Current clinical results demonstrate that recipients of umbilical cord blood (UCB) grafts containing > 5 x 10/434+ cells per kg recipient body weight are at high risk are at high risk delayed neutrophil recovery, graft failure and death. Low graft cell dose clearly limits the usefulness of this hematopoietic stem cell (HSC) source, particularly for adolescents and adults. Therefore, we plan to expand the number of HSC in UCB in order to overcome this obstacle. Specifically, we will evaluate the effect of ex vivo expansion culture on the frequency of long-term culture-initiating cells (LTC-IC) and myeloid-lymphoid initiating cells (ML-IC), and on the ability to reinitiate a secondary long-term myeloid culture, as a measure of 'self renewal' (self-renewing ML-IC) in vitro. In addition, we will evaluate the effect of ex vivo expansion culture on the frequency of Non- Obese Diabetes-Severe Combined Immunodeficiency (NOD/SCID) repopulating cells (SRC) both in primary and secondary recipients. On the basis of these results, we will select the most promising UCB HSC expansion method(s) for testing in myeloablated human recipients (i.e., on the basis of expansion of primitive progenitors with HSC properties). In this proposal, there are three specific aims.
In Specific Aim 1, we will develop clinically relevant culture condition(s) for expanding and marking primitive hematopoietic progenitor cells in a xenogeneic transplant model. We will evaluate possible mechanisms of the homing defect and determine whether the defect can be corrected. And, in Specific Aim 3, we will transplant cultured and genetically marked UCB hematopoietic progenitor cells and evaluate the safety of the culture and marking conditions on long term engraftment as well as verify the validity of the laboratory assays on HSC. Together. the results of these studies will allow us to determine the optimal method of UCB HSC expansion in order to minimize the current limitation of cell dose in human recipients.
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| 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 |
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| 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 |
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