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

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

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

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

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

6. G. S / AIH 2006 Graft-versus-Host disease Physiopathology Proliferation of Th1 T cells and 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

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

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

9. G. S / AIH 2006 Graft-versus-Host disease Physiopathology I: Role of conditioning

10. G. S / AIH 2006 Graft-versus-Host disease Physiopathology 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 major risk factors of GvHD (Tseng et al., Blood 1999; 94:2911)

11. G. S / AIH 2006 Graft-versus-Host disease Physiopathology II a) APC & Acute GvHD

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

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

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

15. G. S / AIH 2006 Graft-versus-Host disease Physiopathology II b) T-Cell activation

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

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

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

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

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

21. G. S / AIH 2006 Graft-versus-Host disease Physiopathology Co-stimulation & acute GvHD (mice) CD 80/86 CTLA4-Ig CD 40/40L LFA1/ICAM ICOS …….

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

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

24. G. S / AIH 2006 Graft-versus-Host disease Physiopathology CD8+ naïve T Cell CD 44 Low CD62-L High CD 44 Low CD62-L High Sca-1 High Memory stem cell CD 44 High CD62-LHigh CD 44 High CD62-L Low Central Memory IL7- IL15

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

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

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

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

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

30. G. S / AIH 2006 Graft-versus-Host disease Physiopathology 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/donorHill et al.Blood 1999 IL-6acute/chronicCavet et al.Blood 2001 IL-10GvHDSocié et al.Transplantation 2001 IL-6 IL1-RaCullup et al.Brit J Haem 2001 TNF  ; IL-10(CBT) No associationKögler et al.Transplantation 2002 Vit D receptoraGvHD and survivalMiddleton et al.BMT 2002 Estrogen receptorMidleton et al BMT 2003 TNRIIStark et al.Transplantation 2003 Mannose BindingInfectiousMulligan et al.Blood 2002 Lectin (MBL)complications Fc  RIIaInfectious complications Rocha et al.Blood 2002

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

32. G. S / AIH 2006 Graft-versus-Host disease Physiopathology T-cell numbers and human GvHD Acute GvHD; III-IV 1-KM 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

33. G. S / AIH 2006 Graft-versus-Host disease Physiopathology Bacigalupo et al. Blood. 2001;98:2942-2947 100 90 80 70 60 50 40 30 20 10 0 3060 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=0.001 A B