Radiation Dose-Fractionation and Dose-Rate Relationships for Long-Term Repopulating Hemopoietic Stem Cells in a Murine Bone Marrow Transplant Model

Fractionated and low-dose-rate total-body irradiation (TBI) were compared with single-dose high-dose-rate TBI for induction of long-term hemopoietic chimerism in a murine syngeneic bone marrow transplantation model. At 5 months after TBI and bone marrow transplantation, the degree of stable blood chimerism was determined from the proportion of stem cell-derived donor (${\rm B}6\text{-}{\rm Gpi}\text{-}1^{{\rm a}}$) and host (${\rm B}6\text{-}{\rm Gpi}\text{-}1^{{\rm b}}$) blood erythrocytes. This end point was used to construct radiation dose-response curves for long-term donor marrow engraftment corresponding to ablation of primitive bone marrow stem cells of the host. Increasing dose fractionation and decreasing dose rate had the effect of restoring host hemopoiesis and required higher TBI doses for equal donor engraftment. Most of the dose recovery occurred within the first 6 h between fractions, consistent with the kinetics of sublethal damage repair. The late chimerism data were fitted to the linear-quadratic model using indirect and direct analysis for a fixed threshold response. Both analyses gave relatively low α/β ratios (below 2 Gy), within the range normally seen in late-responding tissues. The dose-rate data gave a repair half-time of 2 h as estimated by the incomplete-repair model. These estimates contrast with the much higher α/β values and lower repair half-times derived from acute hemopoietic failure as indicated by${\rm LD}_{50/30}$, with the implication that separate target cell populations with differing radiosensitivities are involved in these two bone marrow end points.