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Bovinemilkantibodiesforhealth

ArticleinBritishJournalOfNutrition·December2000

DOI:10.1017/S0007114500002361·Source:PubMed

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Bovine milk antibodies for health

Hannu Korhonen1*, P. Marnila1 and H. S. Gill2

1Agricultural Research Centre of Finland, Food Research, FIN-31600 Jokioinen, Finland2Milk and Health Research Centre, Massey University and New Zealand Dairy Research Institute, Private Bag 11 222,

Palmerston North, New Zealand

The immunoglobulins of bovine colostrum provide the major antimicrobial protection againstmicrobial infections and confer a passive immunity to the newborn calf until its own immunesystem matures. The concentration in colostrum of specific antibodies against pathogens can beraised by immunising cows with these pathogens or their antigens. Immune milk products arepreparations made of such hyperimmune colostrum or antibodies enriched from it. Thesepreparations can be used to give effective specific protection against different enteric diseases incalves and suckling pigs. Colostral immunoglobulin supplements designed for farm animals arecommercially available in many countries. Also, some immune milk products containingspecific antibodies against certain pathogens have been launched on the market. A number ofclinical studies are currently in progress to evaluate the efficacy of immune milks in theprevention and treatment of various human infections, including those caused by antibioticresistant bacteria. Bovine colostrum-based immune milk products have proven effective inprophylaxis against various infectious diseases in humans. Good results have been obtained withproducts targeted against rotavirus, Shigella flexneri, Escherichia coli, Clostridium difficile,Streptococcus mutans, Cryptosporidium parvum and Helicobacter pylori. Some successfulattempts have been made to use immune milk in balancing gastrointestinal microbial flora.Immune milk products are promising examples of health-promoting functional foods, ornutraceuticals. This review summarises the recent progress in the development of these productsand evaluates their potential as dietary supplements and in clinical nutrition.

Immune milk: Colostrum: Immunoglobulins: Passive immunisation

Introduction

Diarrhoeal diseases continue to represent a major threat tohuman health on a global scale. Factors such as malnutri-tion and HIV-immunocompromisation have exacerbatedthe incidence of acute and chronic acquired gastrointestinalinfections, and the increase in global travel has ensured thatnew emerging strains of enteric pathogens can rapidlyspread and become established on other continents. Currentprophylactic or interventionist methods (vaccination orchemotherapy) are often ineffective at controlling diseaseand/or eliminating infection, and have created graveconcerns over a rise in antibiotic-resistant strains throughover-use. Even in cases where measures are effective, quiteoften the treatment regime is economically and logisticallyimpossible to administer, particularly in developingcountries. There is a real need for the development ofnew means to combat gastrointestinal (GI) tract infections,where the major criteria are effectiveness, affordability,ease of administration and safety. Borrowing molecules ofimmune defence from an immunised animal may providean effective strategy in this combat.

It has long been recognised that maternal milk can offerpassive protection to a newborn infant against entericpathogens, primarily via the transfer of immunoglobulinsand associated factors from mother to infant. The historicalconcept of `immune milk', i.e. the transfer of passiveimmunity via lacteal antibodies, dates back to the 1950s(Campbell & Petersen, 1963; Lascelles, 1963). The under-lying mechanisms of passive immunity, however, wereonly recognised in the early 1960s when the chemicalstructure of immunoglobuling (Igs) was elucidated. Parti-cularly the identification of the mucosal or secretoryimmune system in the 1970s provided new insight into therole of secretory antibodies in the prevention or treatmentof enteric infections in mammals (Lamm et al. 1978). Thedevelopment of homologous (human-derived) antibodiesinto an effective treatment for enteric pathogens hassubsequently received considerably less commercial atten-tion than the utilisation of antibodies from the milk ofheterologous species, particularly ruminants. Since the1980s, an increasing number of studies have shown thatimmune milk preparations, based on bovine antibodiesderived from the milk or colostrum of immunised cows,

S135British Journal of Nutrition (2000), 84, Suppl. 1, S135±S146

* Corresponding author: Hannu Korhonen, fax +358 3 4188 3244, email hannu.j.korhonen@mtt.fi

https://www.researchgate.net/publication/284649807_A_review_of_the_literature_on_some_aspects_of_immune_milk?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/281222736_Immune_milk_-_A_historical_survey?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/22398811_Development_of_the_IgA_System_in_the_Mammary_Gland?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

can be effective in the prevention or treatment of humanand animal diseases caused by enteropathogenic microbes(for reviews see Reddy et al. 1988; Goldman, 1989;Boesman-Finkelstein & Finkelstein, 1991; Facon et al.1993; HammarstroÈm et al. 1994; Ruiz, 1994; Bogstedt etal. 1996; Davidson, 1996; Korhonen, 1998; Weiner et al.1999). The efficacy of bovine immune milk products ismainly based on the antimicrobial activity of the specificantibodies and complement factors present in the prepara-tion. This chapter reviews the current state of the art in thedevelopment of bovine immune milk preparations and theirobserved efficacy in clinical trials.

Development of antibody preparations

The progress made in understanding the underlyingmechanisms of immunity has provoked renewed interestin the development of immune milk preparations for theprevention or treatment of microbial infections in humansand domestic animals. Also, the rapid development ofmodern fractionation technologies, based on membraneseparation and chromatography, has enabled large-scaleisolation of Igs from bovine colostrum and milk (Kothe etal. 1987; Abraham, 1988; Stott & Lucas, 1989; Korhonenet al. 1998). Basically, the approaches to the developmentof Ig-based preparations are either the concentration orisolation of Igs occurring naturally in colostrum or milk, orthe hyperimmunisation of pregnant cows during the `dry'period with antigens from pathogens in order to raisespecific antibodies in the colostrum and milk.

Hyperimmunisation of cows with specific microbialantigens provides a method for inducing increased amountsof specific antibodies in the mammary secretions. The mostcommon approach, described in many scientific articlesand patent documents, is the repeated systemic inoculationof cows with an immunogen at the end of the lactationperiod and during the dry period (Korhonen et al. 1977;Saif et al. 1984; Linggood et al. 1990; Beck, 1990; Stolle,1990). Also, immunisation via the mammary gland or byoral administration of the immunogen to pregnant orlactating cows has been tried but with only moderatesuccess (Korhonen, 1973; Korhonen et al. 1977). Highantibody titres in the blood and colostrum have beenachieved using a combination of intramuscular andintramammary inoculations (Schaller et al. 1992). In mostcases, the antibody response has depended on the nature ofthe adjuvant material used in the vaccine. In experimentalstudies, Freund's complete or incomplete adjuvant has beenfound to induce the strongest humoral (antibody-based)immune response (Schaller et al. 1992; Korhonen et al.1994), but its commercial use is limited by concerns overpossible side-effects. In most cases, this has led to the useof `safer' aluminium hydroxide-based adjuvants for theimmunisation of farm animals. In our experience, the healthstatus of the cow is very important. There is still a need toexplore further possibilities of optimising the immunisationprotocol for the maximum yield and safe production ofspecific antibodies in the lacteal secretions, with aminimum of physiological stress to the immunised animals.

Efficacy of antibody preparations

The efficacy of orally administered bovine or humanantibodies has been documented in numerous studiesinvolving experimental animal models as well as clinicalhuman trials (for reviews see Levine, 1991; Facon et al.1993; HammarstroÈm et al. 1994; Ruiz, 1994; Bogstedt etal. 1996; Davidson, 1996; Weiner et al. 1999). Somestudies have provided evidence for the protective andtherapeutic effects of Igs enriched from regular bovinecheese whey or colostrum from non-immunised cowsagainst non-specific diarrhoeal diseases of newborn farmanimals (Zaremba et al. 1993; Nousiainen et al. 1994) andhumans (Fernandez et al. 1973; Lodinova-Zadnikova et al.1987; Stephan et al. 1990). In animal studies, the efficacyof Ig supplements has proved variable (Mee & Mehra,1995). In humans, promising results have been reported inthe treatment of patients with antoimmune deficiencysyndrome (AIDS) who received 10 g/d of normal bovinecolostral Ig concentrate for 10 days (Stephan et al. 1990).Rump et al. (1992) used a similar preparation and dosage inhuman immunodeficiency virus-infected (HIV) patientssuffering from chronic diarrhoea, and reported significantclinical benefits with no side-effects for the duration of thetherapy.

Farm animal infections

There is ample evidence that Ig concentrates, purified Igsderived from colostrum or milk from hyperimmunisedcows, can provide protection against rotavirus in calves(Saif & Smith, 1983; Castrucci et al. 1988; Tsunemitsu etal. 1989) and in agammaglobulinaemic piglets (Lecce et al.1991). Schaller et al. (1992) demonstrated in a gnotobioticpiglet model that both viral shedding and diarrhoea wereeffectively reduced or eliminated in a dose-dependentmanner, as a result of feeding Ig preparations containingantibodies specific for human rotavirus strains. Positiveresults have also been obtained in studies on the protectionof newborn calves and piglets against enterotoxigenicEscherichia coli diarrhoea, using a colostral supplementfrom vaccinated cows or by vaccinating dams with purifiedantigens (Isaacson et al. 1980; Snodgrass et al. 1982; Moon& Bunn, 1993).

Human infections

Bacterial gastrointestinal infections. An increasing num-ber of controlled clinical studies suggest that the oraladministration of Ig preparations containing high titres ofspecific antibodies can provide effective protection and tosome extent may also be of therapeutic value againstgastrointestinal infections in humans. In most of thesestudies, the efficacy of the preparations has been testedagainst enteropathogenic E. coli, rotavirus and Cryptospor-idium infections. Controlled clinical trials have also beencarried out using hyperimmune bovine colostrum contain-ing specific antibodies against Shigella flexneri, Helico-bacter pylori, Vibrio cholerae and caries streptococci.Table 1 presents a summary of studies in which positiveresults against bacterial pathogenes have been achieved in

S136 H. Korhonen et al.

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Table 1. Efficacy of bovine immune milk against bacterial infections in vivo

Subject Target organism Efficacy Reference

CampylobacterChicken C. jejuni In prophylaxis .99 % decrease in number of

C. jejuni in faeces. In therapeutic treatment 80±95 %lower level of C. jejuni in faeces.

Tsubokura et al. 1997

Clostridium difficileHamster C. difficile enterotoxin Protected against disease Lyerly et al. 1991Rat C. difficile enterotoxin Decreased enterotoxic symptoms Kelly et al. 1996

Escherichia coliHumansInfants Enteropathogenic E. coli Reduced E. coli in faeces Mietens et al. 1979Preterms and infants Enteropathogenic E. coli Reduced diarrhoea Lodinova-Zadnikova et al. 1987Healthy volunteers Enterotoxigenic E. coli

H10407Prevented diarrhoea after experimental challenge Tacket et al. 1988

117 children Enteropathogenic E. coliand rotavirus

No reduction in incidence of diarrhoea or otherparameters during 6 months' follow-up

Brunser et al. 1992

Preterms Eight different enterobacteria Positive effects on intestinal flora, reduction ofenterobacteria, more effective than probiotics

Kushnareva et al. 1995

Healthy volunteers Enterotoxigenic E. coli Prevented diarrhoea after experimental challenge Freedman et al. 1998

Animal modelsMouse Indigenous E. coli Prevented indigenous infection after pharmacological

impairment of intestinal microfloraNomoto et al. 1992

Domestic animalsSuckling pigs Enterotoxigenic E. coli Protected against fatal diarrhoea by E. coli Isaacson et al. 1980Neonatal calves Enterotoxigenic E. coli Prevented diarrhoeal disease after experimental

challengeSnodgrass et al. 1982

HelicobacterHumansAdults H. pylori Attenuated gastritis symptoms Tarpila et al. 1994Children H. pylori Attenuated chronic inflammation of gastric antrum Oona et al. 1997Infants H. pylori No eradication or decrease in colonisation of

gastric antrumCasswall et al. 1998

Adults H. pylori No eradication or decrease in colonisation ofgastric antrum

Opekun et al. 1999

Animal modelsMouse H. felis Prevented infection after experimental challenge Rehnberg-Laiho et al. 1995Mouse H. felis Reduced colonisation of H. felis in gastric antrum Marnila et al. 1996

KlebsiellaMouse K. pneumoniae Prevented infection Soboleva et al. 1991

ProteusMouse P. mirabilisand P. vulgaris Prevented infection Soboleva et al. 1991

PseudomonasMouse P. aeruginosa Prevented infection Stephan et al. 1990;

Soboleva et al. 1991

SalmonellaMouse S. pullorum Delayed death Campbell & Petersen, 1959Mouse S. typhimurium Prevented infection Stephan et al. 1990Mouse S. typhimurium and

S. enteritidisPrevented infection Soboleva et al. 1991

ShigellaHuman adults S. flexneri Prevented shigellosis Tacket et al. 1992

StreptococcusHuman adults S. mutans Reduced S. mutans level in dental plaque Filler et al. 1986, 1991Human adults S. mutans Reduced proportion of S. mutans in dental plaque

Elevated resting pH in plaqueLoimaranta et al. 1999b

Rat S. mutans Reduced caries development Mikhalek et al. 1987

Vibrio choleraeRabbits Cholera enterotoxin Decreased mortality and intestinal fluid response McClead & Gregory, 1984Infant rabbits Virulent cholera vibrios Reduced diarrhoea Boesman-Finkelstein et al. 1989

S137Bovine milk antibodies for health

https://www.researchgate.net/publication/21748175_Antibacterial_effect_of_bovine_milk_antibody_against_Escherichia_coli_in_a_mouse_indigenous_infection_model?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13734201_Milk_Immunoglobulin_with_Specific_Activity_against_Purified_Colonization_Factor_Antigens_Can_Protect_against_Oral_Challenge_with_Enterotoxigenic_Escherichia_coli?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

vivo, and examples of these studies are reviewed in moredetail in the following examples.

Tacket et al. (1992) gave immune milk against Sh.flexneri 2a lipopolysaccharide to human volunteers twodays before experimental challenge with a virulent strain ofSh. flexneri. The immune milk prevented the outbreak ofthe illness in all ten subjects whereas five out of elevensubjects fell ill in the control group which was treatedsimilarly with an Ig preparation from non-immunised cows.Mietens et al. (1979) treated 60 infants having diarrhoeadue to enteropathogenic E. coli for 10 days with 1 g/kgbody weight of anti-enteropathogenic E. coli bovine Igconcentrate. The treatment was effective in eliminating thepathogen in forty-three of fifty-one children infected withstrains present in the inoculum. A lyophilised Ig concen-trate (prepared from colostrum of cows immunised withseveral enterotoxigenic E. coli serotypes, fimbria types, E.coli heat-labile enterotoxin, and cholera toxin) was shownto provide complete protection against enterotoxigenic E.coli infection in ten adult volunteers (Tacket et al. 1988).These results suggest that immune colostral or milkpreparations could be useful in the prevention of traveller'sdiarrhoea. However, in a small-scale field trial carried outin Chile, Brunser et al. (1992) failed to demonstrate anyprotective benefit from supplementing an infant formulawith milk-derived antibodies specific for major entero-pathogenic E. coli serotypes (although this failure might beattributed to a low level of antibody in the formula).However, bovine Igs have proven effective in animalmodels in neutralising bacterial toxins in the gastrointest-inal tract. McClead & Gregory (1984) reported that aspecific bovine colostral Ig preparation against choleraenterotoxin was capable of decreasing mortality andintestinal fluid responses in rabbits exposed to choleraenterotoxin. The capability of bovine Igs to neutralisemicrobial toxins was also confirmed by Lyerly et al.(1991), who demonstrated that a colostral Ig preparationproduced by hyperimmunising cows against Clostridiumdifficile toxoid protected hamsters against the manifestationof C. difficile disease. In another study, a basically similarpreparation neutralised the cytotoxic effects of C. difficiletoxins on rat ileum both in vitro and in vivo (Kelly et al.1996). Thus, immune milk products may be clinicallyuseful in the prevention and treatment of C. difficilediarrhoea and colitis.

Encouraging results, although not as good as those withcryptosporidiosis, have also been reported for the admin-istration of an immune bovine colostral Ig concentrate,containing antibodies specific for Helicobacter pylori, to H.pylori-infected patients. This bacterium has been identifiedas the major aetiological agent of active chronic gastritisand peptic ulcer disease (Peek & Blaser, 1997). Bothhyperimmune and nonimmune colostrum have been shownto kill H. pylori bacteria effectively in vitro (Korhonen etal. 1995), and the observed bactericidal activity is known tobe associated with the antibody-complement system. Asimilar preparation containing specific antibodies for H.felis protected mice against H. felis infection (Rehnberg-Laiho et al. 1995). The protection was dependent on thepresence of specific antibodies in milk, the controlpreparation having no protective effect. Similarly, Thomas

et al. (1993) reported a strong negative correlation betweenthe occurrence of H. pylori antibodies in the milk ofGambian mothers and the incidence of H. pylori infectionin their small children. Preliminary clinical trials on chronicgastritis patients and children infected with H. pylori haveshown that a daily treatment for 3±4 weeks with animmune anti-H. pylori bovine Ig concentrate, delivered in adaily dose of 20 g for adults and 12 g for children, candecrease the severity of the symptoms and the rate ofHelicobacter colonisation in most subjects. However, totaleradication of the Helicobacter infection was observed inonly one out of nine adult patients and in none of thetwenty treated children (Tarpila et al. 1994; Oona et al.1997). The decrease observed in the severity of gastricinflammation suggests that the specific H. pylori antibodiesmay help to eliminate pro-inflammatory componentssecreted by Helicobacter and may also reduce (althoughnot necessarily eliminate) bacterial colonisation in thegastric mucosa. These results are consistent with those ofCasswall et al. (1998). H. pylori was eradicated from noneof a group of small children in rural Bangladesh treated for30 days with 1 g of a preparation containing H. pylori-specific antibodies. Correspondingly, Opekun et al. (1999)reported that immune bovine colostrum immunoglobulinswere not effective in decreasing the number of H. pyloripresent in the gastric mucosa of infected volunteers. On theother hand, a reduction of colonisation in the gastric antrumbut not the eradication of H. felis was observed in a mousemodel when the mice were treated with an immune bovineIg preparation (Marnila et al. 1996). Placebo-controlledclinical studies will be required to test the efficacy ofimmune colostral preparations as a potential adjunct to thechemotherapy currently practised in the treatment ofHelicobacter-associated gastritis.

Oral infections. Oral pathogens, like fungal pathogensin immunocompromised patients or dental caries-promot-ing streptococci, should represent feasible targets forintervention with immune bovine Ig preparations. Recently,Tollemar et al. (1999) succeeded in reducing Candidaalbicans colonisation in the oral cavity of immunosup-pressed bone marrow transplantation patients with bovinemilk antibodies.

Dental caries is still one of the most common infectiousdiseases, especially in developing countries. Due to thepotential side-effects of active immunisation againstcariogenic mutans streptococci, passive immunity by anoral administration of antibodies is a more acceptable wayof reducing colonisation and the virulence of these bacteriain human dentition. Studies in humans (Filler et al. 1986,1991) and in rats (Mikhalek et al. 1987) have suggestedthat bovine milk-derived antibodies specific for Strepto-coccus mutans may confer effective protection againstcolonisation by mutans streptococci and the developmentof dental caries. Recent in vitro studies have shown thatimmune bovine colostrum, containing antibodies specificfor S. mutans and S. sobrinus, was capable of inhibiting thebacterial enzymes producing sticky capsule glycopoly-saccharides (Loimaranta et al. 1997), inhibiting in a dose-dependent manner the adherence of S. mutans cells tosaliva-coated hydroxyapatite particles (which simulate thetooth surface); aggregating S. mutans cells (Loimaranta et

S138 H. Korhonen et al.

https://www.researchgate.net/publication/282308406_Helicobacter_pylori_in_children_with_abdominal_complaints_Has_immune_bovine_colostrum_some_influence_on_gastritis?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/282308406_Helicobacter_pylori_in_children_with_abdominal_complaints_Has_immune_bovine_colostrum_some_influence_on_gastritis?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/22749454_Treatment_of_infantile_E_coli_gastroenteritis_with_specific_bovine_anti-E_coli_milk_immunoglobulins?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21826289_Field_Trial_of_an_Infant_Formula_Containing_Anti-rotavirus_and_Anti-Escherichia_coli_Milk_Antibodies_from_Hyperimmunized_Cows?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21631864_Efficacy_of_bovine_immunoglobulins_concentrate_in_preventing_illness_after_Shigella_flexneri_challenge?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21142537_Effect_of_immune_bovine_milk_on_Streptococcus_mutans_in_human_dental_plaque?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21119394_Passive_immunization_against_disease_caused_by_Clostridium_difficile_by_use_of_bovine_immunoglobulin_G_concentrate?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21119394_Passive_immunization_against_disease_caused_by_Clostridium_difficile_by_use_of_bovine_immunoglobulin_G_concentrate?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/19871864_Protection_by_Milk_Immunoglobulin_Concentrate_against_Oral_Challenge_with_Enterotoxigenic_Escherichia_coli?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/19662586_Protection_of_gnotobiotic_rats_against_dental_caries_by_passive_immunization_with_bovine_milk_antibodies_to_Streptococcus_mutans?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/16771527_Resistance_of_bovine_colostral_anti-cholera_toxin_antibody_to_in_vitro_and_in_vivo_proteolysis?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/15098144_Protection_by_human_milk_IgA_against_Helicobacter_pylori_infection_in_infancy?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/15098144_Protection_by_human_milk_IgA_against_Helicobacter_pylori_infection_in_infancy?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14370276_Anti-Clostridium_difficile_bovine_immunoglobulin_concentrate_inhibits_cytotoxicity_and_enterotoxicity_of_C_difficile_toxins?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14370276_Anti-Clostridium_difficile_bovine_immunoglobulin_concentrate_inhibits_cytotoxicity_and_enterotoxicity_of_C_difficile_toxins?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14001133_Pathophysiology_of_Helicobacter_pylori-induced_Gastritis_and_Peptic_Ulcer_Disease?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13935020_Generation_of_bovine_immune_colostrum_against_Streptococcus_mutans_and_Streptococcus_sobrinus_and_its_effect_on_glucose_uptake_and_extracellular_polysaccharide_formation_by_mutans_streptococci?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13395995_Novel_therapies_for_Helicobacter_pylori_infection?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13207325_Fungal_prophylaxis_by_reduction_of_fungal_colonization_by_oral_administration_of_bovine_anti-Candida_antibodies_in_bone_marrow_transplant_recipients?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

al. 1998b), and augmenting the recognition, phagocytosisand killing of S. mutans by human polymorphonuclear(PMN) leucocytes (Loimaranta et al. 1999a). Further, theimmune colostrum did not inhibit in vitro the naturalantibacterial peroxidase-hypothiocyanate system of salivabut did, indeed, in certain circumstances act synergisticallyagainst S. mutans (Loimaranta et al. 1998a). In a short-termclinical trial, the immune colostrum also proved to befunctional in in vivo conditions. Using immune colostrum

as a mouth rinse for 3 days resulted in a higher resting pHin dental plaque and a lower proportion of cariesstreptococci in plaque microbial flora than in controlgroups (Loimaranta et al. 1999b). However, further clinicalstudies will be required to evaluate the in vivo efficacy ofanticaries immune bovine Ig preparations.

Viral infections. Several clinical studies have shownthat hyperimmune bovine colostrum, derived from cowsimmunised with different serotypes of human rotavirus, can

Table 2. Efficacy of bovine immune milk against viral infections in vivo

Subject Virus Efficacy Reference

HumansInfants Poliomyelitis vaccine

of Sabin type 2Prevented infection ofgastrointestinal tract

Gonzaga et al. 1963

Infants Rotavirus Wa 1 Prevented infection Ebina et al. 1985Children Four human rotavirus

serotypesPrevented infection Davidson et al. 1989

117 children Enteropathogenic E. coliand rotavirus

No reduction in incidence ofdiarrhoea or other parametersduring 6 months follow-up

Brunser et al. 1992

Infants Human rotavirus Reduced symptoms of infec-tion but not incidence

Turner & Kelsey 1993

Small children Four human rotavirusserotypes

Prevented infection Davidson et al. 1994

Small children Four human rotavirusserotypes

Shortened duration anddecreased severity of diarrhoea

Mitra et al. 1995

Infants Human rotavirus MO Prevented diarrhoea Ebina, 1996Infants havingacute rotaviralgastroenteritis

Four human rotavirusserotypes

Reduced duration of virusexcretion in stools, no significanteffect on diarrhoea

Hilpert et al. 1987

132 small childrenwith rotaviralgastroenteritis

Rotavirus SA11 Not statistically significant,but trend-setting improvement induration of diarrhoea, weight gainand stool frequency

Ylitalo et al. 1998

40 small childrenwith rotaviralgastroenteritis

Four human rotavirusserotypes

Shortened duration of diarrhoeaand reduced amount and frequencyof stool

Sarker et al. 1998

Animal modelsInfant mice Human rotavirus MO Prevented infection after challenge Ebina et al. 1992Infant mice Human rotavirus MO Prevented infection after

experimental challengeEbina, 1996

Domestic animalsCalves Bovine virus diarrhoea

virus (BVDV)Prevented infection of respiratorytract and protected against viraemiaand leukopenia after experimental challenge.

Howard et al. 1989

Calves Bovine rotavirus Delayed onset of diarrhoea, reducedincidence, duration and severity of diarrhoea

Snodgrass et al. 1982

New-born calves Bovine rotavirus 81/36F Prevented diarrhoea after experimentalinfection

Castrucci et al. 1982

New-born calves Bovine rotavirus Prevented infection Saif et al. 1987Calves Bovine rotavirus 81/36F Prevented diarrhoea after experimental

infectionCastrucci et al. 1988

New-born calves Bovine rotavirusserotypes 1 and 2

Prevented infection Tsunemitsu et al. 1989

Calves Bovine rotavirus 81/36F Prevented infection in most cases,decreased its severity

Castrucci et al. 1989

Neonatal calves IgG from non-immunisedcows, titres against RVproteins VP2, 4, 6 and 7

Protected against diarrhoea,no therapeutic effect on diarrhoea

Osame et al. 1991

Agammaglobulinaemicpiglets

Simian rotavirus SA-11,not porcine rotavirus

Protected against North Carolinaporcine rotavirus

Lecce et al. 1991

Gnotobiotic piglets Human rotavirus Prevented infection after challenge Schaller et al. 1992Calves Bovine herpes virus 1 No prevention, attenuated clinical signs of

infection after experimental challenge.Bradshaw & Edwards, 1996

New-born calves Recombinant SA-11 (P2G3)rotavirus like IND (P/5/G6) particles

Prevented bovine rotavirus shedding anddiarrhoea

Fernandez et al. 1998

Foals Mares immunised with SA11 (G3P2),H2 (G3P12) and Lincoln (G6P1)

Decreased morbidity, shortened durationof clinical signs of diarrhoea

Barrandeguy et al. 1998

S139Bovine milk antibodies for health

https://www.researchgate.net/publication/21504334_Efficacy_of_colostral_immunoglobulins_for_therapeutic_and_preventive_treatments_of_calf_diarrhea?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20613683_Protection_against_respiratory_infection_with_bovine_virus_diarrhoea_virus_by_passively_acquired_antibody?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20329690_Isotypes_of_intestinal_and_systemic_antibodies_in_colostrum-fed_and_colostrum-deprived_calves_challenged_with_rotavirus?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13416561_Combined_inhibitory_effect_of_bovine_immune_whey_and_peroxidase-generated_hypothiocyanite_against_glucose_uptake_by_Streptococcus_mutans?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/12831956_Effect_of_bovine_immune_and_non-immune_whey_preparations_on_the_composition_and_pH_response_of_human_dental_plaque?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/12789442_Colostral_proteins_from_cows_immunised_with_Streptococcus_mutansS_sobrinus_support_the_phagocytosis_and_killing_of_mutans_streptococci_by_human_leucocytes?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

protect infants from acquiring rotavirus and also other viralinfections during a reported outbreak (Table 2). Suchconcentrates also appear to be useful in the treatment ofrotavirus-infected children. Ebina et al. (1985) and Ebina(1996) demonstrated that an antirotavirus antibody con-centrate (Rota-colostrumw) could protect against infection,whereas infants fed commercial milk or purified antibodies(IgG, IgM, and IgA) were not protected against rotavirus.Davidson et al. (1989) fed bovine colostrum, containinghigh antibody titres against the four major human serotypesof rotavirus, to hospitalised children aged 3±15 months.Whereas none of the colostrum-fed children acquiredsymptomatic rotavirus infection during the treatmentperiod, 14 % (9/65) of the control infants developedinfection. A similar study was carried out in Hong Kongand India, confirming the above findings (Davidson et al.1994). The authors concluded that the antibody titre isimportant for protection and that hyperimmune colostrumcould protect against more than one rotavirus serotype. Theimportance of antibody levels was also reflected in anotherstudy (Turner & Kelsey, 1993) which showed that passiveimmunisation of healthy infants with hyperimmune colos-trum was successful in reducing symptomatic rotavirusinfection but had no effect on the actual incidence of theinfection. Hilpert et al. (1987) tested the efficacy of ahyperimmune bovine colostral Ig concentrate in seventy-five hospitalised children with acute rotavirus gastroenter-itis, when the children received Ig concentrate in a dailydose of 2 g/kg body weight for 5 days. A decrease in theduration of rotavirus excretion was noted, but there was noassociated effect on the clinical symptoms. Brunser et al.

(1992) used a milk formula with 1 % (w/w) of bovine milkimmunoglobulin concentrate containing specific antibodiesagainst simian rotavirus SA11 and enteropathogenic E. colifor 6 months. No protection against diarrhoea or beneficialeffect during the disease was seen. In a double-blindcontrolled clinical study, carried out in Bangladesh (Mitraet al. 1995), a group of rotavirus-infected children aged 6±24 months was administered 100 ml of hyperimmune (HI)bovine colostrum per child three times daily for 3 days. Ascompared to the control group, who received non-immunecolostrum, the children treated with HI colostrum showed asignificant reduction in the duration and severity ofdiarrhoea. Ylitalo et al. (1998) used a similar mode ofadministration (100 ml of hyperimmune colostrum fourtimes per day for 4 days for treating rotavirus-infectedchildren) and observed a trend-setting but statistically non-significant improvement in all the evaluated variables(weight gain, duration of diarrhoea and number of stools).Sarker et al. (1998) treated children of age 4±24 monthswith 10 g of Ig concentrate in 20 ml of water four times perday and achieved a significant reduction in daily and totalstool output as well as in the duration of diarrhoea.Altogether, it can be concluded that hyperimmune colostralpreparations have potential not only in prophylaxis but alsoin the treatment of rotavirus infections, although adequateintake of specific Ig is crucial for achieving positive results.

Cryptosporidium infections. Very encouraging resultshave been obtained in clinical studies in which hyper-immune bovine colostrum, containing antibodies specificfor the enteric protozoan parasite Cryptosporidium parvum,has been tested in immunocompromised patients (Table 3)

Table 3. Efficacy of bovine immune and non-immune milk against Cryptosporidium infections in humans

Subject

Route of administrationof immune (1)or non-immune (2) milk Efficacy Reference

A three yearold boy

Via nasogastrictube (1)

Vomiting and diarrhoearesolved in 5 days and oocystsabsent from stools in 8 days

Tzipori et al. 1986

Three humanpatients

Oral (1) Ceased diarrhoea in three ofthree patients

Tzipori et al. 1987

Five human AIDSpatients

Continously vianasogastric tube (1)

Reduced diarrhoea in one ofthree cases and reduction ofoocysts in stools in two of threepatients

Nord et al. 1990

Human adult AIDSpatients

Oral (10 g of Ig preparationdaily) (2)

Relieved symptoms of intestinalinflammations. Cryptosporidiaoocysts in stools absent

Stephan et al. 1990

One human AIDSpatient

Direct duodenalinfusion (1)

Ceased diarrhoea, stools formed,oocysts in stools absent

Ungar et al. 1990

29 HIV patients Oral (10 g of Ig preparationdaily) (2)

Normalized stool frequency in21 of 29, cryptosporidiosisdisappeared in five patients

Rump et al. 1992

Seven human AIDSpatients

Oral (10 g of Ig preparationdaily) (2)

Complete remission in three andpartial in two of sevencryptosporidiosis patients

Plettenberg et al. 1993

4-year-old AIDSpatient

Oral (10 g of Ig preparationdaily) (2)

Permanent elimination ofCryptosporidium, improvementin diarrhoeal symptoms

Shield et al. 1993

Eight human AIDSpatients

Oral (powder) (2) Reduced diarrhoea, body weightstabilised, reduced oocysts in stools

Greenberg & Cello,1996

Healthy human adultvolunteers

Oral (10 g of Ig preparationthree times a day) (1)

Reduced diarrhoea and oocystexcretion after experimental challenge

Okhuysen et al. 1998

S140 H. Korhonen et al.

https://www.researchgate.net/publication/270783918_Passive_protection_against_symptomatic_hospital_acquired_rotavirus_infection_in_India_and_Hong_Kong?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/270783918_Passive_protection_against_symptomatic_hospital_acquired_rotavirus_infection_in_India_and_Hong_Kong?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21826289_Field_Trial_of_an_Infant_Formula_Containing_Anti-rotavirus_and_Anti-Escherichia_coli_Milk_Antibodies_from_Hyperimmunized_Cows?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21826289_Field_Trial_of_an_Infant_Formula_Containing_Anti-rotavirus_and_Anti-Escherichia_coli_Milk_Antibodies_from_Hyperimmunized_Cows?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20585129_Passive_immunisation_of_children_with_bovine_colostrum_containing_antibodies_to_human_rotavirus?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20269073_Chronic_cryptosporidial_diarrhea_and_hyperimmune_cow_colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20046590_Use_of_Bovine_Milk_Concentrate_Containing_Antibody_to_Rotavirus_to_Treat_Rotavirus_Gastroenteritis_in_Infants?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/19093238_Prevention_of_rotavirus_infection_by_oral_administration_of_colostrum_containing_antihuman_rotavirus_antibody?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14784106_Passive_immunization_for_prevention_of_rotavirus_illness_in_healthy_infants?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14547538_Hyperimmune_cow_colostrum_reduces_diarrhoea_due_to_rotavirus_a_double-blind_controlled_clinical_trial?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14547538_Hyperimmune_cow_colostrum_reduces_diarrhoea_due_to_rotavirus_a_double-blind_controlled_clinical_trial?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14194071_Prophylaxis_of_rotavirus_gastroenteritis_using_immunoglobulin?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14194071_Prophylaxis_of_rotavirus_gastroenteritis_using_immunoglobulin?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13720466_Rotaviral_antibodies_in_the_treatment_of_acute_rotaviral_gastroenteritis?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

(Tzipori et al. 1986, 1987; Nord et al. 1990; Ungar et al.1990; Williams, 1992; Okhuysen et al. 1998). In contrast,non-immune colostrum or non-specific bovine Ig concen-trate has been shown to afford little protection againstCryptosporidium infection, again emphasising the impor-tance of specific antibodies (Saxon & Weinstein, 1987;Stephan et al. 1990; Rump et al. 1992; Plettenberg et al.1993; Shield et al. 1993; Greenberg & Cello, 1996). Thepreventive and therapeutic efficacy of specific antibodies isprobably mainly due to their ability to neutralise thesporozoites released from the oocysts in the intestinallumen before they penetrate the epithelial cells (Perrymanet al. 1990). At present, no effective therapy exists forcryptosporidiosis, which is one of the leading contributorsto mortality in AIDS patients.

Immune milk may also be effective against otherparasites. A colostral Ig preparation against Toxocaravitulorum was found to protect mice against this helminthwhen larvae were fed to them (Rajapakse et al. 1994).

Taxonomy and immune milk

Bovine hyperimmune colostrum may at least in some casesexert its beneficial effects over the taxonomic borders.Cryptosporidium parvum immune colostrum proved effec-tive in treating C. serpensis-infected snakes (Graczyk et al.1998) and Cryptosporidium sp. infected geckos (Graczyk etal. 1999). Since birds are immunologically very close toreptiles and bovine immune milk can be effective inreptiles, it can be expected that bovine immunoglobulinsare also functional in birds. Indeed, bovine Igs were aseffective in the prophylaxis and therapy of Campylobacterjejuni-infected chickens as an IgY preparation isolatedfrom hens' eggs (Tsubokura et al. 1997). With bothpreparations a substantial decrease in the number of C.jejuni bacteria in faeces was observed. It is not knownwhether bovine Igs can augment the effector functions ofchicken or reptile leucocytes. However, bovine Igsaugment the recognition, activation and phagocytosis ofmicrobes by human leucocytes (Loimaranta et al. 1999a).These results open new views on the prophylaxis ortreatment of gastrointestinal diseases in domestic orcultivated animals taxonomically distinct from mammals,e.g. fish, frogs and turtles.

Modulation of gastrointestinal microflora with immunemilk preparations

The immune milk preparations used in most clinical studieshave been made against a certain pathogen in order toprevent infection or to treat a disease. However, few studieshave been carried out with the purpose of controlling ormanipulating the gastrointestinal microbial flora in a moregeneral manner, by using an immunoglobulin fraction ofnormal colostrum or immune milk preparations targetedagainst a wider variety of bacteria. Fernandez et al. (1973)reported positive results when treating children havingprolonged infantile diarrhoea with lyophilised bovinecolostrum from non-immunised cows.

Kushnareva et al. (1995) compared the effectiveness of amilk immunoglobulin preparation with bifidobacteria for

the correction of intestinal microflora in human preterminfants with infectious inflammatory diseases. The Igpreparation was administered in a dose of 0.5 g/kg twiceper day orally for 1±3 weeks. The treatment with the Igpreparation gave a more pronounced corrective effect onintestinal microflora than the use of bifidobacteria.Elimination of opportunistic lactose-negative enterobac-teria, Pseudomonas aeruginosa and haemolytic forms of E.coli from the digestive tract as well as an increase of lacticacid bacteria were noted. This result suggests that immunemilk preparations targeted against a wide variety of harmfulpathogens may in future be of use in balancing themicroflora of infants and small children suffering fromgastrointestinal disturbances. A similar approach has beensuggested already by Goldman (1989). Another situationwhere the prophylactic control of intestinal microfloramight be necessary is one of patients under radiotherapyand chemotherapy (which often increases the probability ofindigenous bacterial infections). Kobayashi et al. (1991a)used a model of endogenous infection based on X-rayirradiated mice. The death of mice after irradiation in thismodel was mainly caused by E. coli translocating from theintestine to various organs after a substantial decrease in thelymphocyte functions in gut-associated lymphoid tissues(GALT). GALT are composed of non-organised compo-nents such as intraepithelial and lamina propria lympho-cytes and of various organised components like mesentericlymph nodes and Peyer's patches. A bovine immune milkpreparation (manufactured by Stolle Milk BiologicalsInternational Inc.) containing specific antibodies against26 different bacteria, given to mice orally before and afterthe irradiation, significantly increased the survival rate ofthe animals and decreased the numbers of Enterobacter-iaceae detected from organs like the liver, lung andkidneys, as compared to controls given a milk preparationwithout specific antibodies (Kobayashi et al. 1991b; Ishidaet al. 1992a). Also smaller numbers of enterobacteria werefound in the intestines of the immune milk group than inthe control group (Ishida et al. 1992a). In addition to theprotective effects against severe infection with enteric E.coli and prolonging survival times after irradiation, severalparameters reflecting the immune defence activity of theGALT were augmented (Ishida et al. 1992a). Themechanisms behind this effect are not known. However,one clue is that the immune milk group had a larger numberof lactobacilli in the intestine than the control group.Lactobacilli are known to be potent immune stimulants(Ouwehand et al. 1997; Gill, 1998; Ouwehand & Salminen,1998; Dugas et al. 1999). Also, other milk factors thanimmunoglobulins, e.g. lactoferrin, b-lactoglobulin and fattyacids, have been reported to have pathogen adhesion andtranslocation inhibiting effects (Ouwehand et al. 1997;Bitzan et al. 1998; Teraguchi & Kelsey, 1995).

The immune system also deteriorates with ageing. Thisis associated with autoimmune diseases, cancer and life-threatening infections. The prevention of a continuousstimulation of the immune system by extrinsic factors, suchas the translocation of pathogenic microbes from theintestine, might protect aged individuals. Ishida et al.(1992b) tested the efficacy of the Stolle immune milkpreparation described above in preventing an age-related

S141Bovine milk antibodies for health

https://www.researchgate.net/publication/297498061_Cryptosporidiosis_in_a_child_with_leukaemia?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/291872576_Chronic_cryptosporidial_diarrhoea_and_hyperimmune_cow_colostrum_letter?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/288985225_Protective_Effect_of_Orally_Administering_Immune_Milk_on_Endogenous_Infection_in_X-Irradiated_Mice?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/223496032_Inhibition_of_pathogen_adhesion_by_b-Lactoglobulin?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/223496032_Inhibition_of_pathogen_adhesion_by_b-Lactoglobulin?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/223030008_Stimulation_of_the_Immune_System_by_Lactic_Cultures?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/222210001_The_Health_Effects_of_Cultured_Milk_Products_with_Viable_and_Non-viable_Bacteria?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/222210001_The_Health_Effects_of_Cultured_Milk_Products_with_Viable_and_Non-viable_Bacteria?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/51327305_Inhibition_of_Helicobacter_pylori_and_Helicobacter_mustelae_Binding_to_Lipid_Receptors_by_Bovine_Colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21735184_Administration_of_milk_from_cows_immunized_with_intestinal_bacteria_protects_mice_from_radiation-induced_lethality?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21735184_Administration_of_milk_from_cows_immunized_with_intestinal_bacteria_protects_mice_from_radiation-induced_lethality?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/21211837_The_Analysis_of_the_Defense_Mechanism_against_Indigenous_Bacterial_Translocation_in_X-Irradiated_Mice?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20955379_Treatment_with_bovine_hyperimmune_colostrum_of_cryposporidial_diarrhea_in_AIDS_patients?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20862137_Kinetics_of_Cryptosporidium_parvum_sporozoite_neutralization_by_monoclonal_antibodies_immune_bovine_serum_and_immune_bovine_colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20862137_Kinetics_of_Cryptosporidium_parvum_sporozoite_neutralization_by_monoclonal_antibodies_immune_bovine_serum_and_immune_bovine_colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20861488_Cessation_of_Cryptosporidium-associated_diarrea_in_an_acquired_immunodeficiency_syndrome_patientafter_treatment_with_hyperimmune_bovine_colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20861488_Cessation_of_Cryptosporidium-associated_diarrea_in_an_acquired_immunodeficiency_syndrome_patientafter_treatment_with_hyperimmune_bovine_colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20843319_Antibodies_from_colostrum_in_oral_immunotherapy?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20058747_Remission_of_diarrhea_due_to_cryptosporidiosis_in_an_immunodeficient_child_treated_with_hyperimmune_bovine_colostrum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/19575564_Oral_Administration_of_Bovine_Colostrum_Anti-Cryptosporidia_Antibody_Fails_to_Alter_the_Course_of_Human_Cryptosporidiosis?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/18433594_Lyophilized_bovine_colostrum_in_the_treatment_of_prolonged_infantile_diarrhea?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/15546277_The_efficacy_of_using_an_immune_lactoglobulin_preparation_for_correcting_intestinal_dysbacteriosis_in_newborn_infants?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/15227170_The_effect_of_serum_and_colostrum_immunoglobulins_from_buffaloes_infected_with_Toxocara_vitulorum_on_T_vitulorum_larvae_in_vitro_and_in_vivo_in_mice?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14939173_Bovine_Colostrum_immunoglobulin_concentrate_for_sporodiosis_in_AIDS?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14746570_A_preparation_from_bovine_colostrum_in_the_treatment_of_HIV-positive_patients_with_chronic_diarrhea?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14746570_A_preparation_from_bovine_colostrum_in_the_treatment_of_HIV-positive_patients_with_chronic_diarrhea?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14259810_Treatment_of_Severe_Diarrhea_Caused_by_Cryptosporidium_parvum_with_Oral_Bovine_Immunoglobulin_Concentrate_in_Patients_with_AIDS?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14035725_Oral_administration_of_antibodies_as_prophylaxis_and_therapy_in_Campylobacter_jejuni-infected_chickens?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13718147_Therapeutic_efficacy_of_hyperimmune_bovine_colostrum_treatment_against_clinical_and_subclinical_Cryptosporidium_serpentis_infections_in_captive_snakes?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13718147_Therapeutic_efficacy_of_hyperimmune_bovine_colostrum_treatment_against_clinical_and_subclinical_Cryptosporidium_serpentis_infections_in_captive_snakes?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/13647490_Prophylactic_Effect_of_Bovine_Anti-_Cryptosporidium_Hyperimmune_Colostrum_Immunoglobulin_in_Healthy_Volunteers_Challenged_with_Cryptosporidium_parvum?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/12836708_Immunity_and_Probiotics?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/12822530_Hyperimmune_bovine_colostrum_treatment_of_moribund_Leopard_geckos_Eublepharis_macularius_infected_with_Cryptosporidium_sp?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/12822530_Hyperimmune_bovine_colostrum_treatment_of_moribund_Leopard_geckos_Eublepharis_macularius_infected_with_Cryptosporidium_sp?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/12789442_Colostral_proteins_from_cows_immunised_with_Streptococcus_mutansS_sobrinus_support_the_phagocytosis_and_killing_of_mutans_streptococci_by_human_leucocytes?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

decrease in the immune competence of mice. Immune milkwas administered from age 2 months for 6 or 16 months.The immune milk group had at the ages 8 and 18 monthsless serum antibodies against enteric bacteria, whereasseveral parameters reflecting GALT immune functionswere at higher levels than in the control mice. Themechanisms involved are not known, but alterations inthe intestinal flora, e.g. an increase in the amounts oflactobacilli, may result in augmenting the immune func-tions of GALT. Alternatively, specific immunoglobulinsmay directly augment the immune competence of GALTcells.

An immune milk preparation which is able to modulateGALT immune functions could be assumed to have otherphysiological effects as well. It was reported that the Stolleimmune milk (see above) also had cholesterol loweringeffects in human patients with primary hypercholesterolaemiaand in humans with moderately raised plasma cholesterol.In a randomised, double-blind, placebo-controlled cross-over study, a daily dosage of 90 g of immune milkpreparation for 8 weeks in patients with hypercholesterol-aemia decreased the total serum cholesterol level by 8 %and LDL cholesterol by 4 % (Golay et al. 1990). Inhumans with moderately raised plasma cholesterol, a 10-week period with the same dosage resulted in a 5 %decrease of total and a 7 % decrease of LDL plasmacholesterol (Sharpe et al. 1994). A significant bloodpressure lowering effect (5 mm Hg systolic and 4 mmHg diastolic) was also seen in the latter trial. Themechanisms underlying these effects are not known. It ispossible that the vaccination process of cows for theproduction of specific antibodies stimulates the productionof biologically active compounds, including a low-molecular-weight hypotensive factor in the milk. On theother hand, skim milk containing specific antibodiesagainst enterobacteria may have modulated the gastro-intestinal microflora, which, in turn, is known to have far-reaching physiological effects including the lowering ofcholesterol in rat models (Molin et al. 1992; Fukushima &Nakano, 1996).

Future prospects

Our current knowledge about the in vivo efficacy ofimmune bovine colostral or milk Ig concentrates suggeststhat these preparations could be effective in the prevention,and to a lesser extent also in the treatment, of specificmicrobial gastrointestinal diseases. Such preparationswould be of particular importance for those microbialdiseases which cannot be cured or are difficult to treatusing current chemotherapy, such as rotaviruses, antibiotic-resistant enteropathogens and Cryptosporidium. Futureaims to utilise bovine antibodies as intervention agents inthe prevention or treatment of infection should determine,at an early stage of product development, the specific targetfor which the intervention product is intended. Forexample, antibodies which block the H antigen on fimbriaeof enteropathogenic E. coli strains have proven useful as aprophylactic measure (Tacket et al. 1988). In many casesthere is scope for improvement of the immunisationregimes, such that the ensuing bovine response produces

high titres of strong binding-affinity antibodies, withpolyclonal activity against a range of important pathogendeterminants. In a related context, regulatory and ethicalconsiderations for the immunisation regime should be takeninto account, particularly with respect to the use of`acceptable' immunopotentiating adjuvants and in relationto the frequency of immunisation doses.

The immunosupplementation of clinical diets and specialinfant formulas with specific antibodies appears, therefore,a challenging future approach. Also, the world-wide trendtowards the development of health-promoting functionalfoods offers interesting opportunities for applications whichcontain specific antibody ingredients derived from hyper-immunised cows. However, the optimisation of the dietaryregime still needs to be determined in many cases, from theviewpoint of dose, frequency, duration of use and (in thecase of prophylactics) time of use prior to likely exposureto the pathogen. It is expected that such detailedinformation will only come from clinical trials.

The form in which bovine-derived antibodies aredelivered to patients is also an area worth furtherconsideration with respect to product development. BovineIgG1 (the predominant colostral Ig) is relatively resistant tothe conditions of the human gut and is thought to remainefficacious throughout the GI tract when delivered incolostrum. Contrary to this, it should be borne in mind thatcolostral proteins can act as immunogens in their own right,and in rare cases patients can present with atopic reactionsto milk proteins, including sensitivity to bovine IgG(Bernhisel-Broadbent et al. 1991). Accordingly, intactcolostrum-containing IgG may not be the appropriatetreatment/prophylactic vehicle in these patients, and incases where sensitivity to milk protein has been detected itmay be necessary to develop a purified product based onpepsin-cleaved Ig, comprising two F(ab) 02 fragments,which are less allergenic than the parent molecule(Lefranc-Millot et al. 1996).

There is increasing interest within the food andpharmaceutical industries to develop products which aretargeted towards the manipulation of oral and intestinalmicroflora. Apart from specific antibodies, the possiblebenefits obtained from the application in the diet of specificantibodies together with probiotic bacteria should, there-fore, be investigated. In the past, the commercial develop-ment of hyperimmune bovine colostral or milk-basedpreparations has been constrained by technological limita-tions. Recent developments in membrane separationtechniques enable the concentration and isolation ofantibodies from bovine colostrum and milk in an activeform. There is, however, an obvious need to up-scale thetechnological processes so as to improve the economicsrelated to the manufacture of hyperimmune colostral ormilk preparations or ingredients. From a commercialviewpoint, the profitable exploitation of lacteal productsfrom immunised cows may be limited to early colostrum,which contains the greatest concentration of Ig. Astandardised approach to the production of commercialhealth-intervening bovine Ig products should be undertakento ensure high product quality and consistency. It istherefore suggested that batch production be monitored byestablished in vitro testing of product efficacy (e.g. by in

S142 H. Korhonen et al.

https://www.researchgate.net/publication/21167541_Allergenicity_of_orally_administered_immunoglobulin_preparations_in_food-allergic_children?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/20915848_Cholesterol-lowering_effect_of_skim_milk_from_immunized_cows_in_hypercholesterolemic_patients?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/19871864_Protection_by_Milk_Immunoglobulin_Concentrate_against_Oral_Challenge_with_Enterotoxigenic_Escherichia_coli?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/15052596_Cholesterol-lowering_and_blood_pressure_effects_of_immune_milk?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=https://www.researchgate.net/publication/14554557_Comparison_of_the_IgE_Titers_to_Bovine_Colostral_G_Immunoglobulins_and_their_Fab'2_Fragments_in_Sera_of_Patients_Allergic_to_Milk?el=1_x_8&enrichId=rgreq-2466ada83cf9359cf763cde60315eb72-XXX&enrichSource=Y292ZXJQYWdlOzEyMDkwNjE5O0FTOjk3NTk4MDA2MzY2MjE1QDE0MDAyODA1ODY0OTU=

vitro neutralisation tests against enteric viruses andbacteria).

Summary

In summary, there is a need to carry out well-controlledtrials to establish the in vivo efficacy of the developedpreparations before launching them on the market. On theother hand, since the safety of immune colostrumpreparations has not been studied in the same manner asrequired for pharmaceuticals, further research is stillneeded to assess the potential allergenic, toxic andhormonal effects of immune milk preparations. Theallergenic potential of bovine IgG may be a factor limitingits widespread use for disease prevention (Bernhisel-Broadbent et al. 1991). Is it also not known whether thelong-term use of immune colostrum might, for example,influence the maturation of immune functions, or immuno-logical tolerance in small children. So far, no significanthealth risks have been reported during or after oralingestion of immune milk preparations, and this approachis generally regarded as a non-invasive, and therefore safe,intervention regime. It is anticipated that immune colostralor milk-based preparations, targeted at specific consumergroups, may in the future have remarkable potential tocontribute to human health care, both as part of a health-promoting diet and as an alternative or a supplement to themedical treatment of specified human diseases.

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S143Bovine milk antibodies for health

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