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Trained immunity: impact for non-specific effects …...Thank you ! Our lab Jessica Quintin James...
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Trained immunity: impact for non-specific effects of vaccination Mihai G. Netea
Transcript of Trained immunity: impact for non-specific effects …...Thank you ! Our lab Jessica Quintin James...
Trained immunity: impact for non-specific effects of vaccination
Mihai G. Netea
Innate versus specific immunity
Innate immunity:
- rapid
- effective
- not-specific, indiscriminate
- lacks immunological memory
Adaptive immunity:
- needs 10-14 days
- a specific activation against a particular microorganism, enhancing the effectivity of the response
- builds immunological memory
3
Memory: the ability of a system to store and recall
information on previously encountered characteristics
Holometa-bolous
Annelids
Molluscs
Insects
Heterometa-bolous
Agnathans
UrochordatesEchinoderms
-800 My
-450 My
Gnathostomes
Fishes Amphi-bians
Reptiles Birds Mammals
Placoderms
95%Innate
5%Innate and Adaptive
Plants
-1 By
Systemic acquired resistance
5
Netea et al: Cell Host and Microbe 2011
Increased response to secondary infection
Innate immunity-dependent protection in mice
Quintin et al, Cell H&M, 2012
-+
Methylation status of H3
+
-
Quintin et al, Cell H&M, 2012
MTA: Histone methyltransferase inhibitor
Less Methylation
Quintin et al, Cell H&M, 2012
Trained immunity versus tolerance
tolerance
primary infection
secondary infection
training priming
inn
ate
im
mu
ne
re
sp
on
se
duration (days/weeks?)
homeostasis
(H3K4me3)
Quintin et al., CHM, 2012
(H3K4me3)
Foster et al., Nature 2007
What are the pathways distinguishing Training vs Tolerance ?
signaling
Saeed, Quintin et al, Science, 2014
What are the pathways distinguishing Training vs Tolerance ?
metabolism
signaling
Saeed, Quintin et al, Science, 2014
What are the pathways distinguishing Training vs Tolerance ?
metabolism
signaling
Saeed, Quintin et al, Science, 2014
glucose
pyruvate
glycolysis
Lactic acid
glucose
Oxidative
phosphorylation
Krebs cycle
Electron
transport
36 ATP
2ATP
mTOR Akt
AcetylCoA
Lipid synthesis
Histone acetyl
transferase
HIF-1α
HIF-1α
autophagy
glucose
TLR
stimulation
PDH
ACC
O2 not
present
O2
present
Immune cell
Naïve cellsActive cells
NADH
NAD+
glucose
pyruvate
Increased
glycolysis
High
Lactic acid
glucose
Low
TCA cycle
mTOR AktHIF-1α
PDH
Low
NADHHigh
NAD+Low oxidative
phosphorylation
b-glucan
dectin-1
Metabolic activation of trained
monocyte
Model of metabolic activation
of trained monocytes
Cheng et al, Science, 2014
Tolerance vs Training
Sustained induction of
glycolysis (Warburg)
Maintains Trained status
“Training” stimuli
Metabolic status and epigenetic programming decides
the long-term activation fate of the monocyte
cAMP
PKA
high H3K4me
Latent enhancers
Induction of Trained
Immunity
Metabolic activation
Trained immunity in humans
New Scientist
Aug. 2013
Does this happen in vivo in humans?
Kleinnijenhuis et al, PNAS, 2012
BCG enhances monocyte-derived cytokines
Kleinnijenhuis et al, PNAS, 2012
BCG increases NK cell function
Kleinnijenhuis et al, Clin Immunol 2014
BCG effects on epigenetics and transcription
Kleinnijenhuis et al, PNAS, 2012
BCG protects against candidiasis in a T/B-independent fasion
n=15
n=25
Kleinnijenhuis et al, PNAS, 2012
Is autophagy involved in Trained Immunity induced by BCG ?
SNP in ATG2B (rs3759601)
Buffen et al, PLoS Pathogens, in press
BCG study – in vivo
ATG2B (rs3759601)
ATG2B (rs3759601)
Buffen et al, PLoS Pathogens, in press
Effect on epigenetic level
Buffen et al, PLoS Pathogens, in press
Bladder cancer study
Buffen et al, PLoS Pathogens, in press
A/California/7/2009
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/Texas/50/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
B/Massachusetts/2/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
P=0.72P=0.76
A/California/7/2009
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/Texas/50/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
B/Massachusetts/2/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/California/7/2009
0 7 14 21 280
20
40
60 Placebo
BCG
Time (days)
Fo
ld c
han
ge
A/Texas/50/2012
0 7 14 21 280
10
20
30Placebo
BCG
Time (days)
Fo
ld c
han
ge
B/Massachusetts/2/2012
0 7 14 21 280
10
20
30 Placebo
BCG
Time (days)
Fo
ld c
han
ge
P=0.02
P=0.047
A/California/7/2009
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/Texas/50/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
B/Massachusetts/2/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/California/7/2009
0 7 14 21 280
20
40
60 Placebo
BCG
Time (days)
Fo
ld c
han
ge
A/Texas/50/2012
0 7 14 21 280
10
20
30Placebo
BCG
Time (days)
Fo
ld c
han
ge
B/Massachusetts/2/2012
0 7 14 21 280
10
20
30 Placebo
BCG
Time (days)
Fo
ld c
han
ge
P=0.63
P=0.56
A/California/7/2009
0 7 14 21 280
20
40
60 Placebo
BCG
Time (days)
Fo
ld c
han
ge
A/Texas/50/2012
0 7 14 21 280
10
20
30Placebo
BCG
Time (days)
Fo
ld c
han
ge
B/Massachusetts/2/2012
0 7 14 21 280
10
20
30 Placebo
BCG
Time (days)
Fo
ld c
han
ge
P=0.76
A/California/7/2009
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/Texas/50/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
B/Massachusetts/2/2012
0 7 14 21 280
20
40
60
80
100
Time (days)
% s
ub
jects
reach
ing
sero
co
nvers
ion
A/California/7/2009
0 7 14 21 280
20
40
60 Placebo
BCG
Time (days)
Fo
ld c
han
ge
A/Texas/50/2012
0 7 14 21 280
10
20
30Placebo
BCG
Time (days)
Fo
ld c
han
ge
B/Massachusetts/2/2012
0 7 14 21 280
10
20
30 Placebo
BCG
Time (days)
Fo
ld c
han
ge
Antibody titer Seroconversion
Influenza vaccination
Pandemic H1N1
serotype
H3N2 serotype
B serotype
% s
ubje
cts
re
ach
ing
se
roco
nve
rsio
n
Fold
ch
an
ge
% s
ubje
cts
re
ach
ing
se
roco
nve
rsio
n
Fold
ch
an
ge
% s
ub
jects
re
ach
ing
se
roco
nve
rsio
n
Fold
ch
an
ge
0 7 14 21 28Time (days)
0 7 14 21 28Time (days)
0 7 14 21 28Time (days)
0 7 14 21 28Time (days)
0 7 14 21 28Time (days)
0 7 14 21 28Time (days)
0
10
20
30
40
60
0
20
10
30
0
20
Influenza vaccination
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
A
B
C
D
E
F
BCG increases immunogenicity of influenza vaccine
Leentjens et al, submitted
BCG increases immunogenicity of influenza vaccine
* p<0.05
** p<0.01
*** p<0.001 -100%
-50%
0
+50%
+100%
+150%
+200%
*
IL-6**IL-1β*
IFN-ɣ
IL-10
TNF-α*
IL-6
IL-1β
IFN-ɣ
IL-10**
TNF-α**IL-6IL-1β
**IFN-ɣ
*IL-10
TNF-α
***IL-6
IL-1β
IFN-ɣ
***IL-10
TNF-α *** LPSC. Albicans
S. Aureus
MTB
**
**
***
**
***
*
*
*
**
**
TNF-α * IL-6*
IL-1β
IFN-ɣ
IL-10
LPS
*TNF-α
IL-6
*IL-1β
**IFN-ɣ
***IL-10
C. Albicans
TNF-αIL-6**IL-1β
**IFN-ɣ
*IL-10
TNF-α
IL-6
IL-1β**
IFN-ɣ
IL-10***
S. Aureus
MTB
A B
Leentjens et al, submitted
Classical view
Thank you !
Our lab
Jessica Quintin
James Cheng
Siroon Bekkering
Johanneke Kleinnijenhuis
Jos W.M. van der Meer
Leo Joosten
Reinout van Crevel
Athens UniversityEvangelos Giamarellos
East Tennessee State University
David Williams
Harvard University
Aylwin Ng
Ramnik Xavier
Dept. Molecular Biology - Radboud
Sadia Saeed
Joost Martens
Colin Logie
Henk Stunnenberg
AMC - Amsterdam
Brendon Scicluna
Tom van der Poll
Trinity CollegeLuke O’Neill
Dept. Intensive Care - Radboud
Matthijs Kox
Peter Pickkers
