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.
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.
Xun
C Q
CQ
Department of Medicine, University of Kentucky, and Veterans Affairs Medical Center, Lexington 40536, USA.
Tsuchida
M
M
Thompson
J S
JS
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006086:Graft vs Host Disease / Q000401:mortality* / Q000517:prevention & control; D006183:H-2 Antigens / Q000032:analysis; D007371:Interferon-gamma / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000637:transplantation; D013997:Time Factors; D019172:Transplantation Conditioning; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014916:Whole-Body Irradiation
D006183:H-2 Antigens; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma