Modèle d`allotransplantation rénale chez le babouin

Modèle d’allotransplantation
rénale chez le babouin
Gilles Blancho
Institut de Transplantation – Urology – Nephrology
University Hospital of Nantes - France
État de la transplantation en clinique aujourd’hui
Manque d’organes
Immunosuppression
Rejet Chronique
Effets secondaires
à long terme:
Risques
Infections
Peu influencé par
l’immunosuppression
Cancer
La xénotransplantation
Nouvelles immunosuppressions
Induction de Tolérance
Xénotransplantation
Allotransplantation
• Recherche de stratégies capables
• Études de stratégies visant à
de prolonger la survie d’un
xénogreffon porcin
induire une tolérance allogénique
• Nouvelles immunosuppresssions
Classification
Hominines
Homininés
Hominidés
(98.7%
homologie)
Hominoïdés
Panines
Hominoides
(Anthropomorphes)
Catarrhiniens
(Anthropoïdes)
Hylobatidés
Simiens
Primates
(Haplorrhiniens)
Pongidés
Cercopithécoïdes (93% homologie)
/ Babouins
Platyrrhiniens
Prosimiens
(Strepsirrhiniens)
25
6
millions années
La réponse alloimmune / Costimulation
Cellular cycle
Signal 2
Proliferation
IL-2 synthesis
Immunosuppressive Cytokines
-
Motility (reduce synapse)
CTLA4
B7
APC
-
CD28
T cell
+
MHC-ag
TCR
+
EBVspecific
T cell
clone
poly-L-lysine
Activation threshold
Proliferation
Survival
EBVinfected
B cells
poly-L-lysine
Signal 1
Differenciation
B cell co-operation
Sequential Engagements of
costimulation pathways
B7-1/2
PD-1 Class II
CTLA-4
PD-L1 LAG-3
-
Repression of activation in the TCR pathway
Direct inhibition of proliferation
Induction of Fas-independent apoptosis
Increased motility, less formation of synapses
CD28 / CTLA-4 / B7 / PD-L1 pathway
Human Teff or Treg
Cells
Clones
APC
ICOSL
ICOS
+
CD86
CD28
+
+
CD80
CTLA-4
-
-
PD-L1
PD-L1
PD-1
CD80
CD86
B-EBV
ICOS
ICOS-L
CD28
CD86
CTLA-4
CD80
PD-L1
PD-1
CD80
CD86
PDL1
Blockade of CD28 vs CD80/86
FR104
APC
T cell
APC
BELATACEPT
dAb-001
dAb-002
BMS
The Journal of Immunology November 1, 2013; 191 , 4599
Poirier et al. Transplant Int. 2011
CD28 blockade
Target Epitope and monovalency
MYPPPY
•Superagonist
ex: TGN1412
CD28
CD28 multimerization
TCR-independent
• Conventional
ex: CD28.3, FK734
CD28 capping
TCR-dependent
• Conventional
Monovalent
ex: PV-1 Fab, FR104
No
dimerization
C’’D
Lühder et al.
2003:197:955-966
sc28AT : monovalent CD28 antagonist
Resting PBMC
Resting
PBMC (n=10)
(n=10)
Mixed Lymphocyte
MixedReaction
Lymphocyte Reaction
(n=6)(n=6)
***
5
100
B7 binding site
75
50
**
25
3
ns
2
1
sc
28
A
Ø
T
0
0
Superagonist
binding site
4
0
0
C’’D domain
index
Stimulatory
stimulatory index
proliferation
% of% ofproliferation
**
sc28AT
Ø
s c28AT aCD28.2 aCD28.1
1st mechanism of action:
Blockade of CD80/86
MLR
EC50
FR104: 0.16 µg/ml
Belatacept: 0.18 μg/ml
SuperAg stimulation
Poirier et al, Am. J. Transplant. 2012
2nd mechanism of action:
Preserve Treg activity (CTLA4-dependent)
55000
*
50000
45000
40000
35000
mean CPM
Treg priming
+
CD4+CD25lymphocytes
proliferation assay
30000
25000
20000
15000
10000
5000
0
Poirier et al, Science Transl. Med. 2010
*
Anti CD28 blockade:
Modulate immune synapses (CTLA4-dependent)
EBVspecific
T cell
clone
poly-L-lysine
EBVinfected
B cells
poly-L-lysine
Control
CD28 antag.
(FR104)
CTLA4Ig
(or FR104 +
Anti-CTLA4)
Teff
Treg
Comparison between Teff and Treg
Teff
Treg
***
*
FR104
FR104
 Opposite behavior of the 2 cell types
***
CTLA-4 works also through Trans-endocytosis
CTLA-4
CD80
CD80
CD80
Trans-endocytosis
Qureshi et al Science 2011
CD28/CTLA-4/CD80 pathway
signals transmitted to APC by CD80
Inhibition of
proliferation
Apoptosis
IDO: Indoleamine Dioxigenase (Grohmann et coll, 2002)
17
CD28 antagonists
VH
CD28.3
Half-Life
VL
CD28.3
Sc28AT
VH
VL
CL
VH
CH1
VL
CL
CH2
CH2
CH3
CH3
Human a1antitrypsin
hVH
CD28.3
Vanhove et al, 2003
24h
in NHP
hVL
CD28.3
Mono28Fc
hCH2
hCH2
hCH3
hCH3
W0 2010/82136
Id. IgG
(mouse)
CD28.3
anti-CD28 IgG
FR104 (Effimune SAS)
PCT/IB2011/050646
PCT/IB2010/054562
6-9 days
in NHP
18
Kidney Transplantation in the baboon
Freedom from BPR
100
75
Drug-free « tolerant »
Controls (n=3)
Tacrolimus, 15 ng/ml (n=4)
aCD28, 4 mg/kg (n=4)
aCD28+Tacro (n=5)
50
25
0
0
aCD28
100
200
Day post Tx
tacrolimus
Before
Tx
Donor
Donor
After
Tx
Poirier et al, Science Transl. Med. 2010
3rd Party
0
1
2
3
4
5
index de proliferation
Stimulatory index
6
7
Kidney transplantation in the baboon
FR104
VH
VL
CH1
Igk
• FR104: IV, 5 mg/Kg
d0, 4, 14 & every 2 weeks
(until 3 month)
• MMF: per os - 70 mg/kg
(until 3 month)
Cs: IV, 1 mg/Kg
D0-14
• TAC LD: IM - 0,05mg/Kg
Through level: 5-10ng/ml
(until 3 month)
• RAPA: per os - 1mg/Kg
Through level: 10-25ng/ml
(until 3 month)
Poirier et al. AJT, 2015, 15(1): 88-100
FR104: Efficacy in Kidney transplantation
Ville et al, WTC 2014
FR104: Efficacy in Kidney transplantation
Survival (loss is corticoresistant rejection)
100
FR104
Belatacept
survval (%)
80
Recipient loss
60
Recipient alive
40
20
0
0
100
200
300
400
tacrolimus
FR104/ Belatacept
Ville et al, WTC 2014
FP7 TRIAD Project
Tolerance Restoration in Autoimmune Disease
Effimune SAS
24
Contributors
INSERM, Univ. Nantes
•Gilles Blancho
•Simon Ville
•Julien Branchereau
•Xavier Tillou
•David Minault
•Jeremy Hervouet
•Stéphanie Bernardet
•Mélanie Chevallier
Univ. Maryland Baltimore
•Robin Pearson
•Agnès Azimzadeh
•Tianshu Zhang
Effimune
•Nicolas Poirier
•Caroline Mary
•Nahzli Dilek
•Bernard Vanhove
Necker Hospital
•Lucienne Chatenoud
•Sylvaine You
Univ. Sao Paulo (IIEP)
•Luiz Rizzo
•Pedro Papotto
•Anna-Carla Goldberg
Glasgow Caledonian
Univ.
•Linda Scobie
BPRC
•Michel Vierboom
•Krista Haastra
•Bert ‘t Hart
Oxford Univ.
•Kathryn Wood
•Fadi Issa
•Masaaki Zaitsu