Cytokines: Applications in Domestic Food Animals FRANK BLECHA Depamnent of Anatomy and Physiology Kansas W e Unhrersity Manhattan 66X6 ABSTRACT

Cytokines such as human, bovine, and porcine interferons and human and bovine interleukin-1 and interleukin-2 have been used in vivo in cattle and pigs. Colony-stimulating factors and tumor necrosis factor a have been evaluated in vitro in food animals. Studies to evaluate cytokines in domestic food animals have shown that specific and nonspecific immunomodulation is possible in immunosuppressed or pathogenexposed animals. Cytokine prophylaxis or therapy in food animals may have the greatest potential for control of respiratory disease and mastitis. (Key words: cytokine, bovine, porcine) Abbreviation key: bHV-1 = bovine hexpesvirus-1, bTP = bovine trophoblast protein, GMCSF = granulocytemacrophage colony-stimdating factor, IFN = interferon, IL = interleukin, oTP = ovine trophoblast protein, rbIFN = recombinant bovine interferon, rbIL = recombinant bovine interleukin, rhIFN = recombinant human interferon, rhIL = recombinant human interleukin, TGEV = transmissible gastroents ritis virus, VSV = vesicular stomatitis virus. INTRODUCTION

Cytokines are proteins that are involved in the regulation of the immune response. When these proteins are produced by lymphocytes, they are Eferred to generically as lymphokines (32). and when they are produced by monocytes or macrophages, they may be called monokines. The term interIeukin is applied to proteins that function as communicators between leukocytes (1). Sometimes the term cytokine has been used to refer to biological

Reccicd September 18, 1989. Accepted Dwember 28, 1989. 1991 J Dairy Sci 74328-339

mediators that are produced from nodymphoid cells (41); however, cytokine is generally used as an umbrella term to denote protein biological mediators that participate in immune re& tion. The beginning studies with cell-free supernatants, from which single cytokines would eventually be purified, were of€enviewed with skepticism. This skepticism was undexstandable, considerhg the various sources from which the factors were derived and the pleiotropic nature of their activity. However, with the advances io protein purjfication and recombinant DNA technologies, the study of cytokine regulation has advanced from the examination of factors to the examination of single proteins. The current list of cytokines includes: interferons (a,B, and $, tumor necrosis factor, lymphotoxin, interleukins @-1 to E-10). colony-stimulating factors, and transforming growth factor p. Cytokines exhibit various degrees of species specificity. For example, recombinant human interleukin-2 (rhIL-2) augments some immune functions both in vitro (36, 65,92) and in vivo (3.44) in cattle and pigs. However, in the few cases of domestic food animals in which cytokines have been compared in a homologous system (for example, bovine cytokines evaluated on bovine cells), homologous cytokines were generally more effective (9, 21, 60). These findings have led to the molecular cloning of s e v d cytokines from economically important animals such as cattle and pigs Uable 1). Cytokines influence many different aspects in the maturation and differentiation of cells of the immune system and in the host's response to disease (F5gure 1).Although cytokine regulation of immunity involves a complex network, our knowledge of this network has expanded enough to allow the use of exogenously administered cytokines as modulators of immune function The purpose of this review is to discuss the rationale for using cytokines in domestic food animals and recent data from studies




TABLE 1. Bovine and porcine manbinant cytokiraes.

that have evaluated the in vivo use of cytokines food animals when immune function may be low, such as the neonatal period or periods of in cattle and pigs. stress- or pathogen-induced immunosuppression. For example, natural killer cell activity is RATIONALE FOR USING CYTOKINES very low, if not absent, in neonatal pigs (18,45, Cytokine therapy in human cancer patients 97),but attempts to increase this host defense has received much attention and continues to be mechanism in young pigs with cytokines or therapies have been enan active area of research in tumor biology. *kine-inducing Interleukin-2 is used to produce lyrnphokine- couraging (24, 55). Studies in laboratory activated killer cells, which have enhanced animals also have shown that cytokine-induced tumoricidal activity (83). Colony-stimulating restoration of immune function is possible in factors, such as p u l o c p - m a c r o p ~ e animals that are jmmunocompromised (27,35, colony-stimulating factor (GM-CSF), are being 37). Collectively, these studies produce expecevduated as a means of stimulating hematopoi- tations that cytokine prophylaxis or therapy esis in patients undergoing chemotberapy (31). may be effective in domestic food animals for However, because most domestic food animals which stress- or pathogen-induced immunosup do not live long enough for tumors to present a pression has been linked to disease susceptibilserious health problem, what is the application ity (8, 12, 98). of cytokine prophylaxis or therapy in these

animals? Although vaccination programs have increased tremendously the profitability of livestock production, large economic losses still OCCUT from disease, even in animals that have been vaccinated. Bovine respiratory disease in feedlot animals and mastitis in dairy cattle, estimated to cause annual losses of billions of dollars, are examples of two health problems in food production animals that could benefit from new prophylactic and thempeutic strategies. Cytokines have been used successfully as vaccine adjuvants in laboratory animals (66,70, 72,79,90,%) and may prove to be an effective means of increasing vaccine efficacy in domestic food animals. Additionally, cytokines have potential use to augment immune function in various periods during the production of


Recombinant DNA technology has made it possible to evaluate several qtokines in large domestic food animals. Interferons 0, a and 7 and intedeukin-1 and interleukin-2 have been studied in vivo in domestic food animals, and tumor necrosis factor a and GM-CSF have been studied in vitro on bovine cells. Interferons

Virus interference was the original description for the antiviral properties of the interferons (47). However, research has shown clearly that the proteins and glycoproteins that comprise the interferon family have many biologic activities, including immunomodulation Journal of Dairy Science Vol. 74, No. 1, 1991



Cytokine Interactions Action of

4 Cytokines Cell d i v i s i o n

L__I) D i f f e r e n i i o t i o n TNF IL- I



figure 1. Interrelationship of t k cytokiue network CSP = Colony-stimulating factors; Ig = i m n t u n o g o ~IL = intcrlcukiq TGF = transforming mwth factoq TNP = m o r necrosis factor. M d e d fnrm Blachvill(11).

(40,89). Recombinant human and bovine (13) interferons have been used in domestic food animals, and in vivo studies in pigs with recombinant porcine interferons are in progress (C.L a Bonnardiere and B. Charley, Institut National de la Recherche Agronomique, Jouyen-Josas, France, personal communication). Recombinant Human Integeron. Bovine respiratory disease continues to be a costly production problem for North American cattle pmducers. Consequently, much research has been focused on new prophylactic and therapeutic strategies to combat this disease syndrome. Bovine herpesvirus-1 @HV-1) is one of the viruses involved in the multifactorial etiology of the bovine respiratory disease complex. The prophylactic effect of recombinant human interferon a (rhIFN-a) in preventing bHVJournal of Dairy Scimce Vol. 74, No. 1. 1991

l-induced respiratory disease has been evaluated in cattle (82). Holstein and crossbred Holstein calves were treated i n h a n a d y or intramuscularly witb various dosages of rhIF'N-a and inoculated intranadly with bHV-1 on the first day of the experiment. Calves were treated with rhIFN-a every 12 h for the next 6 d. Calves administered 106 U of IfiIFN-a both intranady and intramuscularly and inoculated with bHV-1 had less severe signs of bovine respiratory disease; no differences were found between calves given lower dosages of rhIFN-cc and bHV-1 and those only challenged with bHV-1. Although clinical disease was less in calves administered a high dose of xbIFN-a, the fever and depression that developed during administration of the cytokine, the necessity of multiple dosages, and the f'act that antibodies to

S y M p o s I u M . RESPONSE

--a were detected in one calf would a p pear to limit the practicality of using rhIFN-a in bovine respiratory disease prophylaxis. The efficacy of rhIFN-a in preventing diar&ea in neonatal calves also has been evaluated. Colostrum-deprived newborn calves were inoculated orally with bovine rotavirus within 24 h after birth (86). Calves that were injected intramusdiuly with at 106 u/kg per day had less severe djarrhea than calves that were challenged with rotavirus but did not receive rhlFN-%. However, rhIFN-4~2treatment did not decrease virus replication. A recent study by the same researchers (87) confinned that rhIl?N-a(2 lowered diarrhea in rotaviruschallenged, colostrumdeprived newborn calves and found the same effect in calves inoculated with a combination of rotavirus and Escherichia coli. Recombinant Bovine Integeron. Several studies have been conducted evaluating the prophylactic or therapeutic effect of m m b i nant bovine interferon (rbIFN+x or rbIFN-y) in viral and bacterial diseases of cattle and pigs and in immunocompromised cattle. Babiuk et al. (7) conducted an extensive series of experiments designed to evaluate the efficacy of rbIFN-al in bovine respiratory disease. Calves (seronegative for bHV-1) were treated with rbIFN-q(l0 mg/calf, intranady) or with a placebo 2 d before challenge with bHV-1. Four days after viral challenge, calves were inoculated with Pasteurella haemolytica. Respiratory disease symptoms were significantly lower in rbIPN-al-treatedcalves than in control animals. Additionally, those animals that received rbIFN-q had fewer number of sick days and less pneumonic lung tissue than control animals. However, rbIFN-al trearment did not appear to have a direct effect on bHV-1 replication because bHV-1 excretion in nasal secretions was not diffennt between control and rbIl?N-al-treated calves. These findings suggest that rbIFN-q may have had an indirect immunomodulating Muence in reducing bHV1 and P. haemolytica respiratory disease in cattle. The efficacy of rbIFN-al in preventing virus-induced diarrhea in pigs also has been evaluated (57). Eight colostrum-deprived pigs were reared in isolation and given rbWN-q (2 x l@ U,orally); eight control pigs received a placebo. Beginning at 6 h of age, pigs were given



rbIl?Nlxl or placebo every 12 h, and, at 48 h of

age, a l l pigs were challenged cith transmissible gastroenteritis virus (TGEW). Although initial in vitro experiments indicated that rbIFN-q decreased TGEV replication in swine testicular cells and a preliminary experiment suggested that rbIFN-al was not degraded completely by gastric secretions, oral treatment of neonatal pigs with rblFN-al did not prevent diarrhea in TGEN-challenged pigs. Although neonatal pigs can absorb intact proteins prior to intestinal closure, rbIFNq was likely degraded sufficiently to limit any protective effect that may have been afforded by its oral administration. Calves administered rbIFNq as an adjuvant to vesicular stomatitis virus (VSV) immunization had i n c r d antibody responses to VSV and were more resistant to a VSV challenge than calves immunized only with vsv (4). Three Merent dosages of rbIF2V-y were administered intran~uscularlyat 2 d before, on the day of, and 2 d after immunization with VSV. Animals that received the highest dose of rbEN-y (5 x 106 U/animal) had a greater primary antibody response to VSV than calves that received only the virus immunization. The authors did not indicate if calves injected with rbm-7at 5 x 106 a ani mal for 3 consecutive d exhibited fever and malaise, a fhquent problem when high dosages of cytokines are used. However, these data suggest that rbm-7 may have potential as an adjuvant in cattle. The capability of in vivo administration of hWN-7 in calves to influence in vitro neutrophil responses against Brucella abortus was studied by Canning and Roth (16). Calves were given a single subcutaneous injection of 2.2 x 1@ or 1.1 x 106 U of rblFN-y or phosphatebuffered saline solution. Bovine neutrophil functions were evaluated 1, 2, and 3 d after rbEP4-y injection. One day after rbIFN-y injection, neutrophil random migration was less in calves injected with 1.1 x 106 U of r b m q than in control calves. Both doses of rbIFN--y increased opsonized zymosan-stimulated iodination in the presence of B. abortus in mmparison with control values when neutrophil function was evaluated 1 d after cytokine injection. Neutrophils from calves injected with 1.1 x 106 U of rbIFNq 1 d after cytokine injection were more bactericidal against B. abortus than those from control calves. These findings indicate that the in vivo treatment of calves with rbIFNJ

o of Dairy ~ S c i m Vol. 74, NO. 1, 199;



y activated neutrophils and increased their ability to kill B. abortus. However, the short-lived nature and the magnitude of the rblFN-yenhanced neutrophil response may limit the biological relevance of this observation. Peel et al. (71) used 3- to 4-wk-old calves infected with a virulent amin of Sulmonella typhimurium to evaluate the prophylactic and therapeutic potential of rbIFN-y. A dose of rbIFN-y at .5 mg/calf had a detrimental effect on the ability of calves to survive 7 d after infection with 1 x lo7 du of S. typhimurium. When the dose of bacteria was increased to 1 x 108 cfu, rbIFN-y at .1 mg/calf had a beneficial effect on calf survival. A second experiment used calves infected with I x 107 cfu of bacteria and treated with various dosages of rbIFN-y (1 to .01 mg/kg per day) beginning at 6 h before infection and continuing for 5 d. This treatment regimen had a detrimental effect on calf survival. These data indicated that rbIFN-y administered before a severe challenge with S. typhimurium (1 x 10s du) was beneficial to catf survival. However, continued administration of rbIFN-y after challenge with S. typhimurium decreased calf survival. The problem of timing of cytokine administration, relative to infection, would appear to limit the practical use of rbIFN-y in salmonellosis. The synthetic glucocorticoid, dexamethasone, decreases lFN-y mRNA (6), and a restraint stressor has been shown to decrease the capacities of stressed mice to produce IFN-y and IFN-a (48). These findings suggest that interferon administration may be effective in stressed animals. Roth and Frank (84) conducted an experiment evaluating the influence of rbIFN-y in dexamethasone-treated calves. Twenty calves were assigned to four groups: 1) controls, 2) dexamethasone (.@ in&), I 3) rbIFN-y (1.1 x 106 U/animal), and 4) dexamethasone and rbIFNq. Dexamethasone and rbIFN-y were administered daily for 2 consecutive d. Calves treated with dexamethasone and rbIFN-y did not exhibit the same degree of leukocytosis as dexamethasone-treated calves. Dexamethasone-induced suppression of mitogen-stimulated lymphocyte blastogenesis was not abrogated by rbWN-'y treatment. However, some neutrophil functions, including random migration, ingestion of Staphylococcus aureus, iodination, and antibodydependent cellular cytotoxicity were improved by combined treatJournal of Dairy Science VoL 74. No. 1, 1991

ment with dexamethasone and rbIFN-y compared with dexamethasone treatment alone. These data imply that rbIFN-y may be an effective inmunomodulator in immunosuppressed animals. Indeed, rbIFN-y has been shown to reduce the percentage and severity of Huemophilus somnus-induced pneumonia in &xamethasone-injected calves compared with those injected with dexamethasone only (26). Recombinant Porcine Interferons. Most studies evaluating the in vivo influence of recombinant porcine interferon (rpIFN-a) (rplFN-?i) in pigs are still being conducted (C. La Bonnardiere and B. Charley, Institut National de la Recherche Agronomique, Jouy-enJosas, France, personal communication, 52). However, a recent study by Campos et al. (15) showed that rpIFN-a and rpIFN-y decreased mortality, increased survival time, and reduced clinical signs of acute and peracute Actinobucillus (formerly Haemphilus) pleuropneumoniue infection in pigs when administered as a single dose 24 h before challenge. Additionally, in vitro experiments have demonstrated that r p l N F ~has antiviral activities against TGEV (23) and Afiican swine fever virus (34) and immunomodulatory capabilities on porcine lymphoid cells (22, 33). In vivo administration of rplFN-a or rpIPN-y in pigs will likely be as effective as in vivo use of rbWN in cattle. Embryonic Interferons. Proteins secreted by the embryonic trophectoderm may be important immunoregulatory cytokines involved in regulating the immune response of the mother to the fetal allograft. Ovine and bovine trophoblast proteins (oTP-1and bTP-1, respectively) have good identity (40 and 55%) with IFN-ar from several species, including humans, murine, rat, porcine, and bovine; however, identity with rbIFN-q is about 70% (25, 46, 81, 91). purified OW-1 has antiviral activity (74, 81): antibodies to human leukocyte interferon can neutralize the antiviral activity (81), and, similar to MFN-a, low concentrations of oTP-1 inhibited mitogen-induced lymphocyte proliferation (67,81). Antiviral activity also has been detected in uterine flushings of sows between d 12 to 20 of pregnancy (51). Studies have shown that bTP-1 inhibits endometrial prostaglandin F2a release and, thus, prevents luteolysis and allows continued progesterone secretion (42, 43). Recently, Wte et al. (73) have shown that intrauterine infusions and intramuscular in-



jection of rbIFN-a1prolong luteal lifespan, and findings collected on d 71 of the study indipreliminary data from Martimod et al. (61) sug- cated that pigs that received the multiple injecgested that daily injections with 20 mg of tions of rhIL-2 (at both dosages) had the least rbIFN-al from d 14 to 20 postestrus may in- amount of lung affected by the bacterial chalcrease conception rate in heifers. These prelimi- lenge; however, a single injection of 1 6 U/kg nary findings imply that exogenous interferon also produced protection comparable with that administration may have potential in improving from multiple injections. Additionally, antibody titers to A. pleuropneumoniae were higher in fertility in domestic food animals. those pigs that received the high dose of rhIL2. These findings were confirmed by Nunberg et lnterleuklns aL (69) in a similar experiment that evaluated Interleukin-1 is a predominantly macro- multiple aaily injections of rhIL-2 (104 or 105 phage- or monocyte-derived protein that modu- Ukg) in A. pleuropneumoniae-vaccinated and lates many of the responses involved in the challenged pigs. Adverse side effects of the process of host defense to infection (30). Inter- rhIL-2 administration were noted during the leukin-2 is secreted by a subset of T cells (64) period of injection (moderate diarrhea and lack and large granular lymphocytes (49) after stim- of appetite), but these initial in vivo studies ulation with mitogen or antigen. This lym- demonstrated the potential of I L 2 as an adjuphokine induces the clonal expansion of acti- vant in pigs. vated T cells (39) and B cells (14, 63) and In vitro studies have shown that rhIL-2 augactivates natural killer cells (50). The very im- ments mitogen-stimulated lymphocyte prolifportant regulatory role that these two interleu- eration in cattle and pigs (2, 10, 36, 92). Addikins play in the immune response have made tionally, several in vitro experiments have them prime candidates for use in im- shown that porcine natural killer cell cytotoxicmunomodulation studies. ity was enhanced by incubating peripheral Recombinant Human Interleukin-2. Ander- blood mononuclear cells with rhIL-2 (10, 21, son et al. (3) conducted one of the first experi- 36). We were interested in determining if in ments evaluating the use of rhIL-2 in domestic vivo injections of rhIL-2 would augment porfood animals. Twenty-four pigs (10 to 15 kg cine immune functions, including natural killer each) were vaccinated on d 0 and 21 with a cell cytotoxicity (44). Eighteen pigs (6 pigs per formalin-inactivated A. pleuropneumoniae group) were injected with either 104 or 1 6 U/ bacterin. At each vaccination, pigs were in- kg BW of rhIL-2 or an equivalent volume of jected intramuscularly with either 103 or I@ u sterile isotonic saline (control) on d 0 through of rhIL-2kg of BW. The two dosages of rhIL-2 4. The activity of the rhIL-2 was 1.3 x lo7 U/ were evaluated in a single injection at each mg and corres ded to .77 and 7.7 pg/kg per vaccination and in a regimen of daily injections day for the 1 E d 1 6 Ukg treatment groups, for 5 consecutive d beginning at each vaccina- respectively. All pigs were immunized with an tion day. Additionally, one control group of E. coli J5 bacterin on d 0. Cytolytic activity to pigs received only the A. pleuropneumoniae porcine fibroblasts was increased in pigs treated bacterin, and another control group was not with rhIL-2 compared with control animals. vaccinated with the bacterin or injected with cytotoxicity to K-562 cells also showed a tenrmL-2. On d 42 of the study, all pigs were dency of increased cytolytic activity in the challenged intranasally with virulent A. rhIl-2-treated pigs. Mitogen-stimulated lympleuropneumoniae serotype 1. Pigs that phocyte blastogenesis, E-2 production, and received the bacterin and five daily injections concentrations of serum iron were not different of rhIL-2 at each vaccination were the least among treatment groups. Antibody concentraseverely affected by the bacterial challenge, tions to E. coli J5 antigens increased si@with no apparent difference between the two cantly in all groups after immunization, but no dosages of rhlL-2 when administered in mul- differences occurred among treatment groups. tiple injections. Pigs that were not vaccinated These data suggest that in vivo injections of and did not receive rhIL-2 and pigs that only rhIL-2 increases natural killer cell activity in received the bacterin were the most severely pigs without influencing other immune activaffected by the bacterial challenge. Necropsy ities. J o d of Dairy Science Vol. 74, No. 1, 1991



Recombinant Bovine Interleukin-2. One of the main pathogens involved in the multifactorial etiology of bovine respiratoxy disease is bHV-1. Because in vivo use of IL-2 in mice had been shown to enhance immunity to herpes simplex virus (85,96), we were very interested in determining if recombinant bovine interleukin-2 (&E-2) could enhance immunity and protection in bHV-1-vaccinated and challenged calves (77). Our initial experiment was designed to determine if r b L 2 alone augmented immunity and protection in bHV-l-challenged calves and if the lymphokine had any adjuvant effect when used in conjunction with a bHV-1 vaccine. The dosage of rbIL-2 that we used was based on an extrapolation, on a B W basis, of the dose of rhL-2 that had induced protection in A. pleuropneumoniae-vaccinated and A. plewopneumoniue-challenged pigs (3). Twenty-four Hereford or Hereford x Longhorn heifers (185 kg each and seronegative for bHV1) were assigned randomly to one of four treatments: 1) no rbIL-2 and no bHV-1 vaccine, 2) ML-2, 3) bW-1 vaccine, and 4) rblL-2 and bHV-1 vaccine. Calves were vaccinated with a modified live bHV-1 vaccine at the beginning and at d 18 of the study and were injected intramuscularly with rbIL-2 (25 p&g per day) for 5 consecutive d at each vaccination. Calves not injected with rbL-2 received an equivalent volume of sterile isotonic saline. On d 28 of the study, all calves were challenged haamsally (1 ml) and conjunctivally (1 ml) with 10s pfu/ml of bHV-1. Peripheral blood mononuclear cell cytotoxicity against bHV-l-infected bovine fibroblasts was increased by rbIL-2 treatment. Cells from calves that received only rbL-2 developed the same capability to lyse virus-infected target cells as cells from calves that received the vaccine in addition to the bHV-1 vaccine. Additionally, serum-neutralizing antibody titers to bHV-1 were increased sixfold, and the amount of virus shed in nasal secretions was four times less in calves vaccinated and treated with rbL2 than in calves that received the vaccine but no rbIL-2. Importantly, calves that were vaccinated with bHV-1 and injected with rbIL-2 had less severe clinical signs of bHV-1 infection, including lower rectal temperatures, after challenge. Unfortunately, treatment of calves with rbL-2 at 25 pgkg per day resulted in adverse side effects, including diarrhea and mild fever, Jonmal of Dairy Science Vol. 74, No. 1, 1991

during the period of lymphokine injection. Although some degree of adverse clinical effects of cytokine immunotherapy can be tolerated in human patients undergoing cancer treatment, it is doubtful that immunomodulators will be used in domestic food animal medicine if their administration produces illness. However, because Baker (9) found that r b L 2 was approximately three times more effective than IliIL-2 when both lymphokines were evaluated on bovine lymphocytes, it seemed reasonable to hypothesize that a lower dose of rbIL-2 might s t i l l enhance resistance to bHV-1 infection without causing illness during its administration. Our second experiment was designed to determine a dose of rbIL-2 that would enhance immunity to bHV-1 without causing adverse side effects (77). Twenty-five Holstein or crossbred beef calves (4 to 6 mo old and seronegative for bHV-1) were allotted by weight to five groups: 25, 2.5, .25, or .025 pg/ kg per day of rbIL-2 for 5 d and controls that received an equivalent volume of sterile isotonic saline. At the start of the experiment, all calves received a modified live bHV-1 vaccine and respective doses of rbIL-2 or placebo. All calves were challenged with lo7 pfu of bHV-1 on d 21. Cytotoxicity of peripheral blood mononuclear cells against bHV-1-infected bovine fibroblasts was i n c r d in rbIL-2-treated calves in a dosedependent manner. Calves treated with 25, 2.5, and .25 pgbg per day of rbIL-2 had higher senun-neutra2izing titers to bHV-1 and after challenge lower bW-1 titers in nasal secretions than control calves. Additionally, clinical disease was less severe in the calves that received rbIL-2 at the three higher dosages. Importantly, although rblL-2 at 25 pg/ kg per day caused adverse side effects similar to those observed in our first experiment, calves that received lower doses of rbIL-2 remained healthy and n o d during the period of rbL2 administration. Similar to other studies that have shown a beneficial adjuvant effect of L 2 (70, 72). these studies with rbIL-2 in cattle clearly indicate the potential value of using this lymphokine as an adjuvant in domestic food animal medicine. Because mastitis is the most expensive disease affecting dairy cows, it is important to find more effective ways to minimize its impact on milk production. The capability of rbL2 to enhance immune responses in mastitic cows



has been evaluated m n t l y by Nickerson et al. tratracheally) with lo7 pNml of bHV-1. To (68). Jersey cows were selected that had two determine if rb&l p influenced the reactivation udder quarters affected with chronic, subclini- of bHV-1 from infected calves, dexamethasone cal Staph. uw-em mastitis and two quarters was injected (.04mg/kg) on d 58 and 59 of the from which Staph. awem had never been isolated. When the cows were dried off, miniosmotic pumps designed to release 1, 10, or 100 pg of rbIL-2 or a placebo over a 1- or 3-wk period were surgically inserted into teat cisterns. Histological evaluation of mammary tissue indicated that total lymphoid cell numbers and IgG1- and IgG2-secreting plasma cells were similar in quarters that had subclinical mastitis and those treated with rbIL-2. The greatest response in lymphoid cell numbers and IgGl and I& plasma cells was found in quarters that had subclinical Staph. uureus mastitis and were implanted with miniosmotic pumps releasing rbIL.-2. Secretions from rbIL-2-treated quarters had higher numbers of lymphocytes and macrophages than the placebo-treated quarters. Neutrophil function and mastitis cure rate also have been enhanced by -ni infusions of rbIL-2 (M. Daley, American Cyanamid Co., Princeton, NJ, personal communication). These results suggest that rbIL2-induced stimulation of marmnary gland immune defenses may be a means of enhancing protection against mastitis. Recombinant Bovine Interleukin-Ip. The encouraging data that we had obtained with hIL2 in a bHV-1 vaccination and challenge protocol prompted us to evaluate other cytokines that also might be effective in enhancing immuNty in cattle. Because of the welldocumented adjuvant effect of IL-1 (37, 66, 79, 90), including its use in viral and bacterial infections in mice (28,29), and because of the availability of recombinant bovine ILlP (rbTL-lp) (59), we conducted a study that was designed to determine the capability of rbIL-lP to augment immunity in bHV-l-vaccinated and challenged calves (75). Twenty-four Holstein bull calves (150 kg each and seronegative for bHV-1) were assigned randomly to four groups. All calves received a modified live bHV-1 vaccination on d 1 and 15 of the study. At each vaccination, calves received one intramuscular injection of rbIL-lP at 33, 100, or 330 ngkg. Control calves received an equivalent volume of sterile isotonic saline. On d 22, all calves were challenged (1 ml intranasally and 1 mI in-

study, and virus e x d o n in nasal secretions

was determined. Serum-neutralizing antibody titers to bHV-1 tended to be higher, and cytotoxic responses against bHV-l-hfected fibroblasts were increased in rbE-ljhramd calves. Calves treated with rbIL-1fi at 100 n&g shed less virus in nasal secretions during the postchallenge period than control calves and calves injected with rbIL-lP at 330 ng/kg. Calves treated with rbIL-lp showed a tendency to have increased BoT4BoT8 cell ratios. During the prechallenge period, the increase in BoT4:BoTS was caused by an increase in the BoT4 subset. The postchallenge increase in BoT4BoT8 was due to a decrease in the BoT8 subset. Seventy of clinical signs of bovine respiratory disease was not different between rbIl-i&tceated calves and control calves. However, calves that had been treated with 100 n a g of rbIL-1s excreted less bHV-1 in nasal secretions after injection with dexamethasone 35 d after viral challenge. Importantly, no adverse si& effects were observed in the calves during treatment with rbIL-1p. Colony-Stlmulatlng Factors The colony-stimulating factors are a group of glycoproteins that regulate differentiation and mamation of hematopoietic precursor cells and functional activities of mature cells (62, 93). Granulocyte-macrophage colony-stimulating factor promotes the growth and diffemwiation of myeloid progenitor cells to granulocytes and macrophages and enhances mature neutrophil functions (38, 88, 93). Recent reports have indicated that colony-stimulating factors, secreted by the uterus in response to seminal components, may increase fertility by inducing beneficial effects at implantation (5, 95). We have conducted a few initial in vitro studies evaluating the capability of GM-CSF to modulate bovine neutrophil function. Recombinant Bovine Granulocyte-Macrophage Colony-Stimulating Factor. Neutrophils were obtained from calves that had been injected with dexamethasone (-04mg/kg) or from Uninjected animals (78). Dexamethasone treatJournal of Dairy Science VoI. 74, No. 1. 1991



ment d e a d several neutrophil functions, ment Station. I thank P. Gopal Reddy and my including luminol-dependent chemilumines- graduate students for helpful suggestions with cence, phagocytosis of Pasteurella multocida this manuscript. and Staph. aureus, and antibodydependent cellular cytotoxicity against bHV-l-infected fibroREFERENCES blasts. Incubating neutrophils with recombinant 1Aarden, L. A., et aL (34 authors). 1979. htter to the bovine GM-CSF (ffiM-CSF) increased neuEditor. Revised nw~en~lature fm ant@en-M@C trophil functions in control animals and in T cell prolifuation and helper factors. J. ImmunoL calves injected with dexamethasone. However, 1232928. rbGM-CSF-induced increases in neutrophil 2 Anderson, G., J. J o h n , and P. Baker. 1986. Bovine neonatal lymphocyte sthnulationwith human recombifunction tended to be greater in calves injected nam interl-2. Page 62 in Proc. 67th h. Mtgwith dexamethasone than in control calves. Cod. Res. Workers Anim. Dis., Chicago, IL. Neutrophils obtained from mastitic cows had 3 Anderson, G., 0.Urban,P. Fedorka-Cray, A. Newell, a lower capability to phagocytize Staph. aureus J. Nunberg, and M. Doyle. 1987. Interleukin-2 and protective immunity in HaemophiIus pleuropnewnothan neutrophils from control cows (76). Howniae: preliminary studies. Page 22 in Vaccmes 87. ever, when neutrophils from mastitic cows were Modern approaches to new vaccines: prevention of cultured with rbGM-CSF, phagocytosis of AIDS and otber viral bacterial and parasitic disease. R Staph. aureus was increased. Additionally, M.chanock,R A. Lema.F.Brown. and H. Ginsberg, treatment of neutrophils from mastitic cows cd Cold Spring Harbor Laboratory,Cold Spring Harbor, m. with rbGM-CSF increased luminoldependent 4Anderson, IC. P.,E. H. Fennie. and T. Yilma 1988. chemiluminescencecompared with that of neuEohancanent of a secondary antibody rrsponse to trophils from control cows. Collectively, these vesicular stomatitis virus “G” protein by JFN-y ireatin vitro data suggest that rbGM-CSF may have ment at primary immunization J. Immml. 14&3599. potential as an immunotherapeutic agent in im5Amskong, D. T., S. Robertson, M. Hadjasavis, P. Graat, and R F.Seamark 1989. Potentialfor increased munocompromised animals. CONCLUSION

Recombinant DNA technologies have made it possible to evaluate the use of several cytokines in large food animals. These protein regulators of the immune response have very potent effects when administered in vivo. Often, the range between toxic and nontoxic doses of cytokines is small when immunomodulation is the desired objective. Additionally, the timing and method of administering cytokines to domestic food animals present considerable obstacles to overcome. However, the encouraging data from the initial studies conducted using cytokines in diseases such as respiratory disease and mastitis suggest that cytokine prophylaxis or therapy may some day be possible in domestic food animals. ACKNOWLEDGMENTS

Research from the author’s laboratory was supported in part by grants from the USDA (84-CRSR-2-2411, 86-CRCR-1-1957, 87CRCR-1-2309, 87-CRSR-2-3195, and 88-34116-3638) and is published as Contribution 90-34-J of the Kansas Agricultural ExperiJournal of Dairy Science Vol. 74, No. 1, 1991

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Journal of Dairy Science Vol. 74, No. 1. 1991

Cytokines: applications in domestic food animals.

Cytokines such as human, bovine, and porcine interferons and human and bovine interleukin-1 and interleukin-2 have been used in vivo in cattle and pig...
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