g. s / aih 2006 graft-versus-host disease physiopathology gérard socié, md phd hospital saint...

G. S / AIH 2006

Graft-versus-Host diseasePhysiopathology

Gérard Socié, MD PhDHospital Saint Louis

Translating experimental into clinical knowledge

G. S / AIH 2006


Acute Graft-versus-Host

Disease

G. S / AIH 2006


G. S / AIH 2006


Billingham; Nature 1966

G. S / AIH 2006


Phase I. Induction of inflammatory cytokines & damage + activation of host tissue during conditioning

Cytokines increased expressionof MHC antigens and adhesionmolecules enhance the recognitionof MHC / minor Ag by mature donor T-cells

G. S / AIH 2006


• Proliferation of Th1 T cellsand secretion of IL-2 & IFN.• IL-2 & IFN : induce further T-cell expansion, induce CTL and NK responses Prime macrophages to produce IL-1 and TNF

Phase 2: Donor T-cell activation

G. S / AIH 2006


Effector functions of macrophagesare triggered via a 2nd signal (LPS)LPS can stimulate tissue-associated Lyand macrophage leading to amplification of local tissue injury

Phase 3: Inflammatory effector mechanisms

G. S / AIH 2006


Hosttissues

Tissue Damage

Smallintestine

APC

(I) Conditioning

TNF-IL-1LPS

LPS

DonorT Cell

(II)DonorT-cellactivation

IFN-

(III)Cellular andinflammatoryeffectors

Th1

Target cellapoptosis

M

CD4CTL

CD8CTL

TNF-IL-1

CD8CTL

TNF-IL-1

G. S / AIH 2006


Hosttissues

Tissue Damage

Smallintestine

APC

(I) Conditioning

TNF-IL-1LPS

LPS

DonorT Cell


IFN-


Th1


M

CD4CTL

CD8CTL

TNF-IL-1

CD8CTL

TNF-IL-1

I: Role of conditioning

G. S / AIH 2006


Late onset a.GvHD

3 mois

Cytokine (TNF alpha)release during conditioning

results in higher GvHD and TRM

(Holler 1990)

Age and dose of TBI as Age and dose of TBI as major risk factors of major risk factors of

GvHDGvHD(Tseng et al., Blood 1999; (Tseng et al., Blood 1999;

94:2911)94:2911)

G. S / AIH 2006


Hosttissues

Tissue Damage

Smallintestine

APC

(I) Conditioning

TNF-IL-1LPS

LPS

DonorT Cell


IFN-


Th1


M

CD4CTL

CD8CTL

TNF-IL-1

CD8CTL

TNF-IL-1

II a)APC & AcuteGvHD

G. S / AIH 2006


G. S / AIH 2006


Hosttissues

Tissue Damage

Smallintestine

APC

(I) Conditioning

TNF-IL-1LPS

LPS

DonorT Cell


IFN-


Th1


M

CD4CTL

CD8CTL

TNF-IL-1

CD8CTL

TNF-IL-1

II b)T-Cell

activation

G. S / AIH 2006


Histoincompatibility between donor and host: GvHD increases with the number of major MHC mismatches minor antigen mismatches in HLA-identical sibling BMT

G. S / AIH 2006


G. S / AIH 2006


Major /minor antigens in miceMajor /minor antigens in mice B6 Dom (Nature Medicine; 7: 789, 2001)Adoptive transfer of minor histocompatibility antigen-specific T

lymphocytes eradicates leukemia cells without causing graft-versus-host disease

H60 ++ (Immunity; 17: 593, 2002 / Blood; 100: 4255, 2002)Real-time T cell Profiling Identifies H60 As a Major Minor Histocompatibility Antigen

in Murine Graft-vs-Host Disease

G. S / AIH 2006


G. S / AIH 2006


Co-stimulation & acute GvHD (mice)CD 80/86CTLA4-IgCD 40/40LLFA1/ICAMICOS …….

G. S / AIH 2006


G. S / AIH 2006


CD8+ naïve T Cell CD 44 LowCD62-L High

CD 44 LowCD62-L High

Sca-1 High

Memory stem cell

CD 44 HighCD62-LHigh

CD 44 HighCD62-L Low

Central Memory Central Memory

IL7- IL15

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G. S / AIH 2006


Experimental Hematology 33 (2005) 894–900

G. S / AIH 2006


G. S / AIH 2006


Non HLA Gene Polymorphisms

•TNF (d3/d3) Middleton et al. Blood 1998

•IL-10-1064 (11-15) Cavet et al. Blood 1999

•IL-1; TNF, IFN Patient/donor Hill et al. Blood 1999

•IL-6 acute/chronic Cavet et al. Blood 2001

•IL-10 GvHD Socié et al. Transplantation 2001

•IL-6

•IL1-Ra Cullup et al. Brit J Haem 2001

•TNF; IL-10 (CBT) No association Kögler et al. Transplantation 2002

•Vit D receptor aGvHD and survival Middleton et al. BMT 2002

•Estrogen receptor Midleton et al BMT 2003

•TNRII Stark et al. Transplantation 2003

•Mannose Binding Infectious Mulligan et al. Blood 2002Lectin (MBL) complications

•FcRIIa Infectious complications Rocha et al. Blood 2002

G. S / AIH 2006


N. Engl. J. Med. 2003;349:2201-10.

G. S / AIH 2006


T-cell numbers and human GvHD

Acute GvHD; III-IV

1-KM

CI CI

1-KM

Chronic GvHD

Lancet 2005; 366: 733–41

Effect of GvHD prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow

G. S / AIH 2006


Bacigalupo et al. Blood. 2001;98:2942-2947

100

90

80

70

60

50

40

30

20

10

030 60

90

A

B

A= ATG n=29 41%B= no ATG n=25 36%

p=ns.

Trial N.1 : ATG 7.5 vs. 0 mg/kg

100

90

80

70

60

50

40

30

20

10

0

Trial N.2 : ATG 15 vs. 0 mg/kg

A= ATG n=27 11%B= no ATG n=28 50%

P=0.001A

B

g. s / aih 2006 graft-versus-host disease physiopathology gérard socié, md phd hospital saint...

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