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.
| de Witte, Moniek A; Sarhan, Dhifaf; Davis, Zachary et al. (2018) Early Reconstitution of NK and ?? T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. Biol Blood Marrow Transplant 24:1152-1162 |
| Zeiser, Robert; Blazar, Bruce R (2018) Acute Graft-versus-Host Disease. N Engl J Med 378:586 |
| Blazar, Bruce R; MacDonald, Kelli P A; Hill, Geoffrey R (2018) Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood 131:2651-2660 |
| Rothenberger, Meghan; Wagner, John E; Haase, Ashley et al. (2018) Transplantation of CCR5?32 Homozygous Umbilical Cord Blood in a Child With Acute Lymphoblastic Leukemia and Perinatally Acquired HIV Infection. Open Forum Infect Dis 5:ofy090 |
| Lu, Yunjie; Gao, Ji; Zhang, Shaopeng et al. (2018) miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg). Cell Death Dis 9:290 |
| Cichocki, Frank; Wu, Cheng-Ying; Zhang, Bin et al. (2018) ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med 215:2379-2395 |
| Taraseviciute, Agne; Tkachev, Victor; Ponce, Rafael et al. (2018) Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer Discov 8:750-763 |
| Felices, Martin; Lenvik, Alexander J; McElmurry, Ron et al. (2018) Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 3: |
| Sarhan, Dhifaf; Hippen, Keli L; Lemire, Amanda et al. (2018) Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res 6:766-775 |
| Williams, Robin L; Cooley, Sarah; Bachanova, Veronika et al. (2018) Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells. Biol Blood Marrow Transplant 24:618-622 |
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