IRRADIATION AND THE IMMUNE SYSTEM

Graft-versus-host disease (GVHD) represent a major complication in allogeneic bone marrow transplantation (BMT) and is characterized by the donor graft responding against recipient HLA and non-HLA antigens. We will study and compare the selective delivery of therapy directly to GVHD-causing cells in vivo using monoclonal antibodies (MoAb) labeled with either ricin toxin A chain (immunotoxins) or the radionuclide yttrium-90. Ricin toxin A chain is a potent catalytic phytotoxin and yttrium-90 is a potent beta-emitting radionuclide. Both have therapeutic potential for antibody-directed cell targeting. Since the nature of cells involved in the effector phase of GVHD is controversial, we will utilize MoAb rendered cytotoxic as tools to define the role of GVHD effector cells in vivo. Our past experience shows that murine GVHD systems can be used as a model for clinical GVHD. Thus, we will use the mouse as an experimental model because toxicity and in vivo efficacy can be detailed in a manner that is not possible in clinical studies. Our preliminary studies show that labeled MoAb will be useful for studying GVHD treatment since immunotoxins can effectively reduce the level of antigen positive cells in vivo and both immunotoxins and radiolabeled antibodies can reduce GVHD in vivo. Thorough studies in the mouse, using MoAb that have counterparts available for human use, will help to establish optimal dose schedules and provide urgently needed information for choosing better MoAb. Another strategy for combating GVHD is to prevent it rather than to treat it once it begins. Our group has been active in the study of GVHD prophylaxis. We have observed that T cell depletion (TCD) using antibody plus complement (C') is effective in preventing GVHD, but increases the incidence of transplant related engraftment problems. Results obtained in our University of Minnesota Bone Marrow Transplant Program are similar to those reported by other institutions. We have devised a unique murine model in which anti-Thy 1+C treatment of donor marrow results in reproducible graft rejection in mismatched recipients analogous to clinical findings in human recipients of T cell depleted marrow. Utilizing engraftment models in conjunction with established GVHD models, we can evaluate new strategies for preventing GVHD without compromising engraftment. Preliminary studies show that treatment of donor marrow with the dipeptide methyl ester L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) prevents GVHD without engraftment problems. Thus, we will study Leu-Leu-OMe pretreatment in attempts to distinguish engraftment-promoting T cells from GVHD-causing T cells in a prophylactic regimen, and as a potential alternative to current TCD techniques.