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disorders: lessons
learned from the
biology of natural killer
T cells
Gnotobiotic model organisms and microbiome research:
Choices, challenges and proposed solutions
December 19, 2016
Richard S. Blumberg
rblumberg@partners.org
Association between antibiotic use in first year of life and pediatric IBD (Shaw,
Am J Gastroenterol 2010)
Macpherson AJ &
McCoy KD, Muc Immunol
2015
Early Life
Later Life
Normal
phenotype
& response
Environmental
Exposure
(specific factors?)
Abnormal
phenotype
& response
Gut monocolonization of
germ-free mice
Cd1d-/- WT
(also L. gasseri, S. aureus, P. aeruginosa)
Nieuwenhuis EES, Nature Med 2002
1.5
1
0.5
P < 0.05
Torsten
Olszak
80
60
GF/n
GF/a
GF
40
20
0
10
8
110
day
100
90
80
70
0
2
3
day
Mean pathology
score
100
6
4
2
0
Oxazolone-induced
colitis
1
0.5
0
GF/n
GF/a
eosinophils
0.30
15
0.25
0.20
0.15
0
GF/n
GF/a
(% of total cells)
1.5
Rn (cmH2O.s/mL)
(% of live
lymphocytes)
10
5
0
GF/n GF/a
p < 0.05
p < 0.01
serum CXCL16
400
200
0
(fold increase)
(fold increase)
(pg/ml)
600
6
4
2
0
GF
CXCL16
lung CXCL16
SPF
2.5
2
1.5
1
0.5
0
GF
SPF
100
80
60
40
20
0
Weight (% of initial)
Survival (%)
2
3
Days
100
90
80
70
CD1d-/- (sulfatrim)
Ja18-/- (sulfatrim)
B6
B6 (sulfatrim)
P < 0.05
2
3
Days
3-Ketosphinganine
Sphinganine
Dihydroceramide
Dingding
An
SPF
GF
BFWT BFSPT
An,Cell2014
OH OH
O
OH
HN
HO
O
OH
C16(OH)H32
C15(OH)H30
GSL-Bf717
Inhibition
HO
O
C25H51
OH
HN
C14H29
OH
KRN7000
Activation
Also, intestinal epithelial cell tolerance to TLR (Chasin C, Cell Host Microbe 2010) and
CD71+ erythrocyte regulation of myeloid responses to microbes (Elahi S, Nature 2013)
Summary
Vision
Atopic as well as numerous complex diseases will be shown to
originate from inappropriate microbial exposures during early life
through pathways that are developmentally regulated and thus
only amenable to manipulation in early life
Future
Identification of the developmentally regulated pathways and
their determinant microbial factors as well as the later life
environmental triggers that activate the pathophysiologic
responses leading to disease
Opportunities
Early life manipulation of the pathways involved or later life
elimination of the stimulating factors might allow for the
prevention and/or treatment of atopic and complex diseases
Challenges
Confirming the existence of these temporally restricted pathways
in humans and defining methods to prevent and/or treat disease
Eosinophilic Esophagitis
EoE during
years 1-5 of life
associated with
antibiotics in
year 1 (Radano
MC, JACI 2014)
Identification of
a diseasespecific EoE
tissue
transcriptome
characterized
by upregulation
of eotaxin-3,
periostin, IL-13
(Blanchard R,
JACI 2007)
Rothenberg ME, Gastroenterology 2009
Relative expression (
Ct)
LTC4S
64
**
32
***
16
8
4
2
1
0.5
1-6 y
EoE
6-18 y
1-18 y
Non-EoE
EoE
Response
Eotaxin-3
105
104
** **
NS
NS
103
102
101
100
10-1
EoE
Response
ct)
Periostin
105
104
** **
NS
NS
103
102
101
100
10-1
EoE
Response
Non
EoE
50
EoE
Response
ct)
100
Relative expression (
**
**
* NS **
Non
EoE
32
16
NS
NS
NS
8
4
2
1
0.5
EoE
Response
Non
EoE
64
LTC4S
Relative expression (
ct)
Relative expression (
Esophageal eosinophilia
* *
NS
NS
EoE
Response
150
30
10
Non
EoE
ct)
EoE
Response
10-1
Relative expression (
100
Non
EoE
0.5
Non
EoE
101
*NS *
40
Non
EoE
*NS *
NS
102
Relative expression (
ct)
NS
16
ct)
Relative expression (
V24
CD1d
CXCL16
Acknowledgments
Torsten Olszak
Miguel Pinilla Vera
Rebecca Baron
Shankar Iyer
Thomas Gensollen
(Brigham and Women's Hospital,
Harvard Medical School)
Sebastian Zeissig
(Technical University of Dresden)
Julia Richter
Andre Franke
(Christian-Albrechts University Kiel )
Dennis Kasper
Dingding An
Sungwhan Oh
(Channing Laboratory,
Harvard Medical School)
Edda Fiebiger
Willem Lexmond
(Childrens Hospital,
Harvard Medical School)