In utero hematopoietic cell transplantation (IUHCT) is a promising therapeutic approach potentially applicable to a large number of genetic diseases. Utilizing the murine model of IUHCT, we have established mixed hematopoietic chimerism across full MHC barriers and gained understanding into the requirements for engraftment and associated donor specific tolerance. We have determined the mechanism of tolerance after IUHCT, and utilized prenatal tolerance to facilitate postnatal bone marrow transplantation and immunotherapy with conversion of partial to complete donor chimerism across full MHC barriers without toxicity. Our long-term objective is the translation of these successful strategies to clinical application, and the development of novel and safe new approaches to achieve therapeutic engraftment by IUHCT alone. In this proposal our specific aims are: 1) To define the components and mechanism of the adaptive immune response that determine the success or failure of allogeneic engraftment after IUHCT. We have observed that there are clear differences in the frequency of engraftment between congenic and allogeneic IUHCT using BM and HSC. These differences have been unmasked by our current technique of intravascular injection of large doses of cells. In this aim we will investigate the hypothesis that many donor reactive cells escape clonal deletion, and that the maintenance of chimerism is dependent upon generation of an adequate peripheral regulatory response prior to rejection of donor cells. 2) To enhance engraftment by specifically targeted prenatal immunotherapy. We will investigate the use of minor histocompatibility immunodominant antigens expressed predominantly on hematopoietic cells as a target for specific immunotherapy to enhance engraftment in the fetus without GVHD. 3) To investigate selective strategies to improve homing and engraftment of donor cells. We have also identified a mechanism to improve homing and engraftment of donor cells after in utero transplantation by blockade of the dipeptidylpeptidase CD26. The studies in this proposal are designed to develop and optimize novel approaches to IUHCT that will be safely translatable to large animal and human systems. The ultimate goal of these studies is to develop safe and effective strategies that can be translated to the in utero treatment of a broad range of human genetic hematologic disorders including Sickle Cell Disease and Thalassemia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hematopoiesis Study Section (HP)
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Thomas, John
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Children's Hospital of Philadelphia
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Peranteau, William H; Hayashi, Satoshi; Abdulmalik, Osheiza et al. (2015) Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants. Blood 126:1245-54
Peranteau, William H; Heaton, Todd E; Gu, Yu-Chen et al. (2009) Haploidentical in utero hematopoietic cell transplantation improves phenotype and can induce tolerance for postnatal same-donor transplants in the canine leukocyte adhesion deficiency model. Biol Blood Marrow Transplant 15:293-305
Niiya, Masami; Endo, Masayuki; Shang, Dezhi et al. (2009) Correction of ADAMTS13 deficiency by in utero gene transfer of lentiviral vector encoding ADAMTS13 genes. Mol Ther 17:34-41
Laje, Pablo; Shang, Dezhi; Cao, Wenjing et al. (2009) Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell-mediated gene therapy. Blood 113:2172-80
Merianos, Demetri J; Tiblad, Eleonor; Santore, Matthew T et al. (2009) Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice. J Clin Invest 119:2590-600
Peranteau, William H; Endo, Masayuki; Adibe, Obinna O et al. (2007) Evidence for an immune barrier after in utero hematopoietic-cell transplantation. Blood 109:1331-3
Peranteau, William H; Endo, Masayuki; Adibe, Obinna O et al. (2006) CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation. Blood 108:4268-74
Ashizuka, Shuichi; Peranteau, William H; Hayashi, Satoshi et al. (2006) Busulfan-conditioned bone marrow transplantation results in high-level allogeneic chimerism in mice made tolerant by in utero hematopoietic cell transplantation. Exp Hematol 34:359-68
Shaaban, Aimen F; Kim, Heung Bae; Gaur, Lasya et al. (2006) Prenatal transplantation of cytokine-stimulated marrow improves early chimerism in a resistant strain combination but results in poor long-term engraftment. Exp Hematol 34:1278-87
Hayashi, Satoshi; Hsieh, Michael; Peranteau, William H et al. (2004) Complete allogeneic hematopoietic chimerism achieved by in utero hematopoietic cell transplantation and cotransplantation of LLME-treated, MHC-sensitized donor lymphocytes. Exp Hematol 32:290-9

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