2 diego vergani rejection& tolerance in lt
DESCRIPTION
international pediatrics conference of gastroenterology & nutrition Hurghada 2013TRANSCRIPT
Diego Vergani - Institute of Liver Studies King’s College London School of Medicine
at King’s College Hospital, London UK
Rejection and tolerance
in liver transplantation
Hyperacute
Liver rejection
Rare
Cellular liver rejection
Common
Due to T-cell recogniton
of alloantigens
Cellular immunity physiology
T-cell activation
T-cell commitment
Th
naive
APC
IFN-
IL-4
Costimuli 1986, Mosmann &
Coffman
Th0
Th2 Th1
Cell mediated
Immunity
Humoral
Immunity
IL-12
IL-4, IL-10
Mo
difie
d fro
m N
icke
rso
n e
t a
l
APC
Mo
difie
d fro
m N
icke
rso
n e
t a
l
Antigen
Th
naive
APC
Costimuli M
od
ifie
d fro
m N
icke
rso
n e
t a
l
Th
naive
APC
Costimuli
Th0
Mo
difie
d fro
m N
icke
rso
n e
t a
l
Th
naive
APC
Costimuli
Th0
Th1
Cell mediated
Immunity
IL-12
Mo
difie
d fro
m N
icke
rso
n e
t a
l
Rejection
Th
naive
APC
IL-4, IL-10
Costimuli
Th0
Th2
Humoral
Immunity
Mo
difie
d fro
m N
icke
rso
n e
t a
l
Tolerance
Th
naive
APC
Costimuli 1986, Mosmann &
Coffman
Th0
Th1
IL-12
Mo
difie
d fro
m N
icke
rso
n e
t a
l
Rejection
Th2
Tolerance
IL-4, IL-10
IFN-
Th
naive
APC
Costimuli 1986, Mosmann &
Coffman
Th0
Th2 IL-4, IL-10
Mo
difie
d fro
m N
icke
rso
n e
t a
l
Tolerance
Th1
IL-12
Rejection
IL-4, IL-10
Immune mechanisms of
Rejection
Tolerance
Th1
APC
IL-2
IL-2R
Costimuli
Allograft
Rejection
Alloantigen
Modified from Nickerson et al
Th1
APC
IL-2
IL-2R
Costimuli
Allograft
Rejection
Alloantigen
Modified from Nickerson et al
Th1 CTL
APC
IL-2 Costimuli
Allograft
Rejection
Alloantigen
Modified from Nickerson et al
Th1 CTL
APC
IL-2R IL-2
IL-2R
Costimuli
Allograft
Granzyme B
Rejection
Alloantigen
Modified from Nickerson et al
Th1
IFN- IFN-
CTL
APC
DTH
Costimuli
Allograft
Rejection
Alloantigen
IL-2
IL-2R
IL-2R
Modified from Nickerson et al
Th2
pCTL
APC
IL-4R IL-2R
Allograft
Tolerance
Alloantigen
Modified from Nickerson et al
Th2
pCTL
APC
IL-4R IL-2R
Allograft
Tolerance
Alloantigen
IL-4
Modified from Nickerson et al
Th2
pCTL
APC
IL-4R IL-2R
Allograft
Tolerance
Alloantigen
IL-10
IL-4
Modified from Nickerson et al
Th2
pCTL
APC
IL-4 IL-4R IL-2R
Allograft
Tolerance
Alloantigen
Th1
IL-10
IL-10
Modified from Nickerson et al
Induction of tolerance
Induction of tolerance
Induction of tolerance
Real life data
PATIENTS
72 paediatric liver transplant recipients
with normal liver function for > 6 months
29 healthy children
(15 M, median age 2 yrs, 2 days - 13 yrs)
CONTROLS
‘Tolerant’
Median CyA trough level 70ng/ml [range: 0-80]:
13 patients [6 M, median age at transplant 4 yrs
(range: 8 mths – 10 yrs.)]
‘Non-Tolerant’
CyA 150ng/ml (90-250), or Tacrolimus 7mg/l (5-12):
59 patients [32 M, median age at transplant 3 yrs
(range: 6 mths - 10 yrs)]
PATIENTS
100
60
20
0
Normal ‘Tolerant’ ‘Non -tolerant’
TG
F-b
1 (p
g/m
l)
Levels of TGF-b1
N S
‘Non-Tolerant’ ‘Tolerant’ Normal
500
0
1000
IL-4
(p
g/m
l)
N S
Levels of IL-4
‘Tolerant’ Normal
0
500
900
IFN
- (
pg
/ml)
Levels of IFN-
P=0.003
‘Non-
Tolerant’
IL-1
0 (
pg
/ml)
‘Tolerant’ ‘Non-
Tolerant’
2000
Normal
0
4000
P= 0.005
6680
6995
7650
7490
9297
9280
Levels of IL-10 9303
IL-1
0/IF
N-
Ra
tio
IL-10/IFN- ratio
‘Tolerant’
1000
3000
5000
‘Non-Tolerant’
P= 0.00001
IL-10/IFN- ratio
P= 0.00001
CONCLUSIONS
A regulatory cytokine profile characterizes
those patients requiring
minimal immunosuppression
Immunosuppressive
strategies
T cell activation
Possible sites of
intervention
Tacrolimus
Calcineurin
inhibitors Ciclosporin
Steroids
IL-2 secretion
Basiliximab
Daclizumab
Anti-IL-2R Mabs
Knowledge of rejection mechanisms is
key to:
Designing rationale regimens
Developing new modes of intervention
Mofetil
Azathioprine
Rapamycin
Rapamycin
Mofetil
Azathioprine