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