Douglas Korver, Implications of Changing Immune Function ...

Implications of Changing Immune
Function Through Nutrition
Doug Korver
University of Alberta

Nutritional Modulation of Immune
Function
• Development of immune system
• Substrate supply
• Nutritional immunity
• Hormonal millieu
• Regulatory actions of nutrients
• Reduction of pathology
• Physical/chemical actions in GI tract
Klasing, 1998 Poultry Science 77:1119-1125

The Immune System
• Two arms of the immune system
– Adaptive Immunity
• Targeted responses
– Antibodies (humoral responses - B cells)
– Directed cytotoxicity (cell-mediated - T cells)
• Memory
• Low energy expenditure

The Immune System
• Two arms of the immune system
– Innate immunity
• Exclusion of pathogens
• Local & systemic effects
– Inflammation – phagocytosis, killing
• No memory
• Energetically costly

The Immune System
• Immune system is a complex network
– Communication between innate and adaptive
• Eg antibody response requires innate cells
– Vaccine adjuvants
Adaptive Innate immunity
Adaptive

Focus on Innate Immunity
• Control disease through management
– Vaccination, biosecurity, sanitation, etc.
• Cost of activation
– A vigorous antibody response requires little in the
way of nutrients and energy
– A vigorous inflammatory response can result in
the loss of body weight

Immunology for Nutritionists
• Innate immunity
– A blunt instrument
• Systemic effects
– Fever
– Decreased appetite
– Metabolic inefficiencies
– Skeletal muscle catabolism
» Acute phase protein synthesis

Environment and Growth
100
90
80
70
60
50
40
30
20
10
0
K. Klasing
IDEAL SANITATION
0 5 10 15 20 25 30 35 40
AGE

Environment and Growth
100
90
80
70
60
50
40
30
20
10
0
K. Klasing
IDEAL SANITATION
BARN ENVIRONMENT
0 5 10 15 20 25 30 35 40
AGE

% OF NON-INJECTED CONTROLS
Inflammation & Performance
110
105
100
SALINE
SRBC
SEPHADEX
LPS
95
90
85
80
10
0
GAIN FEED GAIN/FEED
K. Klasing

% OF NON-INJECTED CONTROL
Inflammation & Body Composition
130
SALINE KILLED S. aureus LPS
120
110
100
90
80
70
60
10
0
K. Klasing
INTESTINE LIVER SPLEEN PECTORALIS

Modern Poultry Production
• Wild Jungle Fowl
– Extensive
– Exposure
– Diet
– SURVIVAL

Modern Poultry Production
• Commercial production
– Intensive
– Biosecurity
– Diet
– Antibiotics
– Vaccines
– PERFORMANCE

Modern Poultry Production
• ↑ risk of
infections
• ↑ importance
of immunity
– Denmark –
DANMAP 2005

The Immune System
• What do we know about the immune system
– Unintended consequences
Adaptive
Innate
– What is advantageous under one set of
circumstances may be deleterious under others
– Are we smart enough to figure this out

Nutritional Modulation of Immune
Function
• Development of immune system
• Substrate supply
• Nutritional immunity
• Hormonal millieu
• Regulatory actions of nutrients
• Reduction of pathology
• Physical/chemical actions in GI tract
Klasing, 1998 Poultry Science 77:1119-1125

• Example -- Zinc
– Zinc deficiency
• ↓ innate immunity
• ↓ adaptive immunity
Minerals
– zinc excess
• ↓ innate immunity
• ↓ adaptive immunity

Implications
• A “change” in immune function doesn’t mean
“immunomodulation”
– What levels must be fed in order to see a
response
– Does the change increase health and/or
productivity

Selection for Growth
• Growth rate has tripled in the last several
decades (Havenstein et al. 2003)
Broiler 50 years ago Broiler 30 years ago Today’s Broiler
M. Zuidhof

Selection for Growth
• Resource allocation theory (Rauw et al. 1998)
– Selection against other traits
• Eg. metabolic, reproductive
Resource
Reproduction
Reproduction
Growth
Growth
Immunity
Immunity
Metabolic
Metabolic

Selection for Growth
• Selection of broilers for performance:
– reduced acquired immunity antibody production
– reduced acquired immunity antibody production
(Qureshi and Havenstein, 1994; Cheema et al., 2003)
HOWEVER….
– effects depend on the response being measured
• modern broilers
– reduced systemic response to pro-inflammatory challenges
– reduced pro-inflammatory cytokines
(Leshchinsky et al., 2001, Humphrey and Klasing, 2004; Xie et al., 2000)

Selection for Growth
• Selection of broilers for growth
– reduced acquired immunity antibody production
– reduced acquired immunity antibody
production
(Qureshi and Havenstein, 1994; Cheema et al., 2003)
HOWEVER….
– effects depend on the response being measured
• modern broilers
– reduced systemic response to pro-inflammatory challenges
– reduced pro-inflammatory cytokines
(Leshchinsky et al., 2001, Humphrey and Klasing, 2004; Xie et al., 2000)

Commercial
“C”
Random bred 1957
“R”

Temperature (°C)
Fever response to
42.2
lipopolysaccharide (LPS)
42
41.8
41.6
41.4
41.2
41
40.8
40.6
40.4
40.2
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
CI
RI
CU
RU
Strain = P

Commercial
“C”
Random bred 1977
“R77”
Random bred 1957
“R57”

Plasma IL-1 Activity after E. coli
Infection
Stimulation Index
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1957 1977 1998
P>0.0785

T-cell Response to IL-1
Stimulation Index
50
40
30
20
10
0
a
b
b
1957 1977 1998
P>0.05

% E.coli killed
Bactericidal Activity
70
60
a
a
50
b
40
30
20
10
0
R57 R77 2006 P

Implications
• Genetic selection for growth has altered
immunity in broilers
– Need good management
– Diet manipulation
– Immunomodulation
• Selecting for innate immunity may be a way to
address these issues
– Selection for both BW and innate immunity can be
achieved (Boa-Amponsem et al., 1998; Yunis et al., 2000)

Nutritional Modulation of Immune
Function
• Development of immune system
• Substrate supply
• Nutritional immunity
• Hormonal millieu
• Regulatory actions of nutrients
• Reduction of pathology
• Physical/chemical actions in GI tract
Klasing, 1998 Poultry Science 77:1119-1125

The Chick
• First week of life becomes more and more
important
– Greater proportion of life before slaughter
M. Zuidhof

Innate Immunity
• Begins to develop during early embryonic
growth
• Functionally immature

Innate Immune Development
• Can we advance the developmental state at
hatch
– In ovo feeding
– Maternal nutrition
– Incubation conditions
• Can we affect the rate of development during
the first week

E. coli Killing by WBC
E. Coli killed
100
80
60
40
b
a
b
a
b
a
Control
25-OH D 3
b
a
%
20
0
Early Mid Late
Day 1
Day 4 Day 1 Day 4 Day 1 Day 4
Proportion of bacteria killed by WBC

Implications
• Early nutrition can influence early immune
function
• Greater reliance on bird’s immune system with
removal of antibiotic growth promoters
• Unintended consequences

Nutritional Modulation of Immune
Function
• Development of immune system
• Substrate supply
• Nutritional immunity
• Hormonal millieu
• Regulatory actions of nutrients
• Reduction of pathology
• Physical/chemical actions in GI tract
Klasing, 1998 Poultry Science 77:1119-1125

n-3 vs n-6 Fatty Acids
Arachidonic Acid (20:4n-6)
COOH
Eicosapentaenoic Acid (20:5n-3)
COOH

n-3 vs n-6 Fatty Acids
Arachidonic acid Eicosapentaenoic acid
(20:4n-6)
(20:5n-3)
Cyclooxygenase Lipoxygenase
Prostaglandin E 2 Leukotriene B 4
Cyclooxygenase Lipoxygenase
Prostaglandin E 3 Leukotriene B 5
Inflammation
Inflammation

20-C PUFA
Cyclooxygenase
Lipoxygenase
Lofrin
Prostaglandin E
Leukotriene B
Inflammation

g/chick/d
Body Weight Gain
40
38
a
a
a
ab
a
a
a
36
34
b
32
30
0
Control Lofrin Control Lofrin
Corn Oil
Non-infected
Fish Oil
Eimeria-infected
Oil P

Stimulation Index
3
Serum IL-1 Activity
2
a
a
ab
b
1
P

Nutritional Modulation of Immune
Function
• Development of immune system
• Substrate supply
• Nutritional immunity
• Hormonal millieu
• Regulatory actions of nutrients
• Reduction of pathology
• Physical/chemical actions in GI tract
Klasing, 1998 Poultry Science 77:1119-1125

Nutritional Modulation of Immune
Function
• Reduction of pathology
– cellular components of the immune system
• reactive oxygen species (ROS)
• catabolic enzymes
– can cause damage to normal cells and tissues of
the host

g/chick/d
Body Weight Gain
40
38
a
a
a
ab
a
a
a
36
34
b
32
30
0
Control Lofrin Control Lofrin
Corn Oil
Non-infected
Fish Oil
Eimeria-infected
Oil P

Lesion Score
2.5
2.0
ab
Histopathology
a
1.5
b
b
1.0
0.5
c
c
c
c
0
Control
Lofrin
Control
Lofrin
Corn Oil
Non-infected
Fish Oil
Eimeria-infected
Diet X Lofrin X Eimeria P

Diet n-3 PUFA and Rodent Survival
Challenge Survival Challenge Survival
Bacterial
Viral
Pseudomonas aeruginosa ↔ ↓ Cytomegalovirus ↔
Klebsiella pneumonia ↑ Murine leukemia virus ↔↑
Staphylococcus aureus ↑ Influenza ↔
Salmonella typhimurium
↔ ↓ ↓
Protozoa
Bacteroides fragilis ↓ Plasmodium yoelii ↑
Streptococcus Group B ↑ Plasmodium berghei ↑
Listeria monocytogenes
GI flora (undefined)
↔↓↓↓
↑ ↑
Anderson & Fritsche, 2002

Implications
• n-3 PUFA can “unlink” local and systemic
responses
• The “benefit” of n-3 PUFA depends on the
type of disease challenge

Summary
• Selection for growth has changed the immune
system
• Many nutrients can change immune function
– Focus on those affecting innate immunity
• Early protection of chicks
• Inflammation reduces growth and efficiency

Conclusions
• Understand the possible consequences
• Using nutrition to manipulate immunity
– Can start with the breeders
– Great potential benefits
– Potential problems
– Good management is essential!