The overall goal of this Program Project Grant is to develop regimens for allogeneic stem cell transplantation. That have minimal toxicity and are nonmyeloablative. Specifically, our goal is to replace the currently used intensive cytotoxic conditioning programs with immunosuppression aimed at controlling both host verssus-graft (HVG) and GVH reactions and establishing stable mixed donor-host hematopoietic chimerism. The novel transplant approach embraces the concepts that 1) stem cell grafts create their own marrow space through graft-versus-host (GVH) reactions, 2) regimens can be safe enough to be administered in the ambulatory care setting, and 3) toxicities can be low enough to allow inclusion of older patients currently not eligible for transplantation. Further, we hypothesize that mixed chimerism will be sufficient by itself to cure phenotypic expression of inherited hematological diseases and that mixed hematopoietic chimerism may serve as a platform for ~adoptive~ immunotherapy with donor lymphocyte infusions in patients with selected hematological malignancies. Three research projects and three cores are proposed. The first project will extend preliminary observations on mixed chimerism made in a preclinical canine model with the goals of developing the least toxic immunosuppresive regimens and of increasing the safety of donor lymphocyte infusions needed to convert mixed chimerism to complete chimerism. The second project will evaluate the application of mixed hematopoietic chimerism to the treatment of inherited canine and human red blood cell disorders. The third project will establish stable mixed chimerism after nonmyeloablative conditioning as a first therapeutic step for older patients with chronic myelocytic leukemia (66-74 years) and selected B-cell malignancies (50-65 years) who are at high risk of toxicity with conventional transplant regimens. This will be followed by donor lymphocyte infusions to convert mixed to full- donor chimerism and eradicate the underlying malignancy. All three projects will be supported by Core A with regard to protocol design, data monitoring and statistics. Core B will provide chimerism analyses and canine histocompatibility typing, and Core C will provide administrative support.
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