Delaying transplantation after total body irradiation is a simple and effective way to reduce acute graft-versus-host disease mortality after major H2 incompatible transplantation

Abstract

Background: We have previously reported that delaying histoincompatible transplantation after total body irradiation (TBI) conditioning markedly decreased the mortality of acute graft-versus-host disease (GVHD) in severe combined immunodeficiency mice. However, it was not clear whether the delayed transplantation would affect the final engraftment and acute GVHD mortality in normal hosts.

Methods: BALB/c mice (H2d) were lethally irradiated with 8.5 Gy TBI and transplanted with C57BL/6 (H2d) bone marrow plus spleen cells on the same day (TBI+day 0) or 4 days after TBI conditioning (TBI+day 4).

Results: We again demonstrated that delaying transplantation by 4 days after TBI conditioning markedly reduced acute GVHD mortality in normal hosts after major histoincompatible transplantation. The survival rates were 66% in TBI+day 4 vs. 0% in TBI+day 0 allogeneic transplanted animals by day +60 (P<0.001). Further analysis demonstrated that the 4-day rest between the TBI and allogeneic transplantation broke the interaction of cell/inflammatory tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 cytokine reactions stimulated by TBI and incompatible transplantation. Flow cytometry revealed 97% donor cells in host marrow by 2 weeks in TBI+day 0 transplantation versus 57% in TBI+day 4 transplantation. There was no difference in percentage of donor CD3+ T-cell engraftment between the TBI+day 0 and TBI+day 4 allogeneic transplanted animals. In TBI+day 4 transplantation, the percentage of donor cells in host marrow steadily increased to 74% by day +60 and 93% by day +100.

Conclusions: This 2- to 3-month early mixed chimerism in TBI+day 4 transplanted animals might be related to lower levels of tumor necrosis factor-alpha and IL-6 both of which have been shown to stimulate lymphohematopoiesis and was associated with lower acute GVHD mortality. The data again demonstrated in immunologically normal BALB/c mice that delaying allogeneic transplantation after TBI is a simple and effective way to reduce acute GVHD mortality, achieve satisfactory engraftment and significantly increase overall survival.