The goal of this proposal is to study a new approach to bone marrow transplantation which preserves the graft-versus-leukemia (GVL) effect of allogeneic T cells while avoiding GVHD. This approach involves the co-administration of T cell depleted (TCD) syngeneic marrow to lethally irradiated recipients of allogeneic BMC and treatment with high-dose IL-2 for the first few days following BMT. We have demonstrated that this treatment regimen protects against GVHD, while retaining the GVL effect of allogeneic T cells against the host-type leukemia/lymphoma, EL4. In order to understand the mechanism causing this dissociation of GVHD from GVL effects, the specific aims are to: 1) Evaluate the hypothesis that IL-2 alters lymphocyte circulation patterns so that GVH reactions in the tissues are abrogated while lymphohematopoietic GVH reactions, leading to GVL effects, are not attenuated. This will be accomplished using histologic studies and two-color tissue immunofluorescence; 2) characterize the cell populations which mediate GVL reactions in IL-2-treated mice and compare them to those which mediate GVHD. By selectively depleting allogeneic donor T cell subsets, the hypothesis that different cell populations mediate these two effects, and that only the activity of the subset producing GVHD is attenuated by IL-2 treatment, will be evaluated; 3) determine which types of histocompatibility barriers are most amenable to the anti-GVHD effect of IL-2 plus TCD syngeneic BMC; 4) extend our studies to additional leukemia models in order to determine whether or not a GVL effect against other types of leukemia will also be preserved in animals protected from GVHD by IL-2 plus TCD syngeneic BMC. The results of these studies will help to determine whether or not this novel method of avoiding GVHD could provide a solution to the clinical dilemma wherein prophylaxis of GVHD is often associated with increased rates of leukemic relapse. We shall attempt to extend our studies to a model involving the murine B cell tumor BCL1 in BALB/c mice. In this system we shall attempt allogeneic BMT using a nonmyeloablative conditioning regimen which has recently been shown in this laboratory to permit alloengraftment across complete MHC barriers. We shall evaluate the hypothesis that infusion of donor-type lymphocytes into mixed chimeras of this kind will lead to completely allogeneic chimerism and will be associated with a GVL effect without causing GVHD. Use of this relatively mild conditioning regimen might permit the application of BMT to the treatment of CLL in elderly patients.
