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Allogeneic Stem Cell Transplantation: The Journey

Allogeneic Stem Cell Transplantation: The Journey. H.A. Messner. Objectives. Hemopoietic stem cells Concepts of blood and marrow transplants Clinical results Long term outcomes New developments Increase the number of transplants Matched unrelated donors

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Allogeneic Stem Cell Transplantation: The Journey

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  1. Allogeneic Stem Cell Transplantation:The Journey H.A. Messner

  2. Objectives • Hemopoietic stem cells • Concepts of blood and marrow transplants • Clinical results • Long term outcomes • New developments • Increase the number of transplants Matched unrelated donors Cord blood transplants Haplo-identical donors Non-myeloablative preparations • New platforms to reduce malignant cells in the recipient • The new paradigm in stem cell biology • Blood and marrow transplants as a form of cell therapy in regenerative medicine

  3. 1949 Jacobson et al: Radioprotection by lead shielding of the spleen of a lethally irradiated animal

  4. 1951 Lorenz et al: Radiation protection of lethally irradiated animals by marrow and spleen cells from non-irradiated animals of the same strain

  5. 1956 Barnes et al: Successful treatment of leukemia in mice after lethal irradiation followed by injection of normal marrow cells

  6. Donnell E. Thomas

  7. The first wave of transplants

  8. The first wave of transplants Engraftment Failure Graft versus Host Disease Relapse

  9. The first wave of transplants Where to go from here?

  10. Establishment of principles : The pillars of modern transplantation • HLA typing • Stem cell biology • Transplant immunology • Supportive care

  11. 45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 The second and sustained wave of transplants Autologous NUMBER OF TRANSPLANTS Allogeneic 1970 1975 1980 1985 1990 1995 2000 YEAR 1

  12. Emerging complexity of the HLA-system HLA-A alleles N=6 HLA-B alleles N=6 1968

  13. Emerging complexity of the HLA-system HLA-A alleles N=6 HLA-B alleles N=6 1968

  14. Jean Dausset

  15. Hemopoietic Stem Cells

  16. Stem Cells: A PMH Tradition

  17. HSC Self renewal Proliferation Differentiation

  18. Stem Cell Subpopulations Weissman et al

  19. Stem Cell Subpopulations Weissman et al

  20. Gene expression patterns in hemopoietic progenitor cells Manfredini R et al Stem Cells 2005; 23: 496 – 506

  21. Gene expression profiles in different hemopoietic progenitor subpopulations Manfredini R et al Stem Cells 2005; 23: 496 – 506

  22. Stem cell migration and homing via SDF-1 and CXCR4 interaction Lapidot T et al 2004

  23. The hemopoietic niche LIF SCF SDF-1 G-GSF TGF-β GM-CSF IL1α FLT 3 IL6 OSM IL7 BMP-4 IL8 PTH IL11 IL12 IL15 IL14 Modified: Dazzi F et al Blood Reviews 2006; 20: 161-171

  24. Sources of Stem Cells • Marrow • Peripheral blood • Cord blood

  25. Transplant Immunology

  26. Alloimmune responses by T cells • Induction phase Priming • Expansion phase Proliferation • Effector phase Interaction with cognate AG on host target cells (Perforin, Granzyme, CK) TH1 cells Type 1 Cytokines IL2, IFN-gamma, TNF-beta Pro-inflammatory IL12 (reciprocal suppression) IL4 Donor T cells Type 2 Cytokines IL4,IL10,IL13 Host APC Anti-inflammatory TH2 cells

  27. The problems after allotransplant Prophylaxis Calcineurin inhibitors MTX ATG Alemtuzumab aGvHD aGvHD Secondary Therapy Primary Therapy Steroids plus Monoclonal antibodies Photopheresis Mesechymal stem cells Steroids

  28. MSC MSC MSC Alloimmune responses by T cells • Induction phase Priming • Expansion phase Proliferation • Effector phase Interaction with cognate AG on host target cells (Perforin, Granzyme, CK) TH1 cells IL12 IL4 Donor T cells Type 2 Cytokines IL4,IL10,IL13 Anti- inflammatory Host APC TH2 cells

  29. Supportive Care

  30. Aspect of supportive care • Improved GvHD prophylaxis and management • Better infectious disease prophylaxis and therapy • Improved transfusion support • Improved graft preparation

  31. Survival of AML Patients Since 1986 Survival Before 1986 YearsafterBMT

  32. Indications for stem cell transplants • Cell deficits Aplastic Anemia Immune deficiencies • Hemopoietic Malignancies Leukemias Lymphomas Multiple Myeloma • Genetic disorders Hemoglobinopathies Inborn errors of metabolism • Autoimmune disorders • Selected solid tumors that may benefit from Marrow ablative therapy Cell therapy • Repair of certain organs

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