title: Intensified postgrafting immunosuppression failed to assure long-term engraftment of dog leukocyte antigen-identical canine marrow grafts after 1 gray total body irradiation.
abstract: BACKGROUND
  Late graft rejection after conditioning with 1 Gy of total body irradiation (TBI) was consistently seen in historical dogs given two postgrafting immunosuppressive drugs.
  
  
  METHODS
  Here, 16 dogs were given four different three-drug combinations of cyclosporine, mycophenolate mofetil, sirolimus, or methotrexate after 1 Gy TBI and dog leukocyte antigen-identical marrow grafts. In addition, we assessed the effects of TBI doses of 0.5, 1.0, 2.0, or 3.0 Gy, respectively, on immune functions in six dogs not given marrow grafts.
  
  
  RESULTS
  All dogs showed initial engraftment, 13 rejected, and three had sustained grafts beyond 26 weeks. The dogs with durable grafts had received greater median numbers of nucleated marrow cells compared with the 13 dogs that rejected their grafts (6.14 vs. 3.6 x 10(8) per kg; P=0.03). In a Cox proportional hazard model, which included data from 16 historical dogs, each increase in transplanted marrow cell numbers by 1 x 10(8) per kg decreased the hazard ratio of rejection by 0.5. Decreasing percents of remaining CD3, CD4, and CD8 cells in peripheral blood and lymph nodes were observed with increasing TBI doses. Further, greater suppressions of B-cell- and T-cell-dependent production of IgM and IgG antibodies in response to sheep red blood cell injections were observed after 2 Gy compared with 1 Gy TBI.
  
  
  CONCLUSIONS
  Overall, triple postgrafting immunosuppression after 1 Gy TBI was well tolerated but failed to prevent graft rejection in this model. In vivo radiation studies have shown higher numbers of remaining host lymphocytes and better T-cell-dependent antibody production after 1 Gy compared with 2 Gy TBI.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
authors.forename: Mohamed L
authors.initials: ML
authors.lastname: Sorror
authors.forename: Wendy
authors.initials: W
authors.lastname: Leisenring
authors.forename: Marco
authors.initials: M
authors.lastname: Mielcarek
authors.forename: Frederic
authors.initials: F
authors.lastname: Baron
authors.forename: Razvan
authors.initials: R
authors.lastname: Diaconescu
authors.forename: William J
authors.initials: WJ
authors.lastname: Hogan
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001803:Blood Transfusion; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004285:Dogs; D006084:Graft Rejection; D006085:Graft Survival; D006649:Histocompatibility Antigens / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D012756:Sheep; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D006649:Histocompatibility Antigens