Mj. Petrus et al., An immunoablative regimen of fludarabine and cyclophosphamide prevents fully MHC-mismatched murine marrow graft rejection independent of GVHD, BIOL BLOOD, 6(2A), 2000, pp. 182-189
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.