GraftversusHost disease Physiopathology Grard Soci MD Ph D

Graft-versus-Host disease Physiopathology Gérard Socié, MD Ph. D Hospital Saint Louis Translating experimental into clinical knowledge G. S / AIH 2006

Graft-versus-Host disease Physiopathology Acute Graft-versus-Host Disease G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology Billingham; Nature 1966 G. S / AIH 2006

Graft-versus-Host disease Physiopathology Cytokines increased expression of MHC antigens and adhesion molecules enhance the recognition of MHC / minor Ag by mature donor T-cells Phase I. Induction of inflammatory cytokines & damage + activation of host tissue during conditioning G. S / AIH 2006

Graft-versus-Host disease Physiopathology Phase 2: Donor T-cell activation • Proliferation of Th 1 T cells and secretion of IL-2 & IFN. • IL-2 & IFN : v induce further T-cell expansion, v induce CTL and NK responses v Prime macrophages to produce IL-1 and TNF G. S / AIH 2006

Graft-versus-Host disease Physiopathology Phase 3: Inflammatory effector mechanisms Effector functions of macrophages are triggered via a 2 nd signal (LPS) LPS can stimulate tissue-associated Ly and macrophage leading to amplification of local tissue injury G. S / AIH 2006

(I) Conditioning Graft-versus-Host disease Tissue Damage Physiopathology Host tissues Small intestine TNF IL-1 LPS Mf APC TNF- IL-1 IFN- Donor T Cell (II) Donor T-cell activation Target cell apoptosis Th 1 CD 4 CTL TNF- IL-1 CD 8 CTL (III) Cellular and inflammatory effectors G. S / AIH 2006

I: Role of conditioning (I) Conditioning Graft-versus-Host disease Tissue Damage Physiopathology Host tissues Small intestine TNF IL-1 LPS Mf APC TNF- IL-1 IFN- Donor T Cell (II) Donor T-cell activation Target cell apoptosis Th 1 CD 4 CTL TNF- IL-1 CD 8 CTL (III) Cellular and inflammatory effectors G. S / AIH 2006

Graft-versus-Host disease Physiopathology Cytokine (TNF alpha) release during conditioning results in higher Gv. HD and TRM (Holler 1990) Late onset a. Gv. HD Age and dose of TBI as major risk factors of Gv. HD 3 mois (Tseng et al. , Blood 1999; 94: 2911) G. S / AIH 2006

(I) Conditioning Graft-versus-Host disease Tissue Damage Physiopathology II a) APC & Acute Gv. HD (II) Donor T-cell activation Host tissues Small intestine TNF IL-1 LPS Mf APC TNF- IL-1 IFN- Donor T Cell Target cell apoptosis Th 1 CD 4 CTL TNF- IL-1 CD 8 CTL (III) Cellular and inflammatory effectors G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

(I) Conditioning Graft-versus-Host disease Tissue Damage Physiopathology Host tissues Small intestine TNF IL-1 LPS Mf APC TNF- IL-1 IFN- Donor T Cell (II) II b) Donor T-Cell T-cell activation Target cell apoptosis Th 1 CD 4 CTL TNF- IL-1 CD 8 CTL (III) Cellular and inflammatory effectors G. S / AIH 2006

Graft-versus-Host disease Physiopathology Histoincompatibility between donor and host: ü Gv. HD increases with the number of major MHC mismatches ü minor antigen mismatches in HLA-identical sibling BMT G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology Major /minor antigens in mice Ø B 6 Dom (Nature Medicine; 7: 789, 2001) Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease Ø H 60 ++ (Immunity; 17: 593, 2002 / Blood; 100: 4255, 2002) Real-time T cell Profiling Identifies H 60 As a Major Minor Histocompatibility Antigen in Murine Graft-vs-Host Disease G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology Co-stimulation & acute Gv. HD (mice) CD 80/86 CTLA 4 -Ig CD 40/40 L LFA 1/ICAM ICOS ……. G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology CD 8+ naïve T Cell CD 44 Low CD 62 -L High IL 7 - IL 15 Memory stem cell Central Memory CD 44 High CD 62 -LHigh CD 44 Low CD 62 -L High Sca-1 High Central Memory CD 44 High CD 62 -L Low G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Graft-versus-Host disease Physiopathology Experimental Hematology 33 (2005) 894– 900 G. S / AIH 2006

Graft-versus-Host disease Physiopathology G. S / AIH 2006

Non HLA Gene Polymorphisms Graft-versus-Host disease Middleton et al. Blood 1998 Physiopathology • TNF (d 3/d 3) • 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 Gv. HD Socié et al. Transplantation 2001 Cullup et al. Brit J Haem 2001 • IL-6 • IL 1 -Ra • TNF ; IL-10 (CBT) No association Kögler et al. Transplantation 2002 • Vit D receptor a. Gv. HD and survival Middleton et al. BMT 2002 • Estrogen receptor Midleton et al BMT 2003 • TNRII Stark et al. Transplantation 2003 • Mannose Binding Lectin (MBL) Infectious complications Mulligan et al. Blood 2002 • Fc RIIa Infectious complications Rocha et al. Blood 2002 G. S / AIH 2006

Graft-versus-Host disease Physiopathology N. Engl. J. Med. 2003; 349: 2201 -10. G. S / AIH 2006

Graft-versus-Host disease Physiopathology T-cell numbers and human Gv. HD Lancet 2005; 366: 733– 41 Acute Gv. HD; III-IV Chronic Gv. HD 1 -KM CI CI Effect of Gv. HD prophylaxis on 3 -year disease-free survival in recipients of unrelated donor bone marrow G. S / AIH 2006

Graft-versus-Host disease Physiopathology 100 90 80 70 60 50 40 30 20 10 0 Trial N. 1 : ATG 7. 5 vs. 0 mg/kg A= ATG B= no ATG p=ns. 30 100 90 80 70 60 50 40 30 20 10 0 n=29 41% n=25 36% 60 A B 90 Trial N. 2 : ATG 15 vs. 0 mg/kg A= ATG n=27 11% B= no ATG n=28 50% P=0. 001 B A Bacigalupo et al. Blood. 2001; 98: 2942 -2947 G. S / AIH 2006