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Bone marrow versus PBPC for allogeneic stem cell transplant: defining the optimal graft

      Randomized trials comparing bone marrow (BM) to G-CSF mobilized peripheral blood progenitor cell (G-PBPC) products for unrelated-donor transplantation, resulted in no significant difference in survival. G-PBPCs were associated with faster engraftment and reduced risk of graft failure but also a significant increase in the risk of chronic graft versus host disease (cGVHD). This has resulted in the proposal that bone marrow be used in preference to G-PBPC for the majority of unrelated-donor transplants. BM grafts contain two types of stem cells: hematopoietic (HSCs) and mesenchymal (MSCs) stem cells. As MSCs have been shown to be immune suppressive and have been used to reverse GVHD, we evaluated whether G-PBPC contain MSCs as well as HSCs. MNCs were isolated from normal donor G-PBPCs and cultured for MSC in flasks in alpha MEM plus 20% FBS. MSCs failed to grow from G-PBPC and the products lacked CD271+CD45- cells. We therefore evaluated different mobilization agents and demonstrated in mice that AMD3100 could mobilize MSCs. Treatment of mice with G-CSF alone failed to mobilize MSCs, while the combination of G-CSF plus AMD3100 resulted in significant levels of MSCs in the peripheral blood of treated mice. These studies have been repeated in a non-human primate. Treatment with G-CSF for days 1 to 5 plus AMD3100 on day 5 resulted in significant levels of MSCs in the peripheral blood collected on day 6. Based upon these data we propose that mobilization of normal donors with G-CSF plus Mozobil will be effective in mobilizing both HSCs and MSCs and generate the optimal stem cell graft providing both rapid engraftment and cGVHD equivalent to BM. We have initiated a clinical trial at MD Anderson to evaluate the safety of G-CSF plus Mozobil mobilization in normal donors and will determine the potential to mobilize MSCs.
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