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(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.

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  1. (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 III a) T-Cell migration

  2. BB&MT 12: 2-8, 2006

  3. Tissue-tropic effector T cells: generation and targeting Opportunities Nature Review Immunology September 2006

  4. (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 III b) Tissue Damage

  5. Inflammatory bowel diseases:Mucosa associated receptors (PRM) decide on tolerance versus activation

  6. NOD2/CARD15 variants associate with severe GvHD

  7. Mesenchymal Stem Cells And GvHD?

  8. Chronic Graft-versus-Host Disease

  9. Gilliam and Murphy, GVHD 2nd ed., 1997, p. 299 Chronic Acute Endothelial Phase Lichenoid Phase Epidermotropic and Target Cell Phase Sclerodermatous Phase

  10. 1) Haploidentical P  F1 (MHC I, II, minor H)  B6  B6D2F1: acute GVHD  D2  B6D2F1: chronic GVHD  D2:  CD8+,  IFNg More CD8s convert to acute GVHD 2) B10.D2  Balb (minor H) Skin disease, immunodeficiency  Sub-lethal radiation (600 day) Lethal radiation  acute GVHD (mixed chimerism needed for chronic?) Hakim and Mackail, GVHD 2nd ed

  11. BB & MT 8:656-661 (2002) Blood. 2005;106:3308-3313 Is T-cell depletion associated with less chronic GVHD ?

  12. Amplified clonal T-cell & c.GvHD. BMT 2002; 30: 509-15 • OX40 (CD134) CD4+ CD8+ T-cell & c.GvHD. Blood 2001; 98: 3162-64 both OX40+ CD4+ and OX40+ CD8+ T cells were higher in patients with c.GVHD than those without ( P< .0001 and P< .001, respectively)

  13. High levels of IL-1, IL-6, IFN, and TNF are associated with more severe chronic GVHD • High serum TGF also was associated with chronic GVHD independent of platelet and white blood cell counts • Patients with chronic GVHD have low levels of IL-10 ( anti-inflammatory) and Ig production Review in BB&MT 9:215–233 (2003)

  14. Blood. 2005;105:2973-2978 DBY; UTY; ZFY; RPS4Y; EIF1AY Transplantation. 1988;46:238–240. Experimental Hematology 34 (2006) 389–396

  15. 1985-2000: • 198 patients / HLA id. sibling D • Good risk ; i.e. AML CR, CML 1st CP, SAA • > 1year without relapse

  16. 1985-2000:

  17. 2nd ESH EBMT Teaching course GvHD / GvL 2007 N. Engl. J. Med. 353;13: September 29, 2005

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