We propose to investigate 4 important questions in the areas of marrow transplantation and total body irradiation (TB1). Answers to these questions have relevance to human marrow transplantation for the treatment of patients with malignant and nonmalignant hematological diseases. We plan to carry out the studies in a well established preclinical model using random bred dogs. The first 3 questions relate to host versus graft reactions and the design of conditioning programs, and the fourth addresses a complication commonly seen after successful engraftment, graft versus host disease (GVHD). With regard to host versus graft """"""""resistance"""""""", we plan to extend our previous studies on the graft enhancing ability of a monoclonal antibody (MAb) directed against CD44. This will include investigations of other anti-CD44 MAbs which, in part, have better cross-reactivity with human cells. We are cloning the gene coding for canine CD44; once sequencing of the cDNA is completed we will attempt to generate products from sub full length clones. These products could be used to determine which of the reactive epitopes is important in resistance to marrow grafts. Other MAbs directed against the leukocyte adhesion family of antigens may be investigated. Restriction fragment length polymorphism analyses of DLA class I and II antigens enable us to ask questions about the role of these antigens in graft resistance in unrelated marrow grafts MAbs to canine natural killer (NK) antigens will become available and will permit us to investigate the role of NK cells in engraftment or resistance. Certain new immunosuppressive agents will be evaluated for their ability to overcome resistance. Results of these studies are important for extending marrow transplantation to include more HLA-nonidentical and unrelated transplant recipients. We plan to explore novel conditioning regiments using MAbs coupled to short lived radioactive isotopes which deposit their energy within a narrow radius. By targeting the radiation with the help of a MAb we hope to avoid the toxicity generally seen with high-dose TBI programs. Also, the more intensive conditioning achieved with this approach is likely to set the stage for more successful application of T-cell depleted marrow grafts. Also we plan to develop improved TBI regimens. We will compare the toxicity and immunosuppressive properties of fractionated and single-dose TBI delivered at high dose rates. These studies have obvious implications for the design of clinical conditioning programs. Finally, we propose to investigate new immunosuppressive agents for prevention and treatment of acute GVHD in dogs. Promising new approaches may then be explored clinically, initially in the setting of steroid- resistant acute GVHD.
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