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Chimerism

Suzanne T. Ildstad

Louisville, KY, United States

Solid organ, vascularized composite tissue, and islet transplantation currently require nonspecific immunosuppressive agents indefinitely for graft maintenance. These agents have significant toxicities, including nephrotoxicity, opportunistic infections, increased rate of malignancy, diabetes, and hypertension. Approaches to induce tolerance are therefore being pursued. It has been known for over 50 years that bone marrow chimerism induces tolerance to transplanted organs, cells, and tissues. The chimerism assoiciated with tolerance is robust and is to date the only approach that has translated successfully form mice to nonhuman primates to humans. However, the requirement for close HLA matching and toxicity of ablative bone marrow transplantation has limited the widespread application of this approach to date. This presentation will review the current status of chimerism and tolerance initiatives underway and update outcomes in an active clinical program addressing kidney/hematopoietic stem cell transplant (HSCT) recipients, metachromatic leukodystrophy, and sickle cell disease transplant in which we have safely established durable chimerism in highly mismatched donor/recipient pairs. The induction of donor-specific tolerance through durable chimerism in mismatched recipients while avoiding graft-versus-host disease (GVHD) would impact organ and tissue recipients as well as for individuals with hemoglobinopathies, inherited metabolic disorders, and autoimmune disorders.