Compromising Effect of Low Dose-rate Total Body Irradiation on Allogeneic Bone Marrow Engraftment

Abstract

The protraction of total body irradiation (TBI) to a continuous low dose-rate has been investigated for its effect on donor marrow engraftment in murine bone marrow transplant (BMT) models of varying histocompatibility. Three different BMT combinations were used: syngeneic [B6-Gpi-1^a → B6-Gpi-1^b], H-2 compatible allogeneic [BALB.B (H-2^b) → B6 (H-2^b)] and H-2 mismatched allogeneic [BALB/c (H-2^d) → B6 (H-2^b)]. TBI was delivered over a range of doses at either a high (HDR, 40 cGy/min) or low (LDR, 2 cGy/min) dose rate followed by infusion of 10⁷ bone marrow cells from syngeneic or allogeneic donors. The level of donor (Gpi-1^a) engraftment was determined from blood Gpi-typing at different times after TBI and BMT. Radiation dose–response relationships corresponding to long-term haemopoietic engraftment at 20 weeks showed a dose-sparing effect of LDR that became more prominent with increasing genetic disparity between donor and host. For fully allogeneic (H-2 incompatible) BMT, a dose as high as 16 Gy LDR was still not sufficient for achieving chimerism in all recipients. In many cases allogeneic BMT gave transient blood chimerism enabling the recipient to survive the acute effects of high dose TBI with full long-term repopulation from surviving stem cells of the host. Radiation cell survival curves were obtained for the frequency of alloreactive precursors of proliferating T-lymphocytes (pPTL) remaining in the spleen at 1 day after TBI. A radiation dose-sparing effect of LDR was also found for pPTL depletion. These data suggest that radiation damage repair during LDR irradiation in an immunocyte target cell population is mainly responsible for enhanced graft rejection thus rendering protracted TBI less effective for application in clinical allogeneic BMT.