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18.12.2006 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424 Early nutrition and immunity-

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Presentation on theme: "18.12.2006 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424 Early nutrition and immunity-"— Presentation transcript:

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

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

3 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr Immunological tolerance 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 3

4 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr Nutrition + immunologic development 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 4

5 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr German Infant Nutritional Intervention Study 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 5

6 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr Dendritic cells + Lactobacilli 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 6

7 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr IMMUNOFLORA study …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) 7

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

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

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

11 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr n-3 family of PUFA -Linolenic acid EPA DHA Increased consumption: incorporation into immune cells d ecrease 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. 11

12 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr n-3 family of PUFA 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 12

13 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr n-3 LCPUFA 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 13

14 Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics, Dr. Alexander Haslberger, LVNr 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

15 Evaluation of Allergenicity of Genetically Modified Foods Report of a Joint FAO/WHO Expert Consulation on Allergenicity of Foods Derived from Biotechnology 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 Yes No +/+ +/- -/- High Low Probability of Allergenicity Likely Allergenic Yes No Yes Sequence Homology Target Serum Screen Source of gene allergenic Sequence Homology Pepsin Resistance & Animal Models Specific Serum Screen

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

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

26 Ines Pree, Immunology and Food, WS 2006 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 1.Hazard identification: situation, symptoms, target organs 2.Hazard characterization: threshold, minimum dose 3.Exposure assessment: intake etc. 4. Risk assessment The probabilistic approach in food allergy

27 Ines Pree, Immunology and Food, WS 2006 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. Hazelnut allergens in chocolate - a case study

28 Ines Pree, Immunology and Food, WS 2006 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. 1.All three brands together: highest mean risk of 0.05%, i.e. less than 500 subjects per million will respond. 2.The risk for breakfast consumption is higher when compared to lunch. There was a lower risk for women, since men consume more. 3.Brand 3: the highest risk of 0.004%; less than 40 subjects will respond which reflects a lower contamination of brand 3

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

30 Ines Pree, Immunology and Food, WS 2006 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: 1.Compare amino acid sequences by computer programs 2.Recruit potentially at-risk individuals (allergic patients) 3.Perform serum testing, skin prick testing, food challenge. Potential allergenicity in GE food

31 Ines Pree, Immunology and Food, WS 2006 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: 1.Allergen databases are incomplete, mainly lacking minor allergens 2.Epitopes are poorly defined and the relevance of conformational epitopes is not fully established 3.Analysis of 3D structures: group proteins into structural families and compare motif recognition patterns Comparison of amino acid sequences

32 Ines Pree, Immunology and Food, WS 2006 Consensus 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)

33 Ines Pree, Immunology and Food, WS 2006 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 risk could avoid unnecessary labelling or recalls. In the prediction 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).

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 Crohns disease (1) Complex genetic disease Mucosal ulceration, ulcers penetrate into the gut wall Antigen is not yet identified Isolated CD 4+ T H1 cells produce large amount of interferon γ Overexpression of transcriptionfactor T-bet Macrophages produce large amount of T H1 inducit cytokines T-cells show resistence to apoptotic signals and have an increased cell cycle

40 Crohns 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 à Gluten is prolin and glutamine rich, has negatively charged residues à tTG deaminates glutamin to glutamic acid and produces negatively charged residues à Necessary for efficient binding to HLA-DQ2 and furthermore activation of gluten specific t-cells à 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, Crohns 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 à 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 Crohns disease Pioneer study to examine the efficacy of E.coli Nissle 1917 in maintaining remission in Crohns 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

51 Atopy and Allergic diseases significant increase in pervalence of allergic deseases in the last years differences in developing and industrial countries risk faktors such als increased exposure to indoor allergens childhood infektions shows a negative association with atopy and allergic diseases

52 Atopy enviromental allergen leads to T cell stimulation release of Cytokines (IL4, IL5, IL13) raised IgE levels à Increased numbers of eosinophiles and mast cells

53 Hygenie Hypothese High hygenie Vaccination Antibiotics Limited exposure to pathogens during early childhood Can lead to atopies and allergies

54 Helminth infections Stimulates TH2 Immunresponses High levels of IgE, eosinophiles and mast cells People with helminth infections are rarely afflicted by allergic diseases TH2 cant be the sole factor for allergic attack

55 IgE blocking hypothesis Highly not specific polyclonal IgE Unspecific IgEs satures the Fc-receptors on mast cells à The binding site is blocked à degranulation is inhibited à Hypersensitiviy will be immediated

56 Blocking antibodies Parasites specific IgG4 antibodies inhibit IgE mediated degranulation of effector cells à Possible mechanism of allergen immunotherapy à IL-10 stimulates the IgG4 differentation à Allergic individulas express lower levels of IL- 10

57 True or False? The Hygenie Hypothesis for Crohns disease Bret A. Lashner M.D. Edward V. Loftus Jr.M.D.

58 Lack of exposures to enteric pathogens makes one susceptible to Crohns disease à Multiple childhood infections and poor hygenie protects Host develops tolerance or immunity to agents that could trigger Crohns disease

59 Crohns disease 2 different studies came to very different conclusions regarding the hygenie hypthesis The results of one study supports the hygenie hypothesis à Exposure to pathogens in childhood stimulates the immune system But the other contradicts à Poor hygenie may contribute to the pathogenesis à much work still needs to be done to determine if childhood exposure are truly important to the pathogenesis of Crohns disease

60 The PRODIA study Probiotics for the Prevention of Beta cell Autoimmunity in Children at Genetic Risk of Type 1 Diabetes VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Section of a pancreas of a dog Source: Gray´s anatomy Ann N Y Acad Sci 1079: (2006)

61 Diabetes mellitus VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Aretaeus of Capadocia: diabaínein passing through or siphon Thomas Willis (1675): mellitus sweet taste Chronic disorder of carbohydrate, fat and protein metabolism caused by lack or non-functionality of insulin Hyperglycemia Polyuria, excessive thirst, polyphagia, weight loss, fatigue, blurred vision, muscle cramps, nausea Ketoacidosis Nonketotic hypersomolar coma Retinal damage Chronic renal failure Diabetic neuropathy Coronary artery disease Gangrene: Diabetic foot

62 VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Type 1 Diabetes mellitus (T1DM) A.k.a Insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes Loss of the insulin-producing β-cells of the pancreas leading to deficiency of insulin Type 2 Diabetes mellitus (T2DM) A.k.a. Non insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes Combination fo defective insulin secretion and defective responsiveness to insulin Type 3 Diabetes mellitus (T3DM) A.k.a. Gestational Diabetes Reduced receptivity to insulin of pregnant women due to their hormone status

63 The Islets of Langerhans Paul Langerhans –80% β-cells producing Insulin and Amylin 15–20% α-cells producing Glucagon 3–10 % δ-cells producing Somatostatin 1% PP-cells producing pancreatic polypeptide Porcine Islet of Langerhans Brightfield Hematoxylin / Immunofluorescence One million islets/pancreas Combined weight 1-1,5 gramms (1-2% of pancreatic mass) ~1000 cells/islet

64 Etiology of T1DM Genetic factors Prevalence in the general population: 0,2–0,4% Concordance rate in monozygotic twins: 40-50% Concordance rate in dizygotic twins and siblings: 5-10% Genetic susceptibility accounts for ~half of the etiology VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Eighteen Loci (IDDM1-IDDM18) identified by positional cloning. All except four have turned out to be statistical artifacts due to underestimation of the sample size required for meaningful statistical power

65 Genetic factors 1. HLA Class II (IDDM1 Locus) VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Predisposing haplotypes: DRB1*0301(DR3)-DQA1*0501-DQB1*0201(DQ2) DRB1*0401(DR4)-DQA1*0301-DQB1*0302(DQ8) Heterozygosity DQ2/DQ8 Protective Haplotypes: DRB1*1501-DQA1*0102DQB1*0602(DQ6) Molecular mechanism: Absence of aspartic acid at position 57 of the β chain of the DQ molecule reversing the electric charge of the peptide binding groove and altering the binding of epitopes 40-50% of the genetic risk Horm Res 2005;64:

66 Genetic factors 2. INS-VNTR (IDDM2 Locus) Polymorphism in the 5´flanking region of the insulin gene, consisting of a variable number of tandem repeats. Either repeats (class I) or repeats (class II). Homozygosity for class I confers a relative risk of 2-3 compared with the dominant protective presence of class II. Probably due to lower thymic insulin levels hampered negative selection VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Horm Res 2005;64:

67 Genetic factors 3. PTPN22 Protein tyrosine phosphatase, nonreceptor type 22 The nonreceptor tyrosine phospahatase Lyp is specific to lymphocytes and suppressesT-cell activation by dephosphorylating three kinases important to T-cell signaling. The R620W SNP has also been associated with other autoimmune diseases like Rheumatoid Arthritis and SLE R620W maps to a solid 293-kb linkage disequilibrium block containing 6 other known genes and 625 known SNPs. VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Horm Res 2005;64:

68 Genetic factors 4. CTLA-4 Cytotoxic T-lymphocyte-associated antigen 4 Encodes T cell receptor that mediates apoptosis in activated T cells Associations also in Graves disease and autoimmune hypothyroidism Functional mechanism of the A6230G polymorphism is unknown. Contribution of the locus is low (relative risk ~ 1,2). Horm Res 2005;64:

69 Early exposure to cow milk and gluten Aberrant development and maturity of the gut immune system Enterovirus and Rotavirus infections Vitamin D3 deficiency Toxins: Rodenticides (Vacor), chemotherapeutic agents (Streptazotocin) VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Environmental factors

70 T1DM and the gut VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann In animal models the incidence of T1DM is highest in a low microbial load environment Diet modifies the development of T1DM in animal models T cells from human diabetic pancreas show mucosal homing properties Microbiotic colonization of the newborn´s gut by bacteria may be important for the initial regulation of the developing immune system. Development of T1DM is associated with intestinal immune activation and enhanced immunity to food antigens. Probiotics have been shown to support the development and maturity of the gut immune system and could therefore support oral tolerance and protection against enteral virus infections.

71 Autoantibodies in T1DM 3 major anti-islet autoantibodies: Glutamic acid decarboxylase (GADA): Useful marker for confirming etiology in long-standing cases Tyrosine phosphatase (IA-2A) Insulin (IAA): The only β-cell specific autoAg, more in DR4 Type 1a patients: Autoimmune, autoAbs present Type 1b patients: No evidence of autoimmunity Most children developing T1DM are positive for at least 2 of these markers. But B cells apparently not strictly required in the autoimmune process.

72 Immune dysregulation in T1DM VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann There has no primary diabetogenic autoantigen been found yet! Trigger ?? Bacterial products? Regulatory Th2 cell anergy? Immunity, Vol 7,

73 The PRODIA study Faculty of Health Sciences, Linköping University, Sweden The aim of the main study will be to determine whether the use of probiotics during the first 6 months of life decreases the appearance of β cell autoantibodies in children with genetic risk for Type 1 Diabetes mellitus. Pilot study to test feasibility and safety of the protocol. Start in February Affected factors involved could be the reduced occurence of enteral virus infection, enhanced maturation of the gut immune system, reduzed immunization to dietary insulin, or induced immune regulation VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann

74 Study design 1. Selection procedure Double-blind randomized placebo controlled study February 2003 to June 2005: Inform all parents to newborn infants at Linköping University Hospital Informed consent by parents for 1200 children (~60%) Screen for HLA risk genotypes (presence of risk alleles without protective haplotypes) VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann

75 Study design 2. Treatment Randomize participants to receive probiotics or placebo Lactobacillus rhamnosus GG (5 x 10 9 cfu) Lactobacillus rhamnosus LC705 (5 x 10 9 cfu) Bifidobacterium breve Bbi99 (2 x 10 8 cfu) Propionibacterium freudenreichii ssp. Shermani (2 x 10 cfu ) Distributed once a day by parents at home in soluble capsules

76 Study design 3. Readouts VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Blood samples taken at 6, 12, and 24 months of age β-cell autoAbs Monocyte and T cell-derived cytokines Intracellular signal proteins (T bet, STAT-4, STAT-6, GATA-3) Monocyte activation markers upon LPS and THA stimulation PHA and insulin-dependent T cell responses Isolation of enterovirus RNA Fecal samples taken at home at 3 months interval Microbiological analyses to detect enterovirus infections Analysis of compliance

77 VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Results 264 children with risk genes among the 1200 participants 1/168 IAA-positive at 6 months of age 1/61 GADA-positive at 24 months of age 1/61 IA-2A positive at 24 months of age Expected: ~2% prevalence of at least one of the autoAbs at 24 months

78 VO + SE Immunologisch relevante Aspekte von Lebensmittel, Probiotika und Nutrigenomics Markus Hoffmann Conclusions The detected number of autoAbs is close to the expected and there is no evidence that the intervention would increase the appearance of beta cell autoimmunity in the children who participate in the study. The PRODIA study protocol seems to be safe and the study protocol is feasible for the families. Mechanistic studies about the development of the immune system and the occurence of eneterovirus infections are ongoing

79 Wirken Phytoöstrogene immun- modulatorisch? Präsentation im Rahmen der LV Immunologisch relevante Aspekte von Lebensmitteln/Nutrigenomics WS 2006 Nina Zimbelius Philipp Schatzlmaier

80 80 Phytoöstrogene/Isoflavone Soja ist Hauptquelle für Genistein, Daidzein, Equol Strukturell ähnlich zu 17 -Östradiol Binden an ER, ER Ziele: Reproduktions-, Immunorgane Bestandteil von natürlicher Diät (v.a. Asien) Ebenfalls in modernen Nahrungsergänzungsmitteln (vielfache Dosis) Bestandteil von Babynahrung (soy-based infant formula) Potentieller Einfluss auf Immunsystem durch zahlreiche Studien untersucht Mäuse, Ratten, Menschen Ergebnisse unvollständig, teils widersprüchlich

81 81 Humanes Östradiol vs. Soja-Genistein Estradiol (a human estrogen) and genistein (a phytoestrogen) The similarly-placed hydroxyl groups at both ends of these two molecules allow them to bind to human estrogen receptors.

82 82 Immun-inhibitorische Effekte von Genistein Protein Tyrosine Kinase Inhibitor NO-Produktion in Makrophagen T-Zellen-Proliferation durch CD28-AK Interleukin-Produktion, TCL tumorizidale Aktivität Leukocyten-Adherenz, T-Zellen-Motilität Aktivierung von NK-Zellen durch LPS Vorsicht: in vitro Ergebnisse bei teils sehr hohen Konzentrationen (100µM) historische Diät: < 1µM im Serum bei japanischen Erwachsenen effiziente Aufnahme bei Kleinkindern: ca. 4 µM keine Abnormitäten im Erwachsenenalter dokumentiert allerdings sensibles Alter für Thymusentwicklung

83 83 in vivo Ergebnisse bei Mäusen und Ratten

84 84 Effekte von Östrogenen auf T-Genexpression Ovariektomisierte Mäuse-Babies Gabe von E2 und Genistein Genexpression durch DNA arrays untersucht Gene für Transkription, Apoptose, ZZ beeinflusst E2 eher, Genistein eher, grosses overlap an Genen Genistein wirkt auch auf E2-nicht-responsive Gene Down-Regulierung von CD4-Transkript

85 85 Ernährungsstudie beim Menschen 23 Männer und 18 Frauen, Hypercholesterinämie, 62 J. Post-Menopause (Ersatztherapie!) Drei kontrollierte Diätphasen à 1 Monat: a) low-fat Kontrollphase b) high isoflavone soy phase (73mg/d intake) c) low isoflavone soy phase (10mg/d intake) Am Anfang und Ende jeder Phase wurden bestimmt: Körpergewicht, Blutdruck, Lipoproteine/Blutfette Proteine der akuten Phase im Serum: CRP, SAA proinflammatorische Cytokine im Serum: IL-6, TNF-

86 86 Ergebnisse Entzündungswerte

87 87 Schlussfolgerungen Geschlechts-spezifischer Effekt IL-6, immun-stimulatorisch Negativ: Autoimmunität, CHD Positiv: Antwort bei Infektionen, Tumor defense IL-6 reduziert Plasmakonzentrationen von ILGF-1 Geringere Mortalität bei Hormon-abhängigen Tumoren in Asien, auch bei Brustkrebs Östrogene & Isoflavone wirken antioxidativ Vermeidung von DNA damage > Anti-cancer effect

88 88 Referenzen Cooke, P.S., Selvaraj, V., and Yellayi, S. (2006) Genistein, Estrogen Receptors, and the Acquired Immune Response. J. Nutr. 136: Jenkins, D.J.A., Kendall, C.W.C., Connelly, P.W., Jackson, C.C., Parker, T., Faulkner, D., and Vidgen, E. (2002) Effects of High- and Low-Isoflavone (Phytoestrogen) Soy Foods on Inflammatory Biomarkers and Proinflammatory Cytokines in Middle-Aged Men and Women. Metabolism 51(7):

89 Nutritional Genomics genes molecular processes nutrients diet health

90 Dietary Factors direct and indirect influence transcriptional, translational and posttranlational control

91 Intestinal Lumen – mucosal immune system nutritional environment gene regulation hormone – independent: > nutrients hormone - dependent

92 Nutrigenetic and nutrigenomic effects nutrigenetic effect: influence of polymorphisms on altering the response to dietary components nutrigenomic effect: ability of different food components to increase or depress gene expression

93 FABPs – fatty acid binding proteins lipid balance control of metabolic and inflammatory pathways modulation of FABP activity > regulation of lipid-sensitive pathways??

94 Cancer prevention ω-3 Poly Unsaturated Fatty Acids (PUFAs) > influence on expression of genes > anti-cancer activity > downregulation of synthesis and expression > induction of pro-apoptotic proteins

95 Leptin communicates information of the bodies fat stores altered levels of leptin > eating disorders (anorexia nervosa) regulates different genes (SCD1) > leptin resistance in obese individuals

96 Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging Kenneth S. Kornman

97 Inflammation healthy person smoking body mass index inflammatory mediators > concentration nutrition genetics no diseasediseasecomplex chronic disease

98 Interleukin 1 IL-1 and TNF- > early activated drugs that block their activity > treatment of rheumatoid arthritis

99 Interleukin 1 gene variations IL-1A IL-1BIL-1RN IL-1 cluster(+4845) or (-511) or(+2018) or haplotype(-889)(+3954)(-31)VNTR b Interleukin 1 (IL-1) single-nucleotide polymorphisms

100 Increased risks haplotype 1 > periodontitis haplotype 1 > cardiovascular disease haplotype 2 > gastric cancer

101 Nutrients interact with inflammatory genes poly unsaturated fatty acids (PUFAs) > inhibition of secretion of IL-1 and TNF- nutrients that alter the oxidation-reduction status of the cell different effects in individuals with different polymorphisms

102 Conclusion better understanding of polymorphisms > identify at-risk persons > interventions screening for bioactive nutrients problems: > costs (testing of asymptomatic people) > primary preventive measures


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