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 Blood, 30 April 2009, Vol. 113, No. 18, pp. 4440-4448.
Prepublished online as a Blood First Edition Paper on January 30, 2009; DOI 10.1182/blood-2008-09-181677.

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TRANSPLANTATION

Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

Arnab Ghosh1,2, Wolfgang Koestner1,2, Martin Hapke1,2, Verena Schlaphoff3, Florian Länger4, Rolf Baumann5, Christian Koenecke6, Markus Cornberg3, Karl Welte2, Bruce R. Blazar7, and Martin G. Sauer1,2

1 Transplantation Research Center and 2 Departments of Pediatric Hematology/Oncology, 3 Gastroenterology/Hepatology, 4 Pathology, 5 Radiation Oncology, 6 Medical Hematology/Oncology, Medizinische Hochschule Hannover, Hannover, Germany; and 7 University of Minnesota Cancer Center and Department of Pediatrics, Division of Pediatric Hematology/Oncology and Blood & Marrow Transplant, Minneapolis

Antigen-presenting cells (APCs) 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 major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs 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 ETCs 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 donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.


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