Early nutrition and immunity- progress and perspectives

1
Early nutrition and immunity- progress and
perspectives
1

• Sonja Lang
• Katja Bohländer

2
Overview
2

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

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 (mothers
  skin, breast milk ? maturation of infants gut

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

5
German Infant Nutritional Intervention Study
5

• Effects of hydrolysed and standard cows 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?

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

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)

8
PUFA
8

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

9
N-6 family of PUFA
9

• Linoleic Acid
• Arachidonic acid

Prostaglandine PGE2
Tromboxanes TXA2
Leukotriene LTB4
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

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.

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

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

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

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
(No Transcript)
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 allergensSpanjers
berg, M.Q.I., Kruizinga, A.G., Rennen, M.A.J.,
Houben, G.F., Food Chem Toxicol, 45 49-54 (2007)
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

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.

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
  subjects will respond which reflects a lower
  contamination of brand 3

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).
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.

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 gt35 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

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 (gt35 identity over 80 amino acids)

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 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 (gt35 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 a4ß7 integrin
• TLR or NOD activate NF?B
• ? 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 TH1 cells produce large amount of
  interferon ?
• 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
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
• 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 -gt 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
• 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 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

52
Atopy

• enviromental allergen leads to T cell stimulation
  
• release of Cytokines (IL4, IL5, IL13)
• raised IgE levels
• 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
• The binding site is blocked
• degranulation is inhibited
• Hypersensitiviy will be immediated

56
Blocking antibodies

• Parasites specific IgG4 antibodies inhibit IgE
  mediated degranulation of effector cells
• Possible mechanism of allergen immunotherapy
• IL-10 stimulates the IgG4 differentation
• 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
• 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
• Exposure to pathogens in childhood stimulates the
  immune system
• But the other contradicts
• Poor hygenie may contribute to the pathogenesis
• 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
Ann N Y Acad Sci 1079 360-364 (2006)

• Probiotics for the Prevention of Beta cell
  Autoimmunity in Children at Genetic Risk of Type
  1 Diabetes

Section of a pancreas of a dog Source Grays
anatomy
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
61
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 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

VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
62
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
63
The Islets of Langerhans
Paul Langerhans 1869
One million islets/pancreas
Combined weight 1-1,5 gramms (1-2 of pancreatic
mass) 1000
cells/islet

• 6580 ß-cells producing Insulin and Amylin
• 1520 a-cells producing Glucagon
• 310 d-cells producing Somatostatin
• 1 PP-cells producing pancreatic polypeptide

Porcine Islet of Langerhans Brightfield
Hematoxylin / Immunofluorescence
64
Etiology of T1DMGenetic factors
Prevalence in the general population
0,20,4 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
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
65
Genetic factors1. HLA Class II (IDDM1 Locus)
40-50 of the genetic risk
Predisposing haplotypes DRB10301(DR3)-DQA10501
-DQB10201(DQ2) DRB10401(DR4)-DQA10301-DQB10302
(DQ8) Heterozygosity DQ2/DQ8
Protective Haplotypes DRB11501-DQA10102DQB106
02(DQ6)
Horm Res 200564180-188
Molecular mechanism Absence of aspartic acid at
position 57 of the ß chain of the DQ molecule
reversing the electric charge of the peptide
binding groove and altering the binding of
epitopes
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
66
Genetic factors2. INS-VNTR (IDDM2 Locus)
Horm Res 200564180-188
Polymorphism in the 5flanking 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
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
67
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 like Rheumatoid Arthritis and
SLE
R620W maps to a solid 293-kblinkage
disequilibrium block containing6 other known
genes and 625 known SNPs.
Horm Res 200564180-188
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
68
Genetic factors4. CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
Horm Res 200564180-188
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).
69
Environmental factors

• 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
70
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 newborns 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.
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
71
Autoantibodies in T1DM
Type 1a patients Autoimmune, autoAbs
present Type 1b patients No evidence of
autoimmunity

• 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 ß-cell specific autoAg,
  more in DR4

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
There has no primary diabetogenic autoantigen
been found yet!
Bacterial products? Regulatory Th2 cell anergy?
Immunity, Vol 7, 727-738
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
73
The PRODIA study
Faculty of Health Sciences, Linköping University,
Sweden
Pilot study to test feasibility and safety of the
protocol. Start in February 2003.
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 ß cell
autoantibodies in children with genetic risk for
Type 1 Diabetes mellitus.
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 design1. Selection procedure
Double-blind randomized placebo controlled study
February 2003 to June 2005 Inform all parents to
newborn infants at Linköping University Hospital
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
75
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
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
76
Study design3. Readouts
Blood samples taken at 6, 12, and 24 months of
age
ß-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
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
77
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
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
78
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
VO SE Immunologisch relevante Aspekte von
Lebensmittel, Probiotika und Nutrigenomics
Markus Hoffmann
79
Wirken Phytoöstrogene immun-modulatorisch?

• Präsentation im Rahmen der LV
• Immunologisch relevante Aspekte von
  Lebensmitteln/Nutrigenomics
• WS 2006
• Nina Zimbelius
• Philipp Schatzlmaier

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
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
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 lt 1µM im Serum bei
  japanischen Erwachsenen
• effiziente Aufnahme bei Kleinkindern ca. 4 µM
• keine Abnormitäten im Erwachsenenalter
  dokumentiert
• allerdings sensibles Alter für
  Thymusentwicklung

83
in vivo Ergebnisse bei Mäusen und Ratten
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
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
Ergebnisse Entzündungswerte
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 gt Anti-cancer effect

88
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

89
Nutritional Genomics

• genes

nutrients
diet
molecular processes
health
90
Dietary Factors

• direct and indirect influence
• transcriptional, translational and
  posttranlational control

91
Intestinal Lumen mucosal immune system

• nutritional environment

hormone independent gt nutrients
hormone - dependent
gene regulation
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
• gt regulation of lipid-sensitive pathways??

94
Cancer prevention

• ?-3 Poly Unsaturated Fatty Acids (PUFAs)
• gt influence on expression of genes
• gt anti-cancer activity
• gt downregulation of synthesis and
  expression
• gt induction of pro-apoptotic proteins

95
Leptin

• communicates information of the bodies fat stores
• altered levels of leptin gt eating disorders
  (anorexia nervosa)
• regulates different genes (SCD1)
• gt 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

genetics
smoking
body mass index
inflammatory mediators gt concentration
nutrition
no disease
disease
complex chronic disease
98
Interleukin 1

• IL-1 and TNF-a gt early activated
• drugs that block their activity
• gt treatment of rheumatoid arthritis

99
Interleukin 1 gene variations
Interleukin 1 (IL-1) single-nucleotide
polymorphisms
  IL-1A IL-1B 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
100
Increased risks

• haplotype 1 gt periodontitis
• haplotype 1 gt cardiovascular disease
• haplotype 2 gt gastric cancer

101
Nutrients interact with inflammatory genes

• poly unsaturated fatty acids (PUFAs)
• gt 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

102
Conclusion

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