Allergy prevention by raw cow s milk - Epidemiological evidence and possible involved mechanisms

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1 Allergy prevention by raw cow s milk - Epidemiological evidence and possible involved mechanisms Agnes Wold Professor of Clinical Bacteriology University of Gothenburg Senior Consultant, Sahlgrenska University Hospital Sweden IgE-mediated (atopic) allergy our most common disease ~ 30% of children and young adults affected inwestern countries Increases globally when living standards improve Often life-long disease Significant negative effects on quality of life Tremendous costs in medications & lost productivity NO effective preventive measures yet found 1

2 Allergens = common, harmless proteins in environment (food, air) Fel d 1 (cat) Bet v 1 (birch pollen) Beta-lactoblogulin (cow s milk) Sensitization = presence of allergen-specific IgE antibodies IgE venule Bet v 1 Symptoms = allergy Tissue swelling, mucus production, vasodilatation histamine Hay fever, asthma, atopic eczema, food reactions (vomiting, skin eruption) mast cell The atopic marsch IgE-mediated allergy food allergy allergy to aiborne allergens symtom: eczema GI symptoms asthma hay fever newborn 1 yr 3 yr adult allergens: cow s milk egg animals pollens 2

3 A normal, healthy immune system reacts to microbes, but tolerates harmless protein antigens (Oral tolerance) microbes food proteins? Peyer s patch? IMMUNITY ACTIVE, ANTIGEN- SPECIFIC TOLERANCE How? Where? regulatory T cells Which type? As infections decrease, immunoregulatory diseases increase JF Bach The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med

4 Immune regulatory disorders Most common in rich countries Increasing last decades, continued increase X inflammatory bowel disease Immune system Immunsystem allergens µ allergy microbes autoantigens autoimmunity Hay fever rare among farmers 30% allergy prevalence 1819 Catharrus aestivus (hay fever) year 1873 Hay fever= reaction to grass pollen Charles Blackley MD with hay fever Why, then, do the farmers and their families have the fewest cases of this disorder? Hay fever, 1926: City pop: 1,3% Rural pop: 0,1% 4

5 Rediscovery of the protective effect of growing up in a farming milieu, studies 2000 from many countries: Austria Germany France Switzerland Finland Denmark Sweden Spain Canada Australia Protective factors: 1) Exposure to stable milieu 1st yr 2) Mother in stables during pregnancy 3) Raw milk consumption Which factors may explain the protective effect of farming on allergy? Hay fever Asthma IgE (sens) Children 6-13 years, Germany, Austria, Switzerland No farm Farm 1st year Farm+ raw milk 1st yr Raw milk 1st yr Farm only after 1st yr Farm is most protective 1st year of life Farm + raw milk most protective Raw milk consumption 1st yr: 3 x less hay fever approx. 40% less asthma, IgE (sensitization) Riedler J, Braun-Fahrländer C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, Schierl R, Nowak D, von Mutius E; ALEX Study Team. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet. 2001;358:

6 The allergic march starts very early The first year of life is most important in determining the risk of developing allergy even if the allergic symptoms may appear in adolescence Protective measures must target the neonatal infant (or even the fetus during late pregnancy) Equal or better protection from raw milk in nonfarming children % children sensitized (IgE) Parents: 4.8x No farm PROTECTION Raw milk consumption No consumption of raw milk 2.9x Farm workers Farmers protection by raw milk 2.8x protection by raw milk Perkin MR, Strachan DP. Which aspects of the farming lifestyle explain the inverse association with childhood allergy? J Allergy Clin Immunol. 2006;117:

7 Raw milk consumption in town children less sensitization % sensitized x Children år, Heraklion, Crete Sensitization to common aeroallergens Allergens: grass pollen (Mediteranean species), mites, cat, Parietaria, goat, olive flowers, Alternaria (mold) Consumption of raw milk Barnes M et al. Crete: does farming explain urban and rural differences in atopy? Clin Exp Allergy 2001;31: Summary, clinical studies on effect of raw milk on allergy 11 cross-sectional and 1 cohort study shows protection against sensitization and/or allergy from consumption of cow s milk The putative protective effect is independent of exposure to farming environment Putative protective effect is quite strong: 2-4 x reduction Is raw milk to infants (in addition to breast feeding/bottle feeding) a possible way to reduce allergy development? 7

8 Which milk components may explain the protective effect of raw milk?? Live immune cells Live bacteria Biologically active proteins macrophages T-cells (many activated) Fat droplets enclosed in phospholipid membrane Denaturing Homogenization The live bacteria? Maybe not the most important factor Human breast milk is also full of bacteria - same groups are found in human and cow s milk: CoNS, S. aureus, Pseudomonas, Klebsiella, group B streptococci etc. Hypothesis: Microbiologically clean raw milk will be equally protective 8

9 The live immune cells? macrophages (with ingested lipid droplets T-cells (many activated) Live milk cells affect infant s immunity MHC child s immune cells tolerance to cell-bound antigens live and active MHC gut lumen of infant live milk cells (from mother) Maternal milk cells cross the gut wall and appear in the infant s circulation This phenomenonon may serve to protect against transplantation reactions between milk and child (mother and child partially tissue incompatible) Maternal milk cells circulate for some days in immunologically active state (temporary DTH positivity in breast-fed infants to tuberculin+ mothers) Maternal MHC are actively tolerized by breastfed offspring (shown in humans, mice) 9

10 Hypothesis cow s milk cells transfer tolerance tolerance to antigens in/on cow s milk macrophage beta-lactoglobulin live cow s milk cells gut lumen of infant Cow s milk macrophages contain not only cow s milk proteins, but also pollen proteins, cow s milk insulin Tolerance to a broad range of environmental antigens Milk is a living tissue with tolerogenic properties But allergy to milk is very common How does tolerogenic milk become highly allergenic? 10

11 What happens when you pasteurize/homogenize? bet v 1 (birch pollen) phospholipid membrane beta-lactoglobulin 4 µm heat (pasteuriz.) heat shock protein cow insulin immunogenicity Pasteurization/ homogenization creates a perfect immunogenic mixture disrupted cells, DNA etc. + lipid droplets 0.5 µm homogenization 64 x surface size, phospholipid cannot cover hydrophobic surface fragmented bacteria. LPS etc oil in water emulsion (=Freund s incomplete adjuvant) =Freund s complete adjuvant) In order to test the possible tolerogenic effect of raw cow s milk on infants, safety must be guaranteed How do we produce microbiologically safe raw milk? Selected farmers, thoroughly supervising the process Catharina Berge Screen each batch by running milk filter eluent through multiplex PCR for EHEC, Campylobacter, Salmonella (+?) PCRs for faecal pathogens detect 1dead bacterium, e.g. of EHEC Sweden: new persons with allergy each year (population 10 million) cases of allergy yearly could be spared 11

12 Allergy = immune mediated hypersensitivity IMMUNE response CLINICAL picture Tolerance No symtoms harmless substances in food/air ( allergens ) Activation Sensitization IgE No symptoms = clinical tolerance Symptoms = allergy Rediscovery of the allergy-protective effect of farming Children raised on small family farms in Bavaria % av barnen som utvecklar x less sensitization IgE hay fever asthma Farm 1st year Control 11 x less asthma 4 x less hay fever Riedler et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358: ,