Clinical applications of mixed chimerism

Bone marrow transplantation (BMT) is currently a procedure that is associated with high morbidity and mortality. Thus, the clinical application of this technique is limited to the treatment of life-threatening hematopoietic malignancies. The morbidity and mortality of BMT is mainly related to graft-versus-host disease (GVHD), failure of engraftment, and toxicity related to fully myeloablative conditioning. GVHD can be prevented by T-cell depletion. However, T-cell depletion increases the risk of failure of engraftment. With the identification of a facilitating cell population that enables engraftment of hematopoietic stem cells across major histocompatibility barriers, the dichotomy between GVHD and failure of engraftment has been resolved. If one could overcome the toxicity of conditioning with the development of partially ablative conditioning strategies, BMT could be used for the treatment of a variety of nonmalignant diseases, as well as in the induction of donor-specific transplantation tolerance. This review outlines the development and advantages of partially ablative conditioning strategies and illustrates possible applications of the technique. Forty years ago E.D. Thomas discussed the potential of BMT for treating immunodeficiencies and for the induction of transplantation tolerance. BMT can be viewed as a natural form of gene therapy to replace a defective cell or enzyme with a functional and normally regulated one.