Nonmyeloablative grafts in littermate dogs

点击翻译按钮获取中文摘要

We propose to develop successful non-myeloablative hematopoietic stem cell transplant (HSCT) strategies using both related and unrelated donors in the treatment of patients with severe aplastic anemia, Fanconi anemia, other genetic and acquired disease, T-cell deficiency diseases, and autoimmune diseases. The strategies will vary depending on the underlying diseases for which HSCT is carried out. The unifying principle is to reduce the intensity of the conditioning regimens to levels which are not associated with pronounced pancytopenias and other common sort- and long-term toxicities of conventional conditioning regimens to levels which are not associated with pronounced pancytopenias and other common short- and long-term toxicities of conventional conditioning regimens. A novel aspect of the non- myeloablative HSCT is the use of post-grafting immunosuppression with the anti-metabolite mycophenolate mofetil and the T-cell activation blocker cyclosporine. Preclinical studies in a canine model have shown that the drug combination not only controlled graft-versus-host disease but also suppressed host-versus-graft reactions. The latter finding allowed the elimination of much of the high-dose suppressed host-versus-graft reactions. The latter finding allowed the elimination of much of the high dose-cytotoxic pre-transplant conditioning therapy, otherwise needed for stable allogeneic engraftment. Further canine studies have indicate that "creation of marrow space" by cytotoxic conditioning regimens is unnecessary for stable allogeneic engraftment. We have successfully applied the principles derived from the canine studies to treat elderly and medically infirm patients with hematological malignancies. Here we propose to extend the studies on non-myeloablative conditioning to include patients with non-malignant diseases. For most of the acquired and genetic diseases addressed in this project, persistence of some host immune or hematopoietic cells (mixed donor/host hematopoietic chimerism) would be acceptable without impairing the transplants' ability to cure the patients' underlying disease manifestations. For other patients, including those with autoimmune diseases, mixed chimerism may not suffice, and hematopoiesis may have to be converted to all-donor chimerism with the use of donor lymphocyte infusions.