TRANSPLANTATION OF UMBILICAL CORD BLOOD PROGENITOR CELLS

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In an attempt to reduce the morbidity and mortality associated with allogeneic bone marrow transplantation, clinical investigators in Asia, Australia, Europe, north America and South America have evaluated umbilical cord and placental blood as an alternate source of hematopoietic stem and progenitor cells for transplantation. Between October 1988 and September 1994, 51 patients aged 1.3-47.8 years with malignant (n=30) and nonmalignant (n=21) disorders received allogeneic umbilical cord blood for hematopoietic rescue after myeloablative therapy. Umbilical cord blood grafts were collected from neonatal sibling donors (n=45, 35 HLA-identical and 10 HLA-mismatched at 1-3 loci) and unrelated donors (n=6; 1 HLA- identical and 5 HLA-mismatched at 102 loci). The clinical experience to date demonstrates that umbilical cord blood does contain long-term marrow repopulating cells and in numbers sufficient for engraftment in most recipients weighing les than 40 kilograms. However, the time to hematopoietic recovery is delayed. The median time to neutrophil and platelet recovery is 28.5 and 48 days, respectively, in patients not treated with hematopoietic growth factors after transplantation. Moreover, donor-derived hematopoiesis was absent or incomplete in 11 of 46 evaluable patients. The overall aim of this proposal is to develop strategies for optimizing the number of primitive and committed hematopoietic cells in the umbilical cord blood inoculum and determine the effect of ex vivo progenitor cell expansion on donor-derived hematopoietic recovery in recipients of allogeneic umbilical cord blood. In Specific Aim 1, we propose to characterize the functional capacities of the long-term culture initiating cells in umbilical cord blood. We will determine the proliferative capacity and multilineage potential of these primitive progenitors with direct comparisons to counterparts found in adult bone marrow and adult peripheral blood. In Specific Aim 2, we will determine the optimal culture conditions for expanding the number of primitive and committed progenitor cells in umbilical cord blood as well as develop the optimal procedure for retroviral transduction. And, in Specific Aim 3, we will perform sequential clinical trials of allogeneic umbilical cord blood transplantation in adult and pediatric recipients, first using unmodified and subsequently ex vivo expanded umbilical cord blood inocula. Together, the results of these experiments will allow us to determine the similarities and differences between umbilical cord blood, adult bone marrow and peripheral blood progenitors as well as optimize the number of hematopoietic progenitors cells for use in clinical transplantation in all size recipients.