Bone marrow transplantation (BMT) is the treatment of choice for a variety of leukemias and other hematologic disorders. Its clinical applicability is limited, however, because most potential recipients lack an appropriate HLA-matched donor and because severe graft-vs-host disease (GVHD) occurs following mismatched transplants. Recent studies in mice have demonstrated that administration of high doses of IL-2 for a short period following MHC- mismatched BMT mediates a potent protective effect against lethal GVHD. Furthermore, this effect was shown to be additive to the protective effect previously demonstrated for T cell depleted syngeneic marrow. The major goal of this proposal is to attempt to extend these findings to BMT across major histocompatibility barriers in miniature swine as a prelude to possible clinical applications. We consider this extension to be extremely important because there are significant differences between rodents and large animals with respect to BMT. In particular, the preparative regimen by which chimerism is routinely achieved in mice is far too toxic for use in most large animals, including human beings. Partially inbred miniature swine have been developed as a large animal preclinical model for studies of transplantation biology and are very similar to man in many parameters related to BMT. In addition, the represent the only large animals in which transplantation across defined major histocompatibility barriers can be reproducibly performed. We therefore propose to: 1) determine the dose- related toxicity of IL-2 in miniature swine, and thereby select the maximum tolerated dose for treatment; 2) examine the effect of this dose of IL-2 on engraftment and GVHD following BMT across selected MHC barriers; 3) attempt fully MHC-mismatched BMT in miniature swine utilizing T cell-depleted autologous marrow plus IL-2; and 4) investigate the cellular subsets mediating GVHD following MHC mismatched BMT, and, if an anti-GVHD effect is observed, evaluate the role of defined host or donor cell populations in the mechanism of this effect. This study represents an important component in our development of miniature swine as a preclinical model for BMT.
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