Download The Importance of Nutrition to Healthy Immune Function

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The Importance of Nutrition to
Healthy Immune Function
Philip Calder, BSc(Hons), PhD, DPhil, RNutr
Professor of Nutritional Immunology
University of Southampton Faculty of Medicine
Agenda
• Overview of the immune system
• How to measure immune function
• Why nutrition is important for
immune function
• Evidence that good nutrition supports
good immune function
• Non-nutrient immune interventions
Agenda
• Overview of the immune system
• How to measure immune function
• Why nutrition is important for
immune function
• Evidence that good nutrition supports
good immune function
• Novel dietary immune interventions
The immune system…
… is a cell and tissue system that protects
the individual from invading pathogens
Immunology 101
Innate
Adaptive
• Slower response
• Specific
• Memory
Components:
•Antibodies
•B cells, Helper
T cells, Killer T
cells, Dendritic
cells
•
•
•
•
1st line of defense
Non-specific
Rapid response
No memory
Components:
•Complement
•White blood
cells;
Macrophages,
Neutrophils,
Natural Killer
cells
The immune system…
… distinguishes “self” from “non-self”
But every day we eat animal and plant materials
-> continuous chronic exposure to “non-self”
And we are exposed to countless
environmental challenges
So, the immune system…
… recognises and tolerates “self” and
non-threatening “non-self”
and…
recognises and attempts to eliminate
(i.e. does not tolerate) threatening “non-self”
The immune response …
• The individual’s response to
infection by bacteria, viruses,
fungi, and parasites
• Involved in protection against
growth of cancer cells
• Distinguishes “self” from
“non-self” => Tolerance
• Typified by cellular interactions and movement
of cells to sites of infection
• Normally it is protective (and so beneficial)
The immune response …
• It includes both non-specific,
innate (natural) responses
and specific, acquired
responses
• Includes a component
of memory
• Involves various cell types including antigen
presenting cells (especially dendritic cells),
macrophages and T and B lymphocytes
How does the immune system work?
1. It is a barrier to entry of invaders
• Skin
• Mucosal surfaces of
the gastrointestinal,
respiratory, and
genitourinary tracts
• Acid pH of stomach
• “Friendly” bacteria
2. If invaders do get in they are
recognised and can be trapped
• Proteins in bloodstream
and secretions
(complement;
antibodies) recognise
foreign cells
• They coat them
• This enables them to be
recognised by cells of
the immune system
3. Once trapped, invaders can be destroyed
• Cells can discriminate “self”
from “non-self”
- Neutrophils,
- Monocytes,
- Macrophages,
- Lymphocytes (T cells, B cells)
• Cells can destroy “non-self”
- Engulf & digest
- Destructive toxic chemicals
(superoxide, hydrogen peroxide,
nitric oxide, cytokines, pore
formers)
How the immune system attacks an infected cell
4. Encounters with the foe are remembered
• After an immune
response is mounted
memory cells remain
for many years
• This gives a faster
response if
reinfection occurs
• This is the basis of
vaccination
The four key activities of the immune system
• Exclusion barrier
• Identification of “non-self”/Tolerance
of “self”
• Elimination
• Memory
Interaction amongst immune cells
B
Activate
Activate
Th
Activate
Antibodies
Activate
Antigen
presentation
Tc
Antigen
presentation
Bacteria
NK
Phagocyte
Lysis
Virus infected cell
Source unknown
=> It is clear that having an immune
system that works well is the key to
preventing infections and in controlling
the effects of being infected
The immune system over the lifecourse
• Babies are born with an immature immune
system -> this will develop over time with
increasing exposure to new antigens (i.e. to
new foods and to new pathogens)
• The function of the immune system declines
with old age (depletion of naïve cells due to
cumulative lifetime antigen exposure?)
Agenda
• How to measure immune function
• Overview of the immune system
• Why nutrition is important for
immune function
• Evidence that good nutrition supports
good immune function
• Novel dietary immune interventions
How to measure immune function
• Measure immune markers in blood or other
accessible sites (e.g. there are certain
antibodies in saliva)
• Isolate immune cells from blood and then study
those cells in culture -> can measure functional
responses
% of cells active
100
80
60
40
20
0
Phagocytosis Resp Phagocytosis Resp
burst
burst
Neutrophils
Cytokine concentration
(ng/ml)
There is significant variation in immune
responses among healthy individuals
100
80
60
40
20
0
TNF-α
IL-1β
Monocytes
Healthy males, aged 40 to 65 years (n = 50 to 83)
Kew et al. (2003) Am. J. Clin. Nutr.77,1278-1286
IL-6
Immune Challenge
• Give a person an immune challenge
(e.g. a vaccination) and follow the response
• Look at pattern of infections – do they occur, how
severe are they, how long do they last
Agenda
• Overview of the immune system
• How to measure immune function
• Why nutrition is important for
immune function
• Evidence that good nutrition supports
good immune function
• Novel dietary immune interventions
“Resting” immune
system
“Activated” immune
system
Increased
demand for
energy and for
building blocks
Nutrients can also be …
• Substrates for the synthesis of chemicals
involved in the immune response (e.g.
arginine and nitric oxide)
• Regulators of aspects of the immune
response (e.g. vitamin A and zinc regulate
cell division)
Meeting the demand
Exogenous
i.e. diet
Endogenous
i.e. body stores
Immune system demand for nutrients
Agenda
• Overview of the immune system
• How to measure immune function
• Why nutrition is important for
immune function
• Evidence that good nutrition supports
good immune function
• Novel dietary immune interventions
Malnutrition
Increasing immune response
• Impairs immune function (& increases susceptibility to infection)
• Effects reversed by improving nutritional status
Rivera et al. (1986) Nutr. Res. 6, 1161-1170
Skin response to an antigen
90 or more
75-89
< 75
% weight for age
Increasing malnutrition
The potential for improved nutrition to save lives through
improved host immune defence is enormous!
Micronutrient deficiencies (vitamin A, Zn, Fe, Cu, …)
-- Impairs immune function (& increase susceptibility to infection)
-- Effects reversed by correcting the deficiency
• Vitamin A deficient infants in
Semba et al (1992) J Nutr 122, 101-107
300
Anti-tetanus IgG
Indonesia
• RCT placebo vs. vitamin A
• Then given tetanus
vaccination
• Response to vaccination
better in the vitamin A
group
200
100
0
Placebo
Vitamin A
Micronutrient deficiencies (vitamin A, Zn, Fe, Cu, …)
healthy elderly women
in Canada
• Some had low Fe status,
some didn’t
• Immune functions
measured using cells
isolated from the blood
• Immune functions were
lower in the Fe deficient
women
Ahluwalia et al. (2204) Am J Clin Nutr 79, 516-521
Increasing immune response
• Homebound but fairly
Fe-sufficient
Fe-deficient
Stimulant concentration
Nutrients shown to improve some aspects
of the immune response in humans
•
Some amino acids – S-containing, glutamine, arginine, leucine,
taurine, and some amino acid metabolites
•
Several fatty acids
•
Fat-soluble vitamins – A, D, E, carotenoids
•
Vitamin B6, folate, B12, C, …..
•
Zn, Cu, Se, Fe ….
•
Flavonoids
•
Prebiotic type saccharides
Appropriate nutrient supply
Appropriate nutrient status (& stores)
Appropriate immune function
Appropriate nutrient supply
Appropriate nutrient status (& stores)
Appropriate immune function
Better defence against pathogens
Vitamin D and influenza A
• Japanese school-
children aged 6 to 15
years
20
% of children with influenza A
• RCT of placebo vs.
Vitamin D daily for 16
weeks during winter
(167 children per group)
• Outcome was
incidence of influenza
A infection
Urasima et al. (2010) Am J Clin Nutr 91, 1255-1260
10
0
Placebo
Vitamin D
Nutritional Immunology
• Caloric Restriction (25-40%) [animal models]
– Prolongs life span
– Inhibits age-related diseases
– Prevents obesity and hyperglycemia
– Increases antioxidant enzymes & DNA repair
processes
– Modulates immune function and alters gene
expression
– Decreases insulin resistance
Fernandes G. (2008) Immunol. Res. 40, 244-61
42
Nutritional Immunology
• Caloric Restriction + Omega-3s [animal models]
–  Th-1/Th-2 cytokines
–  adhesion molecules
–  COX-2/PGE2 levels
–  pro-inflammatory cytokines (e.g., IL-1β, IL-6,
and TNF-α)
–  NF-κB and AP-1 activity
–  body weight and insulin sensitivity
Fernandes G. (2008) Immunol. Res. 40, 244-61
43
The Big Question
Will improved immune function increase
resistance to infection?
YES: in clearly deficient/malnourished
individuals
?? In healthy individuals
Agenda
• Overview of the immune system
• How to measure immune function
• Why nutrition is important for
immune function
• Evidence that good nutrition supports
good immune function
• Novel dietary immune interventions
Intestinal Immune System
Constant and massive antigenic stimulation
Invasive pathogens
Strong protective immunity
Food proteins and commensal bacteria
Mowat (2003) Nat Rev Immunol
3, 331-341
Oral tolerance
Intestinal Immune System
Certain gut bacteria
Interaction with host gut-associated immune system
(via chemical mediators and/or direct interaction)
Improved host immune function
Intestinal Immune System
Preidis & Versalovic (2009)
Gastroenterology 136, 2015-2031
Intestinal Immune System
Can dietary components modify or improve
the immune system response?
Indirect: Gut bacterial immune interaction
Direct: Uptake by gut immune cells
Randomised controlled trial of Actimel
• Healthy elderly subjects
• Plain yoghurt vs. Danone Actimel for 13 wks
• About 100 subjects per group
• After 4 weeks received seasonal flu
vaccination
• Vaccine response measured 3, 6 and 9
weeks after vaccination (blood antibodies
to the vaccine – the flu vaccine contains
three flu viruses -> measure antibodies to
each virus)
Boge et al. (2009) Vaccine 27, 5677-5684.
Wellmune WGP®, a yeast beta glucan
1) Taken orally, Wellmune WGP is
taken up into the body via the
Peyer’s Patches in the intestines.
2) Immune cells called
macrophages containing
Wellmune WGP travel to the
immune organs throughout the
body.
3) Macrophages break down
Wellmune WGP into smaller
fragments that bind to
neutrophils, the most abundant
immune cell in the body.
Hong et al. (2004) J. Immunol. 173, 797-806
4) Neutrophils more quickly
recognize and kill foreign
challenges.
Medical Students Stress Study
Study Protocol
• 100 fourth year medical students
• 90-day study − randomized, double-blinded,
placebo controlled
• 250 mg yeast beta glucan (Wellmune WGP®)
or placebo
• Medically verified cold-flu symptoms-validated
survey (WURSS-21 survey)
• Blood biomarker evaluation included cytokines
and WBC profile
Fuller et al. (2012) Nutr. 28, 665-669
Medical Students Stress Study
< 0.06
• Result: A 22% reduction in the total number of days with URTI *p
symptoms
yeast beta-glucan group vs. placebo (198 days vs. 241 days, p=0.06).
Fuller et al. (2012) Nutr. 28, 665-669
Exercise Stress and Immune Biomarkers
Methods & Study Design
• 60 person cross over design (Wellmune WGP or
placebo), randomized and double blind.
• Subjects completed a cycling session @100 F after
each treatment arm (matched for intensity).
• Blood and saliva samples at baseline, pre-exercise,
post-exercise and 2 hours post-exercise
• Measured immune response via a simulated ex vivo
challenge (LPS stimulation) and measure cytokine
production as a marker for immune responsiveness
LPS-Stimulated Cytokines
(*) Statistically significant difference (P<0.05) between Wellmune WGP and placebo.
Carpenter et al. (2012) Brit. J. Nutr.
Take home messages
• The immune system is important to a healthy life
– it is complex involving several cell types and
numerous chemical mediators.
• The immune system develops in early life and
declines with ageing.
• It is possible to measure aspects of the immune
response in humans.
Take home messages
• Very poor nutrition is associated with a poor
immune response and increased susceptibility to
infection -> can be improved with improved
nutrition.
• There is good evidence that good dietary habits
are important to support good immune function.
• Novel dietary interventions such as prebiotics,
probiotics and yeast beta-glucans support healthy
immune responses.