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international pediatrics conference of gastroenterology & nutrition Hurghada 2013
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RECURRENT AND DE NOVO
AUTOIMMUNITY
POST LIVER TRANSPLANT
Diego Vergani
Institute of Liver Studies
King’s College London School of Medicine
at King’s College Hospital
London, UK
Recurrent
de novo
Two types of autoimmunity after
tranplantation
AUTOIMMUNITY
POST LIVER TRANSPLANT
RECURRENT AUTOIMMUNITY
POST LIVER TRANSPLANT
Primary Biliary Cirrhosis
Neuberger J, Portmann B, Macdougall BR, Calne RY, Williams R.
Recurrence of primary biliary cirrhosis after liver transplantation.
N Engl J Med. 1982;306:1-4
AMA Granuloma
RECURRENT AUTOIMMUNITY
POST LIVER TRANSPLANT
RECURRENT AUTOIMMUNITY
POST LIVER TRANSPLANT
Autoimmune Hepatitis
Neuberger J, Portmann B, Calne R, Williams R.
Recurrence of autoimmune chronic active hepatitis following
orthotopic liver grafting
Transplantation. 1984;37:363-5
ANA
SMA
Interface Hepatitis
RECURRENT AUTOIMMUNITY
POST LIVER TRANSPLANT
RECURRENT AUTOIMMUNITY
POST LIVER TRANSPLANT
Primary Sclerosing Cholangitis
Harrison RF, Davies MH, Neuberger JM, Hubscher SG.
Fibrous and obliterative cholangitis in liver allografts:
evidence of recurrent primary sclerosing cholangitis??
Hepatology. 1994;20:356-61
Autoimmune Hepatitis
Primary Sclerosing Cholangitis
Primary Biliary Cirrhosis
RECURRENT AUTOIMMUNITY
POST LIVER TRANSPLANT
De novo AIH
Kerkar N, Hadzic N, Davies ET, Portmann B, Donaldson PT,
Rela M, Heaton ND, Vergani D, Mieli-Vergani G.
De novo ‘autoimmune’ hepatitis after liver transplantation
Lancet 1998;351:409-413
Historical background:
Between 1991 - 1996, seven patients
(4% of 180 liver transplant recipients)
developed graft dysfunction not due
to infection, surgical complications
or classical rejection
All were positive for non organ specific
autoantibodies and had high levels
of immunoglobulin G
De novo AIH
Median post OLT interval :
24 mths (range 6 - 45 months)
Median age at OLT : 8.3 yrs
(range 0.7 - 19.7 yrs)
Sex M/F : 5/2
Patients:
De novo AIH
Increased AST, median 262 IU/L
(range 58 - 461 IU/L)
Increased IgG levels, median 22g/l
(range 17.2 - 34.4 g/l)
Presence of non organ specific
autoantibodies
Interface hepatitis on biopsy
All seven patients had:
De novo AIH
Interface
hepatitis
De novo AIH
Anti-rejection treatment:
Four on Cyclosporin,
Azathioprine and Prednisolone
Three on Tacrolimus, rescue Rx
for steroid resistant rejection
De novo AIH
Treatment of graft dysfunction:
Prednisolone 2 mg/kg/day
(max 60 mg/day)
Azathioprine 1.5 - 2 mg/kg/day
De novo AIH
Outcome:
AST (10 - 50 IU/L) in a median of
22 days (range 7 - 316 days)
immunoglobulins and autoantibodies
in a median period of 95 days (range
75 - 412 days)
Six of seven patients normalised
De novo AIH
associated with autoimmune phenomena
Following OLT, some patients develop
graft dysfunction
responsive to the addition of classical
treatment for autoimmune hepatitis
Take-home message:
De novo AIH
has been confirmed in several
studies both in adults and
children
De novo AIH post LT Andries S, Casamayou L, Sempoux C, et al.
Posttransplant immune hepatitis in pediatric liver transplant
recipients: incidence and maintenance therapy with azathioprine.
Transplantation 2001;72(2):267-72.
Clemente MG, Vajro P, Musu MP,
et al. Autoimmune manifestations in children transplanted
for non-autoimmune liver diseases.
J Hepatol 2001;34:45
Conti F, Dousset B, Levillayer H, Gruska I, Weill B, Calmus Y.
Autoantibodies after liver transplantation: a marker of allograft disease.
J Hepatol 1997;26:150 (Abstract).
Duclos-Vallee JC, Johanet C, Bach JF, Yamamoto AM.
Autoantibodies associated with acute rejection after liver
transplantation for type-2 autoimmune hepatitis.
J Hepatol 2000;33(1):163-6.
Gupta P, Hart J, Millis JM, Cronin D, Brady L.
De novo hepatitis with autoimmune antibodies and
atypical histology: a rare cause of late graft dysfunction
after pediatric liver transplantation.
Transplantation 2001;71(5):664-8.
Heneghan MA, Portmann BC, Norris SM, et al.
Graft dysfunction mimicking autoimmune hepatitis
following liver transplantation in adults.
Hepatology 2001;34(3):464-70.
Hernandez HM, Kovarik P, Whitington PF, Alonso EM.
Autoimmune hepatitis as a late complication of liver transplantation.
J Ped Gastroenterol Nutr 2001;32:131-6.
Salcedo M, Pons JA, Sousa JM, et al.
De novo autoimmune hepatitis after liver transplantation.
J Hepatol 2001;34:49
Salcedo M, Vaquero J, Banares R, et al.
Response to steroids in de novo autoimmune hepatitis
after liver transplantation.
Hepatology 2002;35(2):349-56.
The mechanism of this type
of graft dysfunction remains to be
clarified
De novo AIH
Molecular mimicry
Effect of calcineurin inhibitors
Possible Mechanisms
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
De novo AIH
Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
Some patients experiencing
de novo AIH post OLT lack the gene encoding
for glutathione-S-transferase T1 and produce
antibodies to this protein present in the
donor’s liver
Aguilera et al. Clin Exp Immunol 2001;126:535-539
De novo AIH
Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
In experimental
animal models both
Cyclosporin and Tacrolimus
induce a ‘paradoxical’
autoaggressive syndrome
Gao et al. Nature 1988;336:176-179
Bucy et al. J Immunol 1993;151:1039-1050
Sakaguchi & Sakaguchi. Immunogenet 2000;2:147-53
Wu et al. J Immunol 1999;162:6926-33
Damoiseaux et al. Folia Biol 1998;44:1-9
De novo AIH
T cell
precursor Self-mimicking
microbial antigen
Micro
organism
High affinity Deletion
by apoptosis
Intermediate
affinity
Export to the
periphery
Low/No affinity Death by neglect
Self-reactive T
cell
Regulatory
T cell
Thymus Bone
Marrow Periphery
Damaged
liver cell
Released
autoantigen
De novo AIH
CyA/Tac CyA/Tac
Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
allogeneneic heart
anti-myosin
antibodies
anti-myosin CD4
T cells
myocarditis
heart
rejection
Fedoseyeva et al. J Immunol 1999;162:6836-42
syngeneic heart
no myocarditis
anti-myosin
antibodies
anti-myosin CD4
T cells
no rejection
Fedoseyeva et al. J Immunol 1999;162:6836-42
allogeneneic skin anti-myosin
antibodies
anti-myosin CD4
T cells
no myocarditis
skin rejection
Fedoseyeva et al. J Immunol 1999;162:6836-42
Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
The molecular target of LKM-1 is Cytochrome P4502D6 (CYP2D6)
LKM-1
similarity with E1 region of HCV
Major epitope of LKM-1
DELLTEHRMTWDPAQ CYP2D6252-66
HCV310-24 PGHITGHRMAWDMMM
AST 1512 IU/l
LKM-1 1/2560
Pt RN, July 1998
July 1998: portoseptal fibro-inflammatory expansion
& interface reactivity = Chronic hepatitis
HCV-RNA negative
Pt RN, July 1998
Response to steroids ++
1280
20
40
80
160
320
640
2560
RE
CIP
RO
CA
L O
F L
KM
-1 T
ITR
E
- + liver HCV RNA
OLT-1 OLT-2 OLT-3
-1 0 1 2 3 4 5 6 MONTHS
- - + + + + + serum HCV RNA ++ +
IgM
IgG
LKM-1
Mackie et al. Gastroenterology 1994;106:1672-1675
anti-HCV IgG: negative
December 1989: OLT for a 1 antitrypsin deficiency liver disease
LKM-1 254-71
neg Pre-HCV
1/160 58d
1/2560 6mo
1/640 8yr
Time
1/20 20d
IgM IgG
CYP2D6
Reactivity to CYP2D6 peptides
LKM-1
1/20 20d
Time
HCV
254-71
CYP2D6
Reactivity to CYP2D6 254-71
Protein database search
DRLSPRPPAQPPRRR IE 175 HSV-1
EHRMTWDPAQPPRDL CYP2D6257-271
E1 HCV GHRMAWDMMMNWSPT
QLPPPAAPAQPPPGV EBNA-2 EBV
PMIAAAPPAQPPSQP IE63 H CMV
AARTAPAPAQPPSPA J1L H CMV
1/20 20d
HCV
254-71
CYP2D6
HSV
CMV
EBV
Reactivity to CYP2D6 254-71
LKM-1 Time
Serological A3,24 B5,22
Patient’s HLA
PCR A3,24 B51,55
Multiple viral/self immunological
cross-reactivity
in LKM1 positive hepatitis C virus
infected patients is associated with
the possession of
HLA B51
Bogdanos et al. Int J Immunopathol and Pharmacol 2004;17:83-92
For molecular mimicry to
become antigenic mimicry
Multiple hits
Predisposing MHC
De novo AIH