FLT-3 LIGAND PROVIDES HEMATOPOIETIC PROTECTION FROM TOTAL-BODY IRRADIATION IN RABBITS

Several hematopoietic cytokines have been investigated for their poten tial to provide protection from the lethal consequences of bone marrow aplasia after total body irradiation (TBI). Some can increase the dos e of irradiation tolerated by the animals; none allow endogenous recov ery after doses such as administered in clinical blood or marrow trans plantation. We tested the radioprotective potential of FLT-3 ligand, a n early acting hematopoietic cytokine, alone and in combination with a late acting cytokine, granulocyte-colony stimulating factor (G-CSF). Adult outbred New Zealand White rabbits were submitted to TBI of 1,200 or 1,400 cGy by a Co-60 source. Recombinant human (rh) FLT-3 ligand a t a dose of 500 mu g/kg and/or rhG-CSF at a dose of 10 mu g/kg were ad ministered for 14 days subcutaneously daily, beginning either 2 days b efore or the day after TBI. All control animals given no growth factor s died of aplasia at day 10 (range, 5 to 16). All 8 animals given G-CS F had severe aplasia and 7 died at day 8 (range, 5 to 10); 1 animal su rvived, with G-CSF being administered before TBI. In contrast, 11 of 1 2 animals given FLT-3 ligand, with or without G-CSF, survived. Radiopr otection was best in the group given FLT-3 ligand together with G-CSF before TBI. In these animals median platelet counts were never <10 x 1 0(9)/L and median white blood cell counts never <0.5 x 10(9)/L. These data show that hematopoietic recovery can occur after 1,400 cGy TBI in rabbits, if protected by FLT-3 ligand, and suggest a radioprotective clinical potential of this cytokine. (C) 1998 by The American Society of Hematology.