PREVENTION OF LETHAL GRAFT-VERSUS-HOST DISEASE FOLLOWING ALLOGENEIC BONE MARROW TRANSPLANTATION IN MICE BY SHORT COURSE ADMINISTRATION OF LF 08-0299

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Abstract
We investigated the ability of LF 08-0299, a new immunosuppressive compound, to prevent murine graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). A short term LF 08-0299 treatment at optimal dosage protected more than 75% of recipient mice from lethal GVHD induced either across minor antigens alone or the full H2 barrier. Furthermore, LF 08-0299 still prevented lethal GVHD when treatment was delayed to 10 days post-BMT. Long-term LF 08-0299-treated survivors were free of clinical signs of GVHD, and histopathologic examination of liver, skin, and intestines was normal, demonstrating that recipient mice did not develop chronic GVHD. We assessed the immunocompetence of long-term surviving recipient mice. Results from MLR and CTL assays showed that reactivities against host antigens were weak whereas responses against unrelated H2 antigens were reduced but still preserved. Moreover, in vivo transfer experiments demonstrated that spleen cells from long-term survivors were unable to induce lethal GVHD in irradiated recipients of host origin, while spleen cells injected in irradiated recipients of a host-unrelated H2 were fully competent to induce a lethal GVHD. Together these results indicate that stable chimeric recipient mice were specifically tolerant to host antigens. We further showed that while LF 08-0299 can protect recipient mice from lethal GVHD, it also preserved a graft-versus-leukemia effect when mice were inoculated with P815 tumor cells. These data suggest that LF 08-0299 may be a novel pharmaceutical agent that would prevent GVHD in human unrelated bone marrow transplantation.