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Recurrent and De Novo Autoimmunity After Liver Transplantation
1. 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
5. 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
9. 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
10. 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
11. 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
12. 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
14. Anti-rejection treatment:
Four on Cyclosporin,
Azathioprine and Prednisolone
Three on Tacrolimus, rescue Rx
for steroid resistant rejection
De novo AIH
15. Treatment of graft dysfunction:
Prednisolone 2 mg/kg/day
(max 60 mg/day)
Azathioprine 1.5 - 2 mg/kg/day
De novo AIH
16. 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
17. 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
18. 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.
19. The mechanism of this type
of graft dysfunction remains to be
clarified
De novo AIH
20. Molecular mimicry
Effect of calcineurin inhibitors
Possible Mechanisms
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
De novo AIH
21. Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
22. 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
23. Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
24. 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
25. 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
26. Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH
30. Molecular mimicry
Effect of calcineurin inhibitors
Effect of allogeneic transplantation
Mismatch for glutathione-S-transferase T1
Possible Mechanisms
De novo AIH