The theme of this program has not changed over the last decade: Understanding the biology of human hematopoietic stem cells (HSC) and their progeny will lead to improved hematopoietic cell-based therapy for a variety of lethal malignant diseases. During the current funding period, Catherine Verfaillie MD has made important observations on mechanisms governing stem cell self-renewal and differentiation. Recently, she has developed a high through-put zebrafish screen to characterize a variety of genes differentially expressed in Rho'x and Rho hi human umbilical cord blood (UCB) progenitors which may affect self-renewal of hematopoietic stem cells. In Project 1, she will exploit the high through-put zebrafish screening assay to assess the potential role of these genes in hematopoiesis, and confirm such a role in subsequent in vitro progenitor assays and murine transplant models. She will employ a similar approach to characterize genes differentially expressed in stromal feeders that support or do not support HSC in non-contact cultures. This approach may identify novel extrinsic factors that regulate HSC self-renewal. Genes and their products implicated by Dr. Verfaillie in hematopoietic stem cell self-renewal will be assessed in preclinical and clinical studies in Project 2 for their capacity to enhance engraftment in UCB transplant trials and in Project 3 to determine their effect on myeloid and lymphoid progenitor differentiation. During the current funding period, John Wagner MD has developed a """"""""double UCB"""""""" transplant approach which has significantly broadened the availability of UCB transplants to treat adults, regardless of body size. The double UCBT model also allows manipulation and tracking of cells from one transplanted UCB unit while providing a second, unmanipulated unit to safeguard engraftment. In Project 2, Dr. Wagner will use the double UCBT model to test novel methods to enhance engraftment by co-infusion of regulatory T-cells (Treg), and use of novel ex vivo expansion approaches evolving from Project 1. He will also use immunocompromised mouse transplant models to explore immunological events underlying double UCB transplants. Jeffrey Miller MD has made the startling observation that infusion of HLA haploidentical NK cells in the non-transplant setting is associated with complete remission in some patients with high-risk AML. Clinical responses are correlated with in vivo donor NK expansion. In Project 3, he will continue a series of clinical trials testing NK cell-based cell therapy for leukemia. He will also continue to examine fundamental events shaping NK cell progenitor differentiation, activation and proliferation, and assess the influence of novel ex vivo HSC expansion conditions developed in Projects 1 on myeloid and lymphoid differentiation. These interactive projects are supported by administrative and biostatistical cores (Cores A and B), as well as cores to provide cell collection and processing (Core C) and immunocompromised mouse assays (Core D).
| 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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