Attenuation of murine graft-versus-host reactivity by azathioprine

The therapeutic effects of azathioprine were evaluated in a murine graft-versus-host (GVH) model. A single high dose (200 mg/kg) of azathioprine, administered to F1 recipients 2 to 3 days after the injection of parental spleen cells, abrogated the ensuing GVH reaction. Lower doses of the drug, even when injected over an extended period of time (14 days), were found to be ineffective. However, high doses of azathioprine failed to protect when F1 recipients were sublethally irradiated or injected with cyclophosphamide before GVH induction, and even the transfer of syngeneic F1 spleen cells immediately after irradiation failed to alter this outcome. Further analysis of the changes that occurred in sublethally irradiated recipients revealed that the protective effect of azathioprine on CBA leads to (CBA x C57BL)F1 GVH reaction was totally abrogated by doses of irradiation as low as 200 rad. Further experiments in which death was used as an indicator of GVH disease showed that lethality could not be reversed in sublethally irradiated F1 recipients by the transfer of syngeneic F1 spleen cells unless approximately 10 days were allowed to elapse between syngeneic reconstitution and GVH induction. Since syngeneic F1 cells from spleen, lymph node, or bone marrow all behaved similarly, it seems likely that the increased severity of GVH reaction induced by prior immunosuppression may not be attributable to a simple cell deletion event.