Succinylacetone is a seven-
carbon organic ketoacid that we have previously shown to inhibit
tumor allograft rejection as well as the primary antibody response to sheep erythrocytes in rats. Because it appeared to be such a potent
immunosuppressive agent in our initial studies, we evaluated
succinylacetone for its ability to block
graft-vs-host disease (GVHD) in adult F1 rats injected with parental strain spleen cells. Untreated ACE X Lewis F1 rats given Lewis strain spleen cells died of GVHD, with a mean survival of 24 days. By contrast, 62% of F1 rats in the group treated with
succinylacetone survived, and the deaths that occurred in this group occurred significantly later. To confirm this observation and determine whether
succinylacetone would interfere with bone marrow engraftment, lethally irradiated adult Wistar-Furth rats were reconstituted with syngeneic or totally allogeneic Fisher 344 lymphohemopoietic cells consisting of equal numbers of bone marrow and spleen cells. All animals given allogeneic cells without additional immunosuppressive treatment developed severe GVHD and died by day 42. By contrast 92% of the allogeneic cell recipients that had been treated with
succinylacetone were long term survivors. Cytotoxicity typing of peripheral lymphocytes demonstrated greater than 90% donor-type lymphocytes persisting in the
succinylacetone-treated recipients as long as 255 days post-
transplantation. No chronic or late developing acute GVHD was observed even though the animals received
succinylacetone as the sole
immunosuppressant for only 28 days after
transplantation. Furthermore, hemopoietic reconstitution in recipients of syngeneic cells was essentially identical between the control group and the group treated with
succinylacetone. In addition, no gross or histologic evidence for renal, hepatic, cardiovascular, endocrine, or neurologic toxicity was observed in the long term transplant survivors treated with
succinylacetone. These data indicate that
succinylacetone treatment is effective in preventing lethal GVHD in this allogeneic
bone marrow transplantation system while permitting normal hemopoietic reconstitution in the absence of significant chronic toxicity to other major organ systems.