title: Late failure of autologous marrow grafts in lethally irradiated dogs given anti-class II monoclonal antibody.
abstract: We established a model of canine marrow autografts after 9.2 Gy total body irradiation (TBI) to study the role of class II antigens in hematopoietic stem cell growth and differentiation. Twenty dogs were given 9.2 Gy TBI, marrow, and intravenous (IV) murine anti-class II monoclonal antibody (MoAb). Infusion of 0.6 mg/kg/d of MoAb H81.98.21, an IgG2a reactive with HLA-DR, on days 0 to 4 after TBI did not prevent initial engraftment, but dogs died with late graft failure. MoAb B1F6, an IgG2a reactive with HLA-DR + DP, had no adverse effect on engraftment, although both MoAbs detect antigens on stem cells. The critical time for the effect of MoAbs is the first 4 days after transplantation. Our findings argue against several pathogenetic mechanisms, including removal of MoAb-coated stem cells by the reticuloendothelial system (RES), canine complement-mediated cytotoxic effects on stem cells, antibody-dependent cellular cytotoxicity, and inactivation of MoAb-coated cells by dog anti-mouse antibody. To distinguish between MoAb-induced damage to microenvironment (ME)/accessory cells (AC) and late graft failure from a lack of pluripotent stem cells, three dogs were given TBI, a marrow autograft, and MoAb H81.98.21 on days 0 to 4; one, given thoracic duct cells on day 6, developed graft failure; the other two, given marrow depleted of AC by L-leucyl L-leucine o-methyl ester (Leu-Leu-OMe), had sustained grafts. Findings support the notion that originally transplanted pluripotent stem cells are no longer present on day 6 and that the ME is functional and able to support newly injected stem cells.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
authors.forename: H T
authors.initials: HT
authors.lastname: Greinix
authors.forename: W C
authors.initials: WC
authors.lastname: Ladiges
authors.forename: T C
authors.initials: TC
authors.lastname: Graham
authors.forename: S
authors.initials: S
authors.lastname: Maslan
authors.forename: R F
authors.initials: RF
authors.lastname: Raff
authors.forename: B M
authors.initials: BM
authors.lastname: Sandmaier
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: F G
authors.initials: FG
authors.lastname: Schuening
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
authors.forename: R
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003131:Combined Modality Therapy; D004285:Dogs; D005260:Female; D006084:Graft Rejection / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D007275:Injections, Intravenous; D008297:Male; D014182:Transplantation, Autologous; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II