title: Low Radiation Dose and Low Cell Dose Increase the Risk of Graft Rejection in a Canine Hematopoietic Stem Cell Transplantation Model.
abstract: The canine hematopoietic stem cell transplantation (HSCT) model has become accepted in recent decades as a good preclinical model for the development of new transplantation strategies. Information on factors associated with outcome after allogeneic HSCT are a prerequisite for designing new risk-adapted transplantation protocols. Here we report a retrospective analysis aimed at identifying risk factors for allograft rejection in the canine HSCT model. A total of 75 dog leukocyte antigen-identical sibling HSCTs were performed since 2003 on 10 different protocols. Conditioning consisted of total body irradiation at 1.0 Gy (n = 20), 2.0 Gy (n = 40), or 4.5 Gy (n = 15). Bone marrow was infused either intravenously (n = 54) or intraosseously (n = 21). Cyclosporin A alone or different combinations of cyclosporine A, mycophenolate mofetil, and everolimus were used for immunosuppression. A median cell dose of 3.5 (range, 1.0 to 11.8) total nucleated cells (TNCs)/kg was infused. Cox analyses were used to assess the influence of age, weight, radiation dose, donor/recipient sex, type of immunosuppression, and cell dose (TNCs, CD34(+) cells) on allograft rejection. Initial engraftment occurred in all dogs. Forty-two dogs (56%) experienced graft rejection at median of 11 weeks (range, 6 to 56 weeks) after HSCT. Univariate analyses revealed radiation dose, type of immunosuppression, TNC dose, recipient weight, and recipient age as factors influencing long-term engraftment. In multivariate analysis, low radiation dose (P < .001) and low TNC cell count (P = .044) were identified as significant independent risk factors for graft rejection. Peripheral blood mononuclear cell chimerism ≥30% (P = .008) and granulocyte chimerism ≥70% (P = .023) at 4 weeks after HSCT were independent predictors of stable engraftment. In summary, these data indicate that even in low-dose total body irradiation-based regimens, the irradiation dose is important for engraftment. The level of blood chimerism at 4 weeks post-HSCT was predictive of long-term engraftment in the canine HSCT model.
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany. Electronic address: sandra.lange@med.uni-rostock.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lange
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Steder
authors.affiliation: Institute for Biostatistics and Informatics in Medicine and Aging Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Änne
authors.initials: Ä
authors.lastname: Glass
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Killian
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wittmann
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Machka
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Werner
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany; Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schäfer
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Catrin
authors.initials: C
authors.lastname: Roolf
authors.affiliation: Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Junghanss
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000528:radiation effects*; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D002452:Cell Count; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D004307:Dose-Response Relationship, Radiation; D000068338:Everolimus / Q000494:pharmacology; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000494:pharmacology; D012189:Retrospective Studies; D012307:Risk Factors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D006680:HLA Antigens; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid
keywords: Allogeneic hematopoietic stem cell transplantation; Chimerism; Dog; Graft rejection; Low-dose irradiation; Nonmyeloablative