title: Delaying DLA-haploidentical hematopoietic cell transplantation after total body irradiation.
abstract: Exposure to accidental or deliberate radiation poses a threat to public health, proving lethal at higher doses in large part because of deleterious effects on marrow. In those cases, allogeneic hematopoietic cell transplantation (HCT) might be required to restore marrow function. Most radiation accident victims will have HLA-haploidentical relatives who could serve as HCT donors. Here, we assessed in a canine HCT model the total body irradiation (TBI) doses after which transplants might be required and successful engraftment would be possible. In an attempt at mimicking the logistical problems likely to exist after radiation accidents, 4-, 8- or 10-day intervals were placed between TBI and HCT. To keep the experimental readout simple, no graft-versus-host disease (GVHD) prevention was administered. All dogs transplanted after a 4-day delay following 700 or 920 cGy TBI successfully engrafted, whereas virtually all those given 450 or 600 cGy rejected their grafts. Transplant delays of 8 and 10 days following 920 cGy TBI also resulted in successful engraftment in most dogs, whereas a delay of 8 days after 700 cGy resulted in virtually uniform graft failure. The time courses of acute GVHD (aGVHD) and rates of granulocyte recovery in engrafting dogs were comparable among dogs regardless of the lengths of delay. In other studies, we showed that most dogs not given HCT survived 700 cGy TBI with intensive supportive care, whereas those given 800 cGy TBI and higher died with marrow aplasia. Thus, DLA-haploidentical HCT was successful even when carried out 4, 8, or 10 days after TBI at or above radiation exposures where dogs survived with intensive care alone.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: Yunchuan
authors.initials: Y
authors.lastname: Ding
authors.forename: Marcello
authors.initials: M
authors.lastname: Rotta
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Peterson
authors.forename: George E
authors.initials: GE
authors.lastname: Sale
authors.forename: Reza
authors.initials: R
authors.lastname: Forough
authors.forename: Eustacia
authors.initials: E
authors.lastname: Zellmer
authors.forename: George E
authors.initials: GE
authors.lastname: Georges
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.forename: Christian S
authors.initials: CS
authors.lastname: Kuhr
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D004285:Dogs; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006084:Graft Rejection / Q000097:blood; D006085:Graft Survival / Q000528:radiation effects*; D006098:Granulocytes / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006649:Histocompatibility Antigens; D008297:Male; D008954:Models, Biological; D020127:Recovery of Function / Q000528:radiation effects*; D013997:Time Factors; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D006649:Histocompatibility Antigens