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Early nutrition and immunity- progress and perspectives

1. Early nutrition and immunity- progress and perspectives. Sonja Lang Katja Bohländer. Overview. 2. Tolerance Role of nutrition Feeding practises Role of dendritic cells, lactobacilli Intestinal colonization PUFA LCPUFA Lipid rafts. Immunological tolerance. 3. Lifelong processes

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Early nutrition and immunity- progress and perspectives

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  1. 1 Early nutrition and immunity- progress and perspectives Sonja Lang Katja Bohländer Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  2. Overview 2 • Tolerance • Role of nutrition • Feeding practises • Role of dendritic cells, lactobacilli • Intestinal colonization • PUFA • LCPUFA • Lipid rafts Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  3. Immunological tolerance 3 • Lifelong processes • Polarization of Th cells: Th2*, Treg ↑↑ • *Recognition of ultra-low antigen dosis (IgE, IgA) • Sterile GIT • Exposure to bacteria at term and after (mother´s skin, breast milk  maturation of infant´s gut Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  4. Nutrition + immunologic development 4 Nutrition • …might affect ID during pregnancy, suckling period, introduction of formula and solide foods  • …source of antigens IS must become tolerant • …provides factors, which modulate immune maturation + responses + influences intestinal flora  antigen exposure, immune maturation, immune response Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  5. German Infant Nutritional Intervention Study 5 • Effects of hydrolysed and standard cow´s milk formula • human milk feeding: ↓ allergic diseases at 1y • Hydrolysed formula: ↓ atopic dermatitis • Extensively hydrolysed formula: - allergy preventive effect • Partially hydrolysed formula: + allergy preventive effect • Keeping pets (dogs!)  atopic diseases ↓ • Caesarean section: different gut flora, antibiotics  diarrhoea, allergic sensitization↑ Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  6. Dendritic cells + Lactobacilli 6 Function of DC: • drive differentiation of naive Th cells into Th1, Th2 or Treg cells • Treg cells: prevention of autoimmunity, allergy • L. reuteri + L. casei prime human DC and drive development of Treg cells by targeting DC-SIGN Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  7. IMMUNOFLORA study 7 • „…how early intestinal colonization affects the development of putative Treg cells and clinical allergy in Swedish infants“ • Western infants have a delayed acquisition of several gut microbes and a reduced turnover of strains in intestinal flora Exposure ↓, variety ↓ of environmental bacteria • Early food allergy ↔ poor colonization with S. aureus (strong T cell stimulation) Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  8. PUFA 8 •  in the intake of saturated fatty acids •  in the intake of n-6 family of PUFA • Linoleic acid Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  9. N-6 family of PUFA 9 Linoleic Acid Arachidonic acid Prostaglandine PGE2 Leukotriene LTB4 Tromboxanes TXA2 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  10. 4-series leukotrien 10 = mediators of allergic inflammation: • Vascular permeability • Leucocyte chemotaxis • Respiratory burst • Production of inflammatory cytokines • HYPOTHESIS:  intake of linoleic acid  prevalence of atopic disease Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  11. n-3 family of PUFA 11 • -Linolenic acid EPA DHA • Increased consumption: → incorporation into immune cells → decrease the production of prostaglandin E2 and other eicosanoids • Protective towards allergic disease • E.g. n-3 LCPUFA status was lower in cord blood serum from pregnancy of allergic compared with non allergic mothers. Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  12. n-3 family of PUFA 12 • Positive results in patients with asthma • n-3 LCPUFA intervention: Stronger impact on fetal and neonatal Th1/Th2 immune responses compared to immune responses beyond early infancy Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  13. n-3 LCPUFA 13 • Influence on T-cell functional responses and signalling • First, prostaglandin E2 influence the activity of DC, differentiation of naive T-cells and activity of Th1 and Th2 cells • Second mechanism: Direct alteration of gene expression through modification of transcription factor activity Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  14. n-3 LCPUFA • EPA and DHA give rise to a novel family of eicosanoid-like mediators, called D- and E- resolvins • Inhibition (in vitro): • T-cell proliferation, • Production of IL-2 and IFN- • Surface expression of CD25 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

  15. Evaluation of Allergenicity of Genetically Modified Foods Report of a Joint FAO/WHO Expert Consulation on Allergenicity of Foods Derived from Biotechnology 22 - 25 January 2001 Rome, Italy

  16. Introduction • 29 May to 2 June 2000 Joint FAO/WHO Geneva, Switzerland • follow-up: 22 to 25 January 2001 Rome, Italy members: 28 experts and authors of discussion papers

  17. Allergenicity • Most frequently asked questions • safety of genetically foods • reliable methodology to assess the allergenicity of foods produced by the recombinant DNA technique needed

  18. Scope • General consideration of allergenicity of genetically modified foods • Consideration of the decision-tree approach • Specific questions arising in relation to the assessment of allergenicity of genetically modified foods

  19. Food Allergies „Overhwhelming pathological reactions of the body due to intercurrent contact with antigens“Clemens von Pirquet 1906 • IgE-mediated allergy • Cell-mediated allergy • Oral allergy syndrome

  20. Decision tree • Criteria • source of the transferred genetic material, • molecular weight, • sequence homology, • heat and processing stability, • effect of ph and/or gastric juices and • prevalence in foods.

  21. Source of gene allergenic Yes No Sequence Homology Sequence Homology Yes No Yes No Specific Serum Screen Target Serum Screen No No Yes Yes Pepsin Resistance & Animal Models Yes Yes +/+ +/- -/- High Low Probability of Allergenicity Likely Allergenic

  22. Post marketing surveillance • Traceability and labelling • Lack of background data • Many confounding food and non-food related factors • Changes in diets over time • Lack of trained experts an infrastructure

  23. Other criteria • Level of expressions • Unintended effects

  24. Evaluation of Allergenicity of Genetically Modified Foods Martina Pomper 9603177

  25. 1. Risk assessment and food allergy:the probabilistic model applied to allergensSpanjersberg, M.Q.I., Kruizinga, A.G., Rennen, M.A.J., Houben, G.F., Food Chem Toxicol, 45: 49-54 (2007) Ines Pree, Immunology and Food, WS 2006

  26. The probabilistic approach in food allergy • Purpose: avoidance of hidden or undeclared allergens  Risk assessment • Conservative determinstic appraches: worst case value „an allergic reaction cannot be excluded“ • Probabilistic approach quantifies health risk asessment by • Hazard identification: situation, symptoms, target organs • Hazard characterization: threshold, minimum dose • Exposure assessment: intake etc. •  Risk assessment Ines Pree, Immunology and Food, WS 2006

  27. Hazelnut allergens in chocolate - a case study Risk assessment of three bars, each of a different brand, according to: • Prevalence • Threshold (LOED*) • Consumption pattern • Allergen concentrations • Computer software *lowest observed eliciting dose Result: The allergen was detectable in each bar but at different concentrations. Ines Pree, Immunology and Food, WS 2006

  28. The probabilistic vs. the deterministic approach • The deterministic model does not distiguish between the different degree of contamination. “An allergic reaction cannot be excluded” is true for all three brands. • The probabilistic model gives more detailed information and avoids overestimation of the risk for the population. • All three brands together: highest mean risk of 0.05%, i.e. less than 500 subjects per million will respond. • The risk for breakfast consumption is higher when compared to lunch. There was a lower risk for women, since men consume more. • Brand 3: the highest risk of 0.004%; less than 40 subjectswill respond which reflects a lower contamination of brand 3 Ines Pree, Immunology and Food, WS 2006

  29. 2. Practical and predictive bioinformatics methods for the identification of potentially cross-reactive protein matches.Goodman, R.E. Mol Nutr Food Res, 50: 655-660 (2006). Ines Pree, Immunology and Food, WS 2006

  30. Potential allergenicity in GE food • If the protein similar to a known allergen, specific IgE may be cross-reactive (recognition of similar epitopes) sequence  conformation  cross-reactivity • How to determine potential allergenicity: • Compare amino acid sequences by computer programs • Recruit potentially at-risk individuals (allergic patients) • Perform serum testing, skin prick testing, food challenge. Ines Pree, Immunology and Food, WS 2006

  31. Comparison of amino acid sequences • FASTA and BLAST alignments (used for species homologies) to identify IgE and T cell epitopes? • Since 1990ies: 8 contiguous amino acid matches • In 2001: 6 amino acid matches are too short, too many matches; >35% identity over 80 amino acids is useful • Points of discussion: • Allergen databases are incomplete, mainly lacking minor allergens • Epitopes are poorly defined and the relevance of conformational epitopes is not fully established • Analysis of 3D structures: group proteins into structural families and compare motif recognition patterns Ines Pree, Immunology and Food, WS 2006

  32. Consensus 2005- workshop in Spain • Short matches are not predictive • FASTA and BLAST algorithms are efficient • Structural comparison may be very useful • There are currently no data to change the guidelines (>35% identity over 80 amino acids) Ines Pree, Immunology and Food, WS 2006

  33. Summary/ Conclusion • In risk assessment of food allergens the current precautionary “may contain” labelling is based on the possible presence of an allergen rather than on the assessment of a quantative risk. The quantative expression of riskcould avoidunnecessary labelling or recalls. • In theprediction of IgE cross-reactivities in food allergy: structural comparison may be useful. However, there is currently not enough data to change current guidelines (>35% identity over 80 amino acids). Ines Pree, Immunology and Food, WS 2006

  34. Immunity, Inflammation and Allergy In The Gut Thomas T. MacDonald and Giovanni Monteleone

  35. The gut (1) • Nutrients get absorbed • Potential to compromise host defense • infection diseases are largely under control • But: gastrointstinal food allergies have increased  Probably because of the absence of gut infections has upset the balance between the commensal in the gut

  36. The gut (2) • High active immunsystem • Barrier is a single layer of epithelium • No completely prevent of antigens entering the tissue • Several mechanism how antigens get trough the epithelium  Immunsystem gets constantly activated

  37. Components of the Immunsystem in the gut • Pattern recognition receptors – recognize conserved structures • Severals receptors like TLR, NOD,.. • Recognition of TLR ligands increases gut barrier function • Hsp25 and hsp70 • CD4+ T cells • Macrophages • Dendritic cells

  38. Activation • B and T Cells activated Expression of α4β7 integrin • TLR or NOD activate NFĸB  Leads to pro-inflammatory gene expression • Chemokine fine-tune the localisation of the tissue

  39. Crohn‘s disease (1) • Complex genetic disease • Mucosal ulceration, ulcers penetrate into the gut wall • Antigen is not yet identified • Isolated CD 4+ TH1 cells produce large amount of interferon γ • Overexpression of transcriptionfactor T-bet • Macrophages produce large amount of TH1 inducit cytokines • T-cells show resistence to apoptotic signals and have an increased cell cycle

  40. Crohn‘s disease (2) • Genes located on the chromosomes 1, 5, 6, 12, 14, 16 and 19 • Different polymorphism in the Nod2 gene  Mutations in the Nod 2 can lead to a decreased ability to kill gut bacteria • OCTN and DGL5 gen  Important for epithelial permeability  Disruption leads to inappropriate exposure of the mucosal immunsystem to bacterial products

  41. Celiac disease (1) • In some genetically susceptible individuals after ingestion of cereal products • Treated by adherence to a gluten free diet • morphological chances to the mucosa of the upper bowel – long crypts and atrophy of villi

  42. Celiac disease (2) • 4 components involved • Gluten is prolin and glutamine rich, has negatively charged residues • tTG deaminates glutamin to glutamic acid and produces negatively charged residues • Necessary for efficient binding to HLA-DQ2 and furthermore activation of gluten specific t-cells • Peptides of gliadin activate gut macrophages to produce IL-15 -> increases MICA and arms IEL to kill MICA and epithelial cells

  43. Control of inflammation in the gut • T-cells involved in tolerance against commensals • Commensals which crossed the barrier will be phagocytosed without cytokinproduction  The T-cells die by apoptosis • The epithelial permeability is genetically determined  Importend factor in the developement of diseases

  44. Probiotics Do They Help to Control Intestinal Inflammation?

  45. Probiotics • In the maintenance therapy for the inflammating bowel diseases, Crohn’s diseases and ulcerative colitis • Specific molecules modulating defined targets in the gut mucosal and systemic immune system

  46. (Active) Ulcerative Colitis • Ulcerative Colitis: Study comparing mesalamine treatment with E.coli Nissle 1917 treatment • relapse rate were not different between groups • E.coli Nissle 1917 is a safe alternative for prevention of relapse in ulcerative colitis • Active Ulcerative Colitis: Trial examining the effectiveness of the fermented milk containing Bifidobacteria strains and Lactobacillus acidophilus.  Remission was achieved in 4 of 12 patients

  47. Pouchitis • Study of the ability of VSL 3 to prevent recurrence of chronical relapsing pouchitis 17 of 20 patients remained in remission • But: Probiotics have failed to demonstrate efficacy

  48. Crohn‘s disease • Pioneer study to examine the efficacy of E.coli Nissle 1917 in maintaining remission in Crohn’s diseases  Groups did not differ in the rate of remission regardless of disease location

  49. Conclusions • More effective in preventing relapse of inflammation than suppressing diseases • In active inflammation sufficient data are missing • Genetically engineered bacteria delivering anti-inflammatory cytokines or other biological molecules

  50. Allergy, Parasites and the Hygenie Hypothese Maria Yazdanbakhsh Peter G. Kremsner Ronald van Ree

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