The broad, long-term objective and specific aims of this project are to understand and improve the outcome of patients receiving allogeneic cord blood transplantation through in vitro and in vivo murine studies. While the use of cord blood transplantation has resulted in improved outcome in selected patients, there remains a significant amount of work that needs to be done to improve on the outcome for all patients. Two areas the need immediate improvement are those of engraftment and immune reconstitution. The major hypothesis we wish to test is whether increased numbers of stem cells (undifferentiated or committed) will result in a more rapid myeloid and lymphoid recovery. Using in vitro studies and in vivo murine studies will allow us to determine the important parameters that will lead to studies in projects II and III. While there are data to suggest that higher numbers of hematopoietic cells results in improved outcome through a more rapid myeloid reconstitution, are specifically also interested in a more rapid lymphoid recovery. We have described a method of stem cell isolation based on aldehyde dehydrogenase (ALDH) by sorting uses using the reagent BODIPY aminoacetaldehyde (BAAA) and know orthogonal light scattering. We propose to utilize this methodology and a novel murine cord blood model to further our understanding of cord blood transplantation. The ability to increase the numbers of hematopoietic stem cells through ex vivo expansion or through the addition of selected sub populations of the common myeloid and lymphoid precursors may result in improved outcome.
Specific Aim 1 will define the population of ALDH/br cells in ex vivo expanded human cord blood.
Specific aim 2 will determine if higher numbers of bulk hematopoietic stem cells results in a more rapid lymphoid recovery in a murine model.
Specific aim 3 will correlate lymphoid phenotype and functional recovery following blood translation with recovery of thymic function.
Specific aim 4 will determine if selected subpopulations of cord blood cells, specifically the common lymphoid progenitor will result in a more rapid lymphoid recovery in our murine model. The advantages of laboratory based studies are several. First, the availability of genetically identical and congenic donor and recipients pairs will allow us to be able to reproduce these experiments and allow us to track the fate of these cells, following transplantation. Second, the ability to monitor the numbers of SSC/19 ALDH/br cells may have predictive value for speed of engraftment. Third, the ability to study immune reconstitution following murine blood transplantation will provide hints to follow in our patients. Lastly, we will be able to ascertain if a more rapid lymphoid recovery could result in a negative outcome such as a higher incidence of GVHD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Duke University
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Zhang, Ping; Wu, Jieying; Deoliveira, Divino et al. (2012) Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice. Biol Blood Marrow Transplant 18:1488-99
Szabolcs, Paul (2011) T-lymphocyte recovery and function after cord blood transplantation. Immunol Res 49:56-69
Szabolcs, Paul (2010) The immunobiology of cord blood transplantation. Korean J Hematol 45:224-35
Szabolcs, Paul; Cairo, Mitchell S (2010) Unrelated umbilical cord blood transplantation and immune reconstitution. Semin Hematol 47:22-36
Kurtzberg, Joanne (2009) Update on umbilical cord blood transplantation. Curr Opin Pediatr 21:22-9
Szabolcs, Paul; Niedzwiecki, Donna (2008) Immune reconstitution in children after unrelated cord blood transplantation. Biol Blood Marrow Transplant 14:66-72
Mazur, Melissa A; Davis, Craig C; Szabolcs, Paul (2008) Ex vivo expansion and Th1/Tc1 maturation of umbilical cord blood T cells by CD3/CD28 costimulation. Biol Blood Marrow Transplant 14:1190-6
Urs, Nikhil M; Kowalczyk, Andrew P; Radhakrishna, Harish (2008) Different mechanisms regulate lysophosphatidic acid (LPA)-dependent versus phorbol ester-dependent internalization of the LPA1 receptor. J Biol Chem 283:5249-57
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Szabolcs, P; Niedzwiecki, D (2007) Immune reconstitution after unrelated cord blood transplantation. Cytotherapy 9:111-22

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