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Megadose stem cell administration as a route to mixed chimerism

Or-Geva, Noga; Reisner, Yair

Current Opinion in Organ Transplantation: August 2014 - Volume 19 - Issue 4 - p 334–341
doi: 10.1097/MOT.0000000000000095
TOLERANCE INDUCTION: Edited by Herman Waldmann

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Correspondence to Yair Reisner, Department of Immunology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7600, Israel. Tel: +972 8 934 4423; fax: +972 8 934 4145; e-mail: yair.reisner@weizmann.ac.il.

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins