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

18.12.2006

Immunologisch relevante Aspekte von Lebensmittel, Probiotika und

Nutrigenomics, Dr. Alexander Haslberger, LVNr. 300424

Early nutrition and immunity- progress and perspectives

Sonja Lang

Katja Bohländer

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Overview• Tolerance• Role of nutrition• Feeding practises• Role of dendritic cells, lactobacilli• Intestinal colonization• PUFA• LCPUFA• Lipid rafts

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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

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Nutrition + immunologic developmentNutrition• …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

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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↑

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Dendritic cells + LactobacilliFunction 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

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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)

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PUFA

• in the intake of saturated fatty acids• in the intake of n-6 family of PUFA• Linoleic acid

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N-6 family of PUFA

Linoleic Acid

Arachidonic acid

Prostaglandine

PGE2

Tromboxanes

TXA2

Leukotriene

LTB4

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4-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

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n-3 family of PUFA• -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.

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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

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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

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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

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 2001Rome, Italy

Introduction

• 29 May to 2 June 2000 Joint FAO/WHO Geneva, Switzerland

• follow-up: 22 to 25 January 2001Rome, Italymembers: 28 experts and authors of discussion papers

Allergenicity

• Most frequently asked questions– safety of genetically foods

• reliable methodology to assess the allergenicity of foods produced by the recombinant DNA technique needed

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

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

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.

Yes

YesYes

No

NoNo

No

+/+ +/- -/-High

LowProbability of Allergenicity

LikelyAllergenic

Yes Yes

No

Yes

Yes

Sequence Homology

Target SerumScreen

Source of gene allergenic

Sequence Homology

Pepsin Resistance &

Animal Models

Specific Serum Screen

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

Other criteria

• Level of expressions

• Unintended effects

Evaluation of Allergenicity of Genetically Modified Foods

Martina Pomper9603177

Ines Pree, Immunology and Food, WS 2006

1. 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: 49-54 (2007)


• 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 by1. Hazard identification: situation, symptoms, target organs

2. Hazard characterization: threshold, minimum dose

3. Exposure assessment: intake etc.

Risk assessment

The probabilistic approach in food allergy


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


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


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).


• 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 programs2. Recruit potentially at-risk individuals (allergic patients)3. Perform serum testing, skin prick testing, food challenge.

Potential allergenicity in GE food


• 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


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)


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).

Immunity, Inflammation and Allergy In The Gut

Thomas T. MacDonald and Giovanni Monteleone

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

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

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

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

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

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

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

Celiac disease (2)

• 4 components involvedà Gluten is prolin and glutamine rich, has negatively

charged residuesà tTG deaminates glutamin to glutamic acid and produces

negatively charged residuesà Necessary for efficient binding to HLA-DQ2 and

furthermore activation of gluten specific t-cellsà Peptides of gliadin activate gut macrophages to produce

IL-15 -> increases MICA and arms IEL to kill MICA and epithelial cells

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

ProbioticsDo They Help to Control Intestinal

Inflammation?

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

(Active) Ulcerative Colitis

• Ulcerative Colitis: Study comparing mesalamine treatment with E.coli Nissle 1917 treatment

• relapse rate were not different between groupsà 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

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

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

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

Allergy, Parasites and the Hygenie Hypothese

Maria YazdanbakhshPeter G. Kremsner

Ronald van Ree

Atopy and Allergic diseases

• significant increase in pervalence of allergic deseases in the last 20-30 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

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

Hygenie Hypothese

• High hygenie• Vaccination• Antibiotics• Limited exposure to pathogens during early

childhood

Can lead to atopies and allergies

Helminth infections

• Stimulates TH2 Immunresponses High levels of IgE, eosinophiles and mast cells

• People with helminth infections are rarely afflicted by allergic diseases

TH2 can‘t be the sole factor for allergic attack

IgE blocking hypothesis

• Highly not specific polyclonal IgE

• Unspecific IgEs satures the Fc-receptors on mast cells

à The binding site is blockedà degranulation is inhibitedà Hypersensitiviy will be immediated

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 differentationà Allergic individulas express lower levels of IL-

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True or False? The Hygenie Hypothesis for Crohn‘s disease

Bret A. Lashner M.D.Edward V. Loftus Jr.M.D.

• Lack of exposures to enteric pathogens makes one susceptible to Crohn‘s disease

à Multiple childhood infections and poor hygenie protects

Host develops tolerance or immunity to agents that could trigger Crohn‘s disease

Crohn‘s disease• 2 different studies came to very different conclusions regarding the

hygenie hypthesis

• The results of one study supports the hygenie hypothesisà Exposure to pathogens in childhood stimulates the immune system

• But the other contradictsà 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 Crohn‘s disease

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 dogSource: Gray´s anatomy

Ann N Y Acad Sci 1079: 360-364 (2006)

Diabetes mellitus


Aretaeus of Capadocia: diabaínein „passing through“ or „siphon“Thomas Willis (1675): mellitus „sweet taste“

Chronic disorder of carbohydrate, fat and protein metabolism caused bylack 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“


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 diabetesCombination 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

The Islets of LangerhansPaul Langerhans 1869

• 65–80% 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 LangerhansBrightfield Hematoxylin / Immunofluorescence

One million islets/pancreas Combined weight 1-1,5 gramms (1-2% of pancreatic mass) ~1000 cells/islet

Etiology of T1DMGenetic 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


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

Genetic factors1. HLA Class II (IDDM1 Locus)


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;64:180-188

Genetic factors2. INS-VNTR (IDDM2 Locus)

Polymorphism in the 5´flanking region of the insulin gene, consisting of a variable number of tandem repeats. Either 30-60 repeats (class I) or 120-170 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


Horm Res 2005;64:180-188

Genetic factors3. 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 associatedwith other autoimmune diseases likeRheumatoid Arthritis and SLE

R620W maps to a solid 293-kblinkage disequilibrium block containing6 other known genes and 625 known SNPs.


Horm Res 2005;64:180-188

Genetic factors4. CTLA-4

Cytotoxic T-lymphocyte-associated antigen 4

Encodes T cell receptor that mediates apoptosis in activated T cellsAssociations also in Graves disease and autoimmune hypothyroidismFunctional mechanism of the A6230G polymorphism is unknown.Contribution of the locus is low (relative risk ~ 1,2).

Horm Res 2005;64:180-188

• 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)


Environmental factors

T1DM and the gut


• 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 importantfor 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.

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 presentType 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.

Immune dysregulation in T1DM


There has no primary diabetogenic autoantigen been found yet!

Trigger ??

Bacterial products?Regulatory Th2 cell anergy?

Immunity, Vol 7, 727-738

The PRODIA studyFaculty 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 2003.

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



Study design1. 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)



Study design2. Treatment

Randomize participants to receive probiotics or placebo

Lactobacillus rhamnosus GG (5 x 109 cfu)Lactobacillus rhamnosus LC705 (5 x 109 cfu)

Bifidobacterium breve Bbi99 (2 x 108 cfu)Propionibacterium freudenreichii ssp. Shermani (2 x 10 cfu)

Distributed once a day by parents at home in soluble capsules

Study design3. Readouts


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


Results

264 children with risk genes among the 1200 participants

1/168 IAA-positive at 6 months of age1/61 GADA-positive at 24 months of age1/61 IA-2A positive at 24 months of age

Expected: ~2% prevalence of at least one of the autoAbs at 24 months


Conclusions

„The detected number of autoAbs is close to the expected and thereis 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

Wirken Phytoöstrogene immun-

modulatorisch?

Präsentation im Rahmen der LVImmunologisch relevante Aspekte von

Lebensmitteln/Nutrigenomics

WS 2006Nina Zimbelius

Philipp Schatzlmaier

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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

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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.

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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

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in vivo Ergebnisse bei Mäusen und Ratten

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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

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-

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Ergebnisse Entzündungswerte

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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

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Referenzen

• Cooke, P.S., Selvaraj, V., and Yellayi, S. (2006) Genistein, Estrogen Receptors, and the Acquired Immune Response. J. Nutr. 136: 704-708

• 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): 919-924

Nutritional Genomics

genes

molecular processes

nutrients

diet

health

Dietary Factors

• direct and indirect influence

• transcriptional, translational and posttranlational control

Intestinal Lumen – mucosal immune system

nutritional environment

gene regulation

hormone – independent:

> nutrientshormone - dependent

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

FABPs – fatty acid binding proteins

• lipid balance

• control of metabolic and inflammatory pathways

• modulation of FABP activity > regulation of lipid-sensitive

pathways??

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

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

Interleukin 1 genetics, inflammatory mechanisms,

and nutrigenetic opportunities to modulate diseases of aging

Kenneth S. Kornman

Inflammation

healthy personsmoking

body mass index

inflammatory mediators > concentration nutrition

genetics

no disease disease complex chronic disease

Interleukin 1

IL-1 and TNF-a > early activated

drugs that block their activity

> treatment of rheumatoid arthritis

Interleukin 1 gene variations

IL-1A IL-1B IL-1RN

IL-1 cluster (+4845) or (-511) or (+2018) or

haplotype (-889) (+3954) (-31) VNTR

1 2 2 1 1

2 1 1 2 1

2b 1 1 2 2

3 1 1 1 1

Interleukin 1 (IL-1) single-nucleotide polymorphisms

Increased risks

• haplotype 1 > periodontitis

• haplotype 1 > cardiovascular disease

• haplotype 2 > gastric cancer

Nutrients interact with inflammatory genes

• poly unsaturated fatty acids (PUFAs) > inhibition of secretion of IL-1 and TNF-a

• nutrients that alter the oxidation-reduction status of the cell

• different effects in individuals with different polymorphisms

Conclusion

• better understanding of polymorphisms > identify at-risk persons > interventions

• screening for bioactive nutrients

• problems: > costs (testing of asymptomatic people) > primary preventive measures

Documents

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