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

6. 1949 Jacobson et al: Radioprotection by lead shielding
of the spleen of a lethally irradiated animal

7. 1951 Lorenz et al: Radiation protection of lethally irradiated
animals by marrow and spleen cells from
non-irradiated animals of the same strain

8. 1956 Barnes et al: Successful treatment of leukemia in mice
after lethal irradiation followed by injection
of normal marrow cells

9. Donnell E. Thomas

10. The first wave of transplants

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

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

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

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

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

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

17. Jean Dausset

18. Hemopoietic Stem Cells

19. Stem Cells: A PMH Tradition

21. HSC
Self renewal
Differentiation
Proliferation

22. Stem Cell Subpopulations
Weissman et al

23. Stem Cell Subpopulations
Weissman et al

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

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

26. Stem cell migration and homing via SDF-1 and CXCR4 interaction
SDF-1 binds exclusively to its receptor CXCR4
Secretion of SDF-1 by bone marrow is critical for the colonization of marrow by fetal liver derived hemopoietic stem cells
SDF-1/CXCR4 knock out mice have developmental defects in the heart, brain, and large vessels
SDF-1 is highly expressed in bone marrow, lymph nodes, lung, liver, kidney and skeletal muscle.
SDF-1 secretion increases with tissue damage eg hypoxia, radiation, chemotherapy.
HIF-1 and NFΚB upregulate both SDF-1 and CXCR4
VEGF, IFN alpha, IL 2,4,&
Transcription factors of the PAX-family may regulate CXCR4 expression in a tissue specific manner (eg PAX1 for osteoblastic SC, PAX5 for B lymphocytic progenitors)
Lapidot T et al 2004

27. The hemopoietic niche LIF SCF SDF-1 G-GSF TGF-β GM-CSF IL1α FLT 3 IL6
Bony niche lined with osteoblasts positioned proximal to the endosteal surface. Frequency of HSC increases with increasing numbers of osteoblasts. Their number can be influenced by BMP and PTH/PTHR. In vitro osteoblasts suppress proliferation of HSC and maintain their immature phenotype. Stromal niche composed of reticular cells, fibroblasts, adipocytes, endothelial cells and macrophages. Reticuler stroma has the opposite effect, Adipocytes
IL6
OSM
IL7
BMP-4
IL8
PTH
IL11
IL12
IL15
IL14
Modified: Dazzi F et al Blood Reviews 2006; 20:
Cell contact
Notch and Wnt/beta catheninsignalling
BMP4
Tie2/Ang1 pathways
Soluble factors
Transcription factors
Cell cycle regulators
Chromosome modifiers such as telomerase
Adhesion molecules

28. Sources of Stem Cells
Marrow
Peripheral blood
Cord blood

29. Transplant Immunology

30. 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

31. The problems after allotransplant
Prophylaxis
Calcineurin inhibitors
MTX
ATG
Alemtuzumab
aGvHD
aGvHD
Secondary Therapy
Primary Therapy
Hemopoietic stem cell transplants are associated with a number of problems that influence survival. These complications are usually assessed independent of each other and strategies are usually employed to address specific complications. This approach does not take into account linkeages where alteration of one complication may influence incidence and/or severity of others.
Steroids plus
Monoclonal antibodies
Photopheresis
Mesechymal stem cells
Steroids

32. 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
MSC
MSC
IL12
MSC
IL4
Donor
T cells
Type 2
Cytokines
IL4,IL10,IL13
Anti-
inflammatory
Host
APC
TH2 cells

33. Supportive Care

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

35. Survival of AML Patients
Since 1986
Survival
Before 1986
Years after BMT

36. 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