Submitted September 30, 2008
Accepted January 25, 2009
Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft versus leukemia effects across MHC barriers in full chimeras
Arnab Ghosh, Wolfgang Koestner, Martin Hapke, Verena Schlaphoff, Florian Langer, Rolf Baumann, Christian Koenecke, Markus Cornberg, Karl Welte, Bruce Blazar, and Martin Sauer*
Transplantation Research Center, Medizinische Hochschule Hannover, Hannover, Germany
Department of Pediatric Hematology/Oncology, Medizinische Hochschule Hannover, Hannover, Germany
Department of Gastroenterology/Hepatology, Medizinische Hochschule Hannover, Hannover, Germany
Department of Pathology, Medizinische Hochschule Hannover, Hannover, Germany
Department of Radiation Oncology, Medizinische Hochschule Hannover, Hannover, Germany
Department of Medical Hematology/Oncology, Medizinische Hochschule Hannover, Hannover, Germany
University of Minnesota Cancer Center and Department of Pediatrics, Division of Pediatric Hematology/Oncology and Blood & Marrow Transplant, Minneapolis, MN, United States
* Corresponding author; email: sauer.martin{at}mh-hannover.de.
Antigen-presenting cells (APC) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across MHC barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APC in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro generated and expanded T cells (ETC) mediate anti-leukemia effects only when primed on recipient-derived APC. Loading of APC in vitro with leukemia cell-lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETC resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD-rates observed after the transfer of naive DLI. Upon early transfer, GVL effects were more pronounced with ETC but at the expense of significant GVHD. The degree of GVHD was most severe in MC after transfer of ETC, that had been in vitro primed either on non pulsed recipient-derived APC or with donor-derived APC.
