title: Notch-Expanded Murine Hematopoietic Stem and Progenitor Cells Mitigate Death from Lethal Radiation and Convey Immune Tolerance in Mismatched Recipients.
abstract: The hematopoietic syndrome of acute radiation syndrome (h-ARS) is characterized by severe bone marrow aplasia, resulting in a significant risk for bleeding, infections, and death. To date, clinical management of h-ARS is limited to supportive care dictated by the level of radiation exposure, with a high incidence of mortality in those exposed to high radiation doses. The ideal therapeutic agent would be an immediately available, easily distributable single-agent therapy capable of rapid in vivo hematopoietic reconstitution until recovery of autologous hematopoiesis occurs. Using a murine model of h-ARS, we herein demonstrate that infusion of ex vivo expanded murine hematopoietic stem and progenitor cells (HSPCs) into major histocompatibility complex mismatched recipient mice exposed to a lethal dose of ionizing radiation (IR) led to rapid myeloid recovery and improved survival. Survival benefit was significant in a dose-dependent manner even when infusion of the expanded cell therapy was delayed 3 days after lethal IR exposure. Most surviving mice (80%) demonstrated long-term in vivo persistence of donor T cells at low levels, and none had evidence of graft versus host disease. Furthermore, survival of donor-derived skin grafts was significantly prolonged in recipients rescued from h-ARS by infusion of the mismatched expanded cell product. These findings provide evidence that ex vivo expanded mismatched HSPCs can provide rapid, high-level hematopoietic reconstitution, mitigate IR-induced mortality, and convey donor-specific immune tolerance in a murine h-ARS model. Stem Cells Translational Medicine 2017;6:566-575.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Filippo
authors.initials: F
authors.lastname: Milano
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Merriam
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Nicoud
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ted A
authors.initials: TA
authors.lastname: Gooley
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Shelly
authors.initials: S
authors.lastname: Heimfeld
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Suzan
authors.initials: S
authors.lastname: Imren
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Delaney
mesh_terms: D054508:Acute Radiation Syndrome / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects*; D006648:Histocompatibility; D006649:Histocompatibility Antigens / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D020127:Recovery of Function; D015398:Signal Transduction; D016038:Skin Transplantation; D013997:Time Factors; D023001:Transplantation Tolerance
chemical_list: D006649:Histocompatibility Antigens; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein
keywords: Hematopoietic-acute radiation syndrome; Mismatched mouse progenitor cells; Notch expansion; Skin grafts; Tolerance induction