An immunoablative regimen of fludarabine and cyclophosphamide prevents fully MHC-mismatched murine marrow graft rejection independent of GVHD

The prevention of graft rejection in the setting of nonmyeloablative transp lant approaches might be mediated by chemotherapy-induced host immunoablati on and by the graft-promoting effects of graft-versus-host disease (GVI-ID) . To evaluate whether host immunoablation alone might allow for alloengraft ment, we developed an F1-into-parent murine marrow rejection model using ho st preparative regimens of lethal total body irradiation (TBI; 950 cGy), su blethal irradiation (600 cGy), or combinations of fludarabine (Flu) and cyc lophosphamide (Cy). A preparative regimen selectivity index (SI) was calcul ated to determine whether host lymphocytes were preferentially depleted rel ative to myeloid cells (SI = number of host myeloid/number host T lymphoid cells remaining after preparative regimen administration). Saline-treated r ecipients were assigned an SI value of 1.0. Recipients of lethal TBI had re duced 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/k g 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 re cipients of Flu (100 mg/kg per day)/Cy (50 mg/kg per day) far 19 or 27 days (SI = 74.6). The 10-day regimen of Flu/Cy (50 mg/kg per day) did not sever ely 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 p er day) reduced T-cell numbers below that of lethal TBI recipients and prev ented F1 marrow rejection (11.4% chimerism, n = 15); donor chimerism was pr edominant in lymphoid cells and was stable through day 240 post-BMT. Additi onally, the 19- or 27-day regimen of Flu/Cy, which most selectively deplete d host T cells, also prevented F1 marrow rejection (6.3% chimerism, n = 15) . These results therefore demonstrate that optimized Flu-containing, immuno ablative preparative regimens can prevent fully MHC-disparate marrow reject ion independent of GVHD.