title: An immunoablative regimen of fludarabine and cyclophosphamide prevents fully MHC-mismatched murine marrow graft rejection independent of GVHD.
abstract: The prevention of graft rejection in the setting of nonmyeloablative transplant approaches might be mediated by chemotherapy-induced host immunoablation and by the graft-promoting effects of graft-versus-host disease (GVHD). To evaluate whether host immunoablation alone might allow for alloengraftment, we developed an F1-into-parent murine marrow rejection model using host preparative regimens of lethal total body irradiation (TBI; 950 cGy), sublethal irradiation (600 cGy), or combinations of fludarabine (Flu) and cyclophosphamide (Cy). A preparative regimen selectivity index (SI) was calculated to determine whether host lymphocytes were preferentially depleted relative to myeloid cells (SI = number of host myeloid/number host T lymphoid cells remaining after preparative regimen administration). Saline-treated recipients were assigned an SI value of 1.0. Recipients of lethal TBI had reduced myeloid cells relative to T cells (SI = 0.6). In contrast, all Flu/Cy regimens preferentially depleted host T cells: recipients of Flu (100 mg/kg per day)/Cy (50 mg/kg per day) for 10 days (SI = 28.1); recipients of Flu (100 mg/kg per day)/Cy (100 mg/kg per day) for 10 days (SI = 64.1); and recipients of Flu (100 mg/kg per day)/Cy (50 mg/kg per day) for 19 or 27 days (SI = 74.6). The 10-day regimen of Flu/Cy (50 mg/kg per day) did not severely reduce host T cell numbers, nor did it prevent F1 marrow rejection (<1% chimerism, n = 14). In contrast, the 10-day regimen of Flu/Cy (100 mg/kg per day) reduced T-cell numbers below that of lethal TBI recipients and prevented F1 marrow rejection (11.4% chimerism, n = 15); donor chimerism was predominant in lymphoid cells and was stable through day 240 post-BMT. Additionally, the 19- or 27-day regimen of Flu/Cy, which most selectively depleted host T cells, also prevented F1 marrow rejection (6.3% chimerism, n = 15). These results therefore demonstrate that optimized Flu-containing, immunoablative preparative regimens can prevent fully MHC-disparate marrow rejection independent of GVHD.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Petrus
authors.forename: J F
authors.initials: JF
authors.lastname: Williams
authors.forename: M A
authors.initials: MA
authors.lastname: Eckhaus
authors.forename: R E
authors.initials: RE
authors.lastname: Gress
authors.forename: D H
authors.initials: DH
authors.lastname: Fowler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D019070:Cell Lineage; D003520:Cyclophosphamide / Q000494:pharmacology*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control*; D006086:Graft vs Host Disease; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D006648:Histocompatibility / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014916:Whole-Body Irradiation
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine