Bone marrow cell graft engineering: From bench to bedside

Bone marrow transplantation (BMT) has the potential to treat hemoglobinopat hies (sickle cell and thalassemia) autoimmunity (diabetes, lupus, multiple sclerosis, rheumatoid arthritis, Crohn's colitis) and enzyme deficiency sta tes. Graft versus host disease (GVHD) is a major complication and limitatio n to the therapeutic application of BMT. There have been many clinical tria ls and experimental animal models that have attempted to control GVHD throu gh the engineering of the donor bone marrow cells (BMC). Historically, seve ral methods have demonstrated effectiveness in controlling GVHD; however th ey were also associated with a marked increase in the rate of graft failure . Highly purified hematopoietic stem cells (HSC) engraft quite readily in g enetically-matched recipients while they do not engraft as: easily in MHC-d isparate recipients. The numbers of HSC must be increased 100-200 fold in o rder to overcome the allogeneic barrier, We were the first to phenotypicall y and to functionally characterize a novel cell in the bone marrow that ena bles engraftment of highly purified HSC in allogeneic recipients. The disco very of graft facilitating. cell populations has resulted in the restoratio n of the engraftment-potential of purified HSC between genetically-disparat e individuals. The addition of facilitating cells (FC) to T cell-depleted B MC grafts results in allogeneic engraftment without GVHD or graft failure. New strategies of BMC engineering that retain FC and HSC but avoid GVHD hav e allowed successful engraftment in mismatched and older recipients. These techniques have expanded the therapeutic potential of BMT to virtually ever y candidate as: well as to non-malignant diseases in which the morbidity as sociated with conventional BMT could not be accepted. This article reviews the transition of the FC technology from bench to bedside and discuss the p otentially broad-reaching applications of BMT and mixed chimerism.