Post on 07-Jan-2016
description
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
Gérard Socié, MD PhDHospital Saint Louis
Translating experimental into clinical knowledge
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
Acute Graft-versus-Host
Disease
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
Billingham; Nature 1966
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
• 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
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
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
I: Role of conditioning
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
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
II a)APC & AcuteGvHD
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
II b)T-Cell
activation
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
Co-stimulation & acute GvHD (mice)CD 80/86CTLA4-IgCD 40/40LLFA1/ICAMICOS …….
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
Experimental Hematology 33 (2005) 894–900
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
N. Engl. J. Med. 2003;349:2201-10.
G. S / AIH 2006
Graft-versus-Host diseasePhysiopathology
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
Graft-versus-Host diseasePhysiopathology
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