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IMMUNOTHERAPIE DU DIABETE
AUTO-IMMUN
INSTITUT UNIVERSITAIRE
DE FRANCE INSERM U1013
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Time
Natural history of type 1 diabetes
b cell function
(%)
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EURODIAB registered 29 311 new cases of T1D in children before 15 years
of age between 1989-2003.
The overall annual increase was 3.9%,
New cases in Europe in 2005 : 15 000
(24%: 0-4 years, 35%: 5-9 years, and 41%: 10-14 years).
In 2020, the predicted number of new cases is 24 400, with a doubling in
numbers in children younger than 5 years.
Prevalence under age 15 years is predicted to rise from 94 000 in 2005, to
160 000 in 2020.
Doubling of new cases of type 1 diabetes in children younger than 5 years
and prevalent cases younger than 15 years will rise by 70%.
AN ALARMING EPIDEMIOLOGICAL TREND
Patterson et al. Lancet 2009, 373, 1999
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30
Months
Re
mis
sio
n (
%)
Placebo (n = 127)
20
10
0 3 6 9 12 15 18 24
CsA (n = 155)
40
PLACEBO-CONTROLLED TRIAL OF CYCLOSPORIN A IN RECENTLY DIAGNOSED IDDM (CDF study)
EFFECT ON REMISSION RATE
G. Feutren et al. Lancet 1986; 2: 119-124
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M. Pescovitz et al. New Engl J
Med 2009, 361: 2143-2152
RITUXIMAB IN T1D
One course
4 doses (375 mg/m2 )
1 year
p=0,0195
Over time p< 0,038
Over time p< 0,004
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TWO STRATEGIES TO INDUCE IMMUNE
TOLERANCE
1. Administration of b-cell autoantigens
2. Use of monoclonal antibodies
mediating T cell signaling
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Antigen Trial Reference
Oral Insulin New onset T1D Chaillous L et al.
The Lancet 356, 545, 2000
Oral Insulin New onset T1D Pozilli P et al.
Diabetologia 43, 1000, 2000
APL insulin B chain (NBI-6,024) New onset T1D Walter M et al.
Diabetes Care 32, 2036, 2009
Hsp60 p277 New onset T1D Raz I et al.
The Lancet 358, 1749, 2001
i.v. + s.c. insulin
DPT-1
Late preclinical T1D Skyler J et al.
New Engl J Med 346, 1685, 2002
Oral insulin
DPT1
Insulin-autoantibody positive
relatives
Skyler J et al.
New Engl J Med 346, 1685, 2002
Intranasal insulin Insulin-autoantibody positive
relatives
Näntö-Salonen K et al.
The Lancet 372, 1746, 2008
Alum formulated GAD Recent onset T1D Ludvigsson J et al.
New Engl J Med 359, 1909, 2008
AUTOANTIGEN TRIALS
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- Expresses the unique ability to restore self-
tolerance in established autoimmunity
- The therapeutic effect initially demonstrated in
the experimental setting was successfully
transferred to the clinic
- The mode of action involves 'resetting' of active
tolerance
CD3 antibody therapy
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ACTIVE TOLERANCE
Tolerance requiring active contribution of
antigen-specific activated T cells
Related concepts
dominant tolerance
infectious tolerance
immunoregulation
T-cell mediated suppression
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CD4+
CD8+
CD8+
T cell
CD4+
T cell
CD4+
CD25+high
Foxp3+
CD4+
CD25-
Foxp3-
CD4+
CD25-
Foxp3-
CD4+
CD25+high
Foxp3+
CD4+ Th1
Effector
CD25-
Foxp3-
Tr1
Th2
Th3
Systemic Ag
Oral Ag
TGF-b
IL-4/ IL-10
IL-10/ TGF-b
Ag Stimulation
Pro-inflammatory
context
HETEROGENEITY OF CD4+ REGULATORY T CELLS
THYMUS -
- - -
CD4+
CD25+low
Foxp3+
Ag Stimulation
‘tolerogenic’
context
Cell contact
TGF-b, GITR, CTLA-4…
- IN AUTOIMMUNE PRONE
INDIVIDUALS
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CD4
CD
25
CD4+CD25low
CD4+CD25high
CD4+CD25-
Diab
Diab/CD25low
Diab/CD25high
Weeks after transfer
% D
iabete
s
20
40
60
80
100
0 2 4 6 8 10
Both CD4+CD25high and CD4+CD25low T cells are
suppressive in vivo in NOD mice
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0
2 0
4 0
6 0
8 0
1 0 0
%
r e m
i s s
i o n
( n = 2 0 )
( n = 1 6 )
( n = 1 6 )
( n = 1 7 )
p < 0 . 0 0 1
p < 0 . 0 0 5
T r e a t m e n t ( d 0 - d 5 )
2 4 6 8 1 0 1 2 W e e k s
A n t i - C D 3 C o n t r o l s
REMISSION OF ESTABLISHED DIABETES IN
CD3 ANTIBODY-TREATED NOD MICE
L. Chatenoud et al. Proc.Natl.Acad.Sci. USA 1994; 91: 123-127
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-Belghith M et al. Nat Med 9:1202-1208, 2003
-You S et al. Immunol Rev 212:185-202, 2006
- You S et al. (2007) Proc Natl Acad Sci (U S A) 104: 6335-6340, 2007
-Chatenoud L & Bluestone JA. Nat Rev Immunol 7:622-632, 2007
-You S et al. Adv Immunol 100: 13-37, 2008
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THERAPY OF ONGOING R-EAE USING CD3 ANTIBODIES
Day 0-4 Treatment
3.2
2.6
0
0.5
1
1.5
2
2.5
3
3.5
0 2 4 6 8 10 11 13 14 15 17
Days Post Disease Induction
Mean
Cli
nic
al S
co
re
Control aCD3 F(ab')2
Rx
Day 6-10 Treatment
2.2
0.4
0
0.5
1
1.5
2
2.5
0 2 4 6 8 10 11 13 14 15 17
Days Post Disease Induction
Mean
Cli
nic
al S
co
re
Control aCD3 F(ab')2
Rx
1.2
2.8
1.6
2.6 2.6
0.4
0.6
0
0.5
1
1.5
2
2.5
3
3.5
0 4 8 11 14 17 21 25 29 33
Days Post Disease Induction
Me
an
Cli
nic
al S
co
re
Control aCD3 F(ab')2
Day 13-17 Treatment
Rx
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Rat YTH 12.5
hIgG1
Reshaped
Humanized YTH 12.5 (CAMPATH 3)
Mutation Asn to Ala position 297
(prevents glycosylation)
S. Bolt et al European J Immunol, 1993, 23, 403
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Treatment of established Type 1 diabetes with a
non-mitogenic CD3 antibody
Phase II trial – Multicenter – Placebo Controlled
Between 07/06/2000 and 07/03/2003
210 consecutive recent onset diabetic patients were screened
80 patients included
12-39 years old. positive for ICA and/or GAD Abs
insulin-treatment <4 weeks
8mg/day of ChAglyCD3 for 6 consecutive days
EBV IgG positive.
Keymeulen B. N. Engl. J. Med 2005, 352:2598-2608
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0 6 12 18 24 36 48
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
IU/k
g/d
ay
Months
HbA1c
Insulin dose
p=0.004 p<0.001 p=0.001 p=0.001
n=31
n=31
n=29 n=31
n=31
n=27
n=28
n=33
n=33
n=31
n=32
n=33
n=32 n=33
0 6 12 18 24 36 48
5
6
7
8
9
Months
%
p=0.761 p=0.984 p=0.990 p=0.428
ChAglyCD3
Placebo
Keymeulen B. Diabetologia 2009, 53: 614-623
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6 6.5 7 7.5
0.25 NS NS 0.01 0.01
0.5 NS NS NS
0.75 NS
HbA1C %
Insu
lin d
ose
U/K
g/d
ay
NS NS
NS*
*
NS NS
NS
12 MONTHS AFTER TREATMENT
NS: non significant difference between placebo and
CD3 antibody-treated patients (Chi Square)
Data from European Phase II trial using otelixizumab (Keymeulen B. N. Engl. J.
Med 2005, 352:2598-2608 )
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Lancet. 2011; 378 :487-497
Phase III Study : teplizumab
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AUTOIMMUNE DIABETES MULTIPLE SCLEROSIS D
ISA
BIL
ITY
GE
NE
TIC
PR
ED
ISP
OS
ITIO
N
OVERT HYPERGLYCEMIA
BETA CELL
AUTOANTIBODIES
BETA CELL
AUTOANTIBODIES
BETA CELL
AUTOANTIBODIES
BETA CELL
AUTOANTIBODIES
BENIGN
RELAPSING
REMITTING
SECONDARY CHRONIC
PROGRESSIVE
PRIMARY CHRONIC
PROGRESSIVE
LO
SS
OF
BE
TA
CE
LL
FU
NC
TIO
N
GE
NE
TIC
PR
ED
ISP
OS
ITIO
N
GE
NE
TIC
PR
ED
ISP
OS
ITIO
N
GE
NE
TIC
PR
ED
ISP
OS
ITIO
N
CD3 mAb Therapeutic Window
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M1
M1
NOD 38% MFI=142
NOD-huCD3e 40% MFI=72
human PBMCs 75% MFI=244
NOD-huCD3e 36% MFI=119
mCD3
co
un
ts
17 <1
82
2 85
10
2 14
2
2 87
8
thymus
NOD NOD-huCD3e
<1 82
3 3
spleen
NOD NOD-huCD3e
44 1
54
13 <1
32
4 43
<1
13 <1
31
<1 53
55 55
huCD3
mC
D3
mCD4
mC
D8
huCD3
co
un
ts
Transgenic Human CD3e-NOD mice
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0
20
40
60
80
100
0 5 10 15 20 25 30 35 40
weeks of age
% d
iab
ete
s
(n = 32)
NOD NOD-huCD3e
(n = 40)
islets with invasive infiltration
islets with peripheral infiltration
islets w/o infiltration
0
20
40
60
80
100
% i
nfi
ltra
ted
is
lets
6-wk diabetic Otelixizumab 12-wk
0
20
40
60
80
100
5 10 15 20
weeks after treatment
% r
em
iss
ion
NOD-huCD3e + Otelixizumab
NOD + F(ab’)2-2C11
anti-CD3
(n = 26)
(n = 23)
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merge
CD3
FoxP3 Insulin merge
6-w
k
12-w
k
dia
be
tic
Ote
lixiz
um
ab
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0
20
40
60
80
100
0 2 4 6 8
weeks after transfer
% d
iab
ete
s
CD25-CD62L- diabetic
CD25-CD62L- Otelixizumab
SPLEEN
6wk 16wk diab 2wk >8wk
remission
0
200
400
600
800
SP
U / 1
06 c
ell
s
IGRP 206-214
BLOOD
SP
U / 1
06 c
ell
s
0
200
400
600
6wk 16wk diab 2wk >8wk
remission
0
10
20
30 SPLEEN
PI B:15-23
0
BLOOD
100
200
300
6wk 16wk diab 2wk >8wk
remission
6wk 16wk diab 2wk >8wk
remission
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BEFORE
TREATMENT
CD3Ab
TREATMENT
AFTER
TREATMENT
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CONCLUSIONS
CD3 antibodies are effective at preserving b cell
function and decreasing insulin needs in newly
diagnosed Type 1 diabetic patients
The effect is long lasting
Patients are responsive to unrelated antigens
CD3 antibodies induce/ expand TGF-b dependent
adaptive Tregs
These results are a proof of concept and pave the way
for the use of CD3 antibodies as tolerance-promoting
agents in various T cell-mediated autoimmune
diseases, in transplantation and cell therapies
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IDDM
Multiple sclerosis
Crohn's disease
Asthma
55
Incidence of prototype infectious diseases and immune disorders
75 85 95
100
50
Infectious diseases
%
100
200
Immune disorders
%
300
0
65
Hepatitis A
Rheumatic fever
Measles
Tuberculosis
55 75 85 95 65
JF Bach, N Engl J Med, 2002
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5.3
1.9 (56-74)
3.78
1.69 24
0.96 (mortality or incidence)
2.2
5
1.1
2.24
3.94
3.3
1.72
Incidence of multiple sclerosis (per 100,000)
24 (77-85)
9.4
7.3 (66-89)
8.05 (54-86)
11.5 (67-90)
19.9
10.9 (85-88)
7.7
19.7
35.8 (87-99)
13.7
Incidence of IDDM (per 100,000)
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Adapted from : www.eatlas.idf.org
Incidence per 100,000 children
(0 – 14years)
High (> 16)
Intermediate (8 – 16)
Low (0 – 8)
No estimate
Type 1 Diabetes (incidence in children 0 – 14 years)
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Adapted from : www.atlasofms.org
Prevalence per 100,000 (2007)
High (> 60)
Intermediate (20 - 60)
Low (0 – 20)
No estimate
Multiple Sclerosis
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Adapted from : Masoli et al. Allergy. 2004:59
Proportion of clinical asthma *
High (> 10%)
Intermediate (5.1% – 10%)
Low (0% – 5%)
No estimate
Childhood Asthma
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Risk level
High
Intermediate
Low
Hepatitis A virus antibodies prevalence
Adapted from : wwwn.cdc.gov
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IDDM incidence in children of migrants from Pakistan to Yorkshire
Staines A. (1997) and Bodansky H.J. (1992)
0
2
4
6
8
10
12
Pakistan Migrant's children
Yorkshire
Incidence of diabetes /10 5
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CAUSAL LINK
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PREVENTION OF IDDM IN NOD MICE
BY INFECTIOUS AGENTS
Bacteria streptococci
salmonella
mycobacteria (CFA, BCG, …)
Viruses LCMV
MHV
LDHV
Parasites schistosoma
pimworms
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TGF-b antibody treatment abrogates
diabetes protection by OM-85
0
20
40
60
3 7 1 1 15 19 23 27
Age (weeks)
OM-85 anti-TGF-b
NOD OM-85
NOD controls
NOD OM-85
+ anti-TGF-b
% d
iabete
s
, , , , , , , ,
, , , , , ,
, , , , , ,
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Immune response of dendritic
cell to TLR agonists
v v
v v
TLR4
TLR5
TLR2
Flagellin Endotoxins or LPS
Mycobacterial soluble
factor
Proteine MMLV
Mannan
Fibrinogen
HSP70, HSP60
Hyaluronan
Beta-defensin
Surfactant Protein A
Lipoproteins
Zymosan
P. Gingivalis LPS
Lipoteichoic acid
Lipoarabinomannan
HCMV
Trypanosoma cruzi GPI
KOmpA
HSP70
v v
v v TLR7
v v TLR9
TLR3
TLR1
TLR11
v v TLR8
v v TLR6
Bacterial DNA (CpG)
Herpes simplex virus 2
upec
Imidazoquinoline
dsARN
ssARN
Poly(I:C)
Lipopeptide
lipopeptide
IRF3 NF-kB
AP-1
Imidazoquinoline MyD-88 TRIF
IFN
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TLR2, TLR3,TLR4 and TLR7 agonists
delay autoimmune diabetes onset
Dia
bete
s incid
ence (
%)
Age (weeks)
TLR2 TLR3 TLR4 TLR7
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25
Non treated
P40
p=0.0064
Treatment
0
10
20
30
40
50
60
70
80
90
100
5 15 25
Non treatedPoly(I:C)
p=0.000450
10
20
30
40
50
60
70
80
5 10 15 20 25
Non treatedLPS
p=0.00850
10
20
30
40
50
60
70
80
90
5 10 15 20 25
Non treated
R848
p=0.0143
Similar protective results were obtained with TLR agonists : synthetic lipopetide Pam3CSK4 (TLR2 agonist) or dsRNA
Poly(I)Poly(C) …
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p <0.05
p <0.05
Thieblemont N et al. PLoS ONE 2010, 5(7): e11484
p <0.05
PROTECTION BY TLR AGONISTS
AND IMMUNE REGULATION
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ALLERGIC ASTHMA IN NOD
MICE
Immunization
1, 10, 100 µg OVA
+ Alum i.p./ s.c.
D0 D10
Measurement of airway
hyperreactivity to
metacholine Sacrifice and collection of
Sera (cytokines, IgE)
BALFs (cells, cytokines)
Lungs (cytokines)
D7, D8, D9
OVA challenge
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Eosin
ophils
in B
AL 1
05/m
l
OVA
p< 0.005
p< 0.005
Araujo LM et al. Eur.J.Immunol. 2004, 34: 327
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Prevention of allergic asthma
by a TLR2 agonist
-2 -1 0 1 2 3 4 5 6 7 8 9
1.53.04.56.07.59.0
OVA/P40
Saline/Vehicle Saline/P40
OVA/Vehicle
Pe
nh
OVA Saline OVA Saline0
1500
3000
4500
6000
P40-treated Vehicle-injected
p=0,0357
Lung e
ota
xin
level (p
g/m
l)
OVA Saline OVA Saline0
50
100
150
200 p=0,0736
Lung IL-4
level (p
g/m
l)
P40-treated Vehicle
0
7
14
21
28
Eosinophils Neutrophils
Macrophages Lymphocytes
Saline SalineOVA OVABA
LF
cell c
ount
(10
5)
P40-treated Vehicle