (S. R. Niekamp, M. A. Sutherland, and J. L. Salak-Johnson; University of Illinois, unpublished data). Pigs weaned at 14 d of age and kept on a schedule of 8 h of light per day may be shifted toward a Th2 response (Niekamp et al., 2007).
At 7 d postPRRS challenge, infected pigs appear to be able to maintain a balanced Th1/Th2 response based on their cytokine and immune profile; thus these animals were able to resolve the infection. Based on these studies, it is theorized that stress does not always suppress the immune system or disrupt the Th1/Th2 balance, or both. In fact, in some situations stress may enhance some components but suppress others to shift the balance between the Th1 and Th2 systems.
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CONCLUSIONS |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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Footnotes |
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2 Corresponding author: johnso17{at}uiuc.edu
Received for publication August 4, 2006. Accepted for publication October 21, 2006.
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LITERATURE CITED |
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TopAbstractINTRODUCTIONTHE BRAIN AND ADRENAL...IMMUNITY AND GLUCOCORTICOIDSSTRESS EFFECTS ON IMMUNITYOTHER FACTORS AFFECTING STRESS...STRESS SHIFTS THE TH1/TH2...CONCLUSIONSLITERATURE CITED |
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/IL-10 balance. Ann. N. Y. Acad. Sci. 917:94–105.[Medline]This article has been cited by other articles:
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  J. D. Lippolis and T. A. Reinhardt CENTENNIAL PAPER: Proteomics in animal science J Anim Sci, September 1, 2008; 86(9): 2430 - 2441. [Abstract] [Full Text] [PDF]
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