Megadose stem cell administration as a route to mixed chimerism

To discuss recent innovations for the application of mismatched haploidentical hematopoietic stem cell transplantation as a means to achieve immune tolerance prior to allograft transplantation. We highlight the advantages of utilizing novel 'veto' cells, to facilitate induction of mixed chimerism, under nonmyeloablative conditioning. Haploidentical hematopoietic stem cell transplantation has been used for leukemia patients, where reduction of graft-versus-host disease risk has been routinely attained by depleting grafts of T-cells, and escalated doses of CD34 progenitors (i.e. megadose) to overcome graft rejection. These 'megadose' transplants overcome rejection through a unique immunoregulatory 'veto' capacity. The importance of attaining mixed chimerism for allograft tolerance induction in humans has been highlighted by several studies of combined haploidentical hematopoietic stem cell transplantation and kidney transplants. However, stable chimerism could only by attained by making use of T-cell replete haploidentical hematopoietic stem cell transplantation, posing a significant risk for graft-versus-host or other immune abnormalities. The use of nonalloreactive 'veto' cells, such as anti-third-party central memory CD8 T cells, could potentially overcome this barrier. Achieving stable mixed chimerism after haploidentical hematopoietic stem cell transplantation, key to utilizing transplantation as a prelude for organ tolerance, may be realized by coadministration of 'veto' cells under current nonmyeloablative protocols.