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Gérard Socié, MD PhD Hospital Saint Louis

AIH. Gérard Socié, MD PhD Hospital Saint Louis. Translating experimental into clinical knowledge. Acute Graft-versus-Host Disease. Billingham; Nature 1966. Cytokines increased expression of MHC antigens and adhesion molecules enhance the recognition of MHC / minor Ag by mature

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Gérard Socié, MD PhD Hospital Saint Louis

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  1. AIH Gérard Socié, MD PhD Hospital Saint Louis Translating experimental into clinical knowledge

  2. Acute Graft-versus-Host Disease

  3. Billingham; Nature 1966

  4. 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

  5. Phase 2: Donor T-cell activation • 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

  6. Phase 3: Inflammatory effector mechanisms 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

  7. (I) Conditioning Tissue Damage Host Small tissues intestine LPS TNF-a IL-1 LPS f M APC TNF-a IL-1 CD4 CTL IFN-g Donor T Cell Target cell apoptosis (III) (II) CD8 CTL Cellular and Donor TNF-a IL-1 inflammatory T-cell Th 1 CD8 CTL effectors activation

  8. (I) Conditioning Tissue Damage Host Small tissues intestine LPS TNF-a IL-1 LPS f M APC TNF-a IL-1 CD4 CTL IFN-g Donor T Cell Target cell apoptosis (III) (II) CD8 CTL Cellular and Donor TNF-a IL-1 inflammatory T-cell Th 1 CD8 CTL effectors activation I: Role of conditioning

  9. 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)

  10. (I) Conditioning Tissue Damage Host Small tissues intestine LPS TNF-a IL-1 LPS f M APC TNF-a IL-1 CD4 CTL IFN-g Donor T Cell Target cell apoptosis (III) (II) CD8 CTL Cellular and Donor TNF-a IL-1 inflammatory T-cell Th 1 CD8 CTL effectors activation II a) APC & Acute GvHD

  11. (I) Conditioning Tissue Damage Host Small tissues intestine LPS TNF-a IL-1 LPS f M APC TNF-a IL-1 CD4 CTL IFN-g Donor T Cell Target cell apoptosis (III) (II) CD8 CTL Cellular and Donor TNF-a IL-1 inflammatory T-cell Th 1 CD8 CTL effectors activation II b) T-Cell activation

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

  13. Major /minor antigens in mice • B6 Dom(Nature Medicine; 7: 789, 2001) Adoptive transfer of minor histocompatibility antigen-specificT lymphocytes eradicates leukemia cells without causinggraft-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 inMurine Graft-vs-Host Disease

  14. Co-stimulation & acute GvHD (mice) CD 80/86 CTLA4-Ig CD 40/40L LFA1/ICAM ICOS …….

  15. CD 44 Low CD62-L High CD 44 High CD62-LHigh CD 44 High CD62-L Low CD8+ naïve T Cell IL7- IL15 Memory stem cell CD 44 Low CD62-L High Sca-1 High Central Memory Central Memory

  16. Experimental Hematology 33 (2005) 894–900

  17. 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 • FcRIIa Infectious complications Rocha et al. Blood 2002

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

  19. Lancet 2005; 366: 733–41 Acute GvHD; III-IV Chronic GvHD 1-KM 1-KM CI CI T-cell numbers and human GvHD Effect of GvHD prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow

  20. Trial N.1 : ATG 7.5 vs. 0 mg/kg 100 90 80 70 60 50 40 30 20 10 0 A= ATG n=29 41% B= no ATG n=25 36% A B p=ns. 90 30 60 100 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% B P=0.001 A Bacigalupo et al. Blood. 2001;98:2942-2947

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