Submitted April 25, 2006
Accepted May 18, 2006
Trans-presentation of donor-derived interleukin 15 is necessary for the rapid onset of acute graft versus host disease but not for graft versus tumor activity
Bradley W Blaser, Noah R Schwind, Seth Karol, Dennis Chang, Samuel Shin, Sameek Roychowdhury, Brian Becknell, Amy K Ferketich, Donna F Kusewitt, Bruce R Blazar, and Michael A Caligiuri*
The Ohio State University, Integrated Biomedical Sciences Graduate Program, USA
The Ohio State University, Department of Internal Medicine, Division of Hematology and Oncology, USA
The Ohio State University, Department of Molecular Virology, Immunology and Medical Genetics, USA
The Ohio State University Comprehensive Cancer Center, Division of Epidemiology, USA
The Ohio State University Comprehensive Cancer Center, Department of Veterinary Biosciences, USA
University of Minnesota Cancer Center and Department of Pediatrics, USA
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, USA
* Corresponding author; email: michael.caligiuri{at}osumc.edu.
The " holy grail" of allogeneic stem cell transplantation is to preserve the graft versus tumor (GVT) effect while eliminating graft versus host disease (GVHD). Endogenous donor-derived IL-15 has been implicated in the pathogenesis of acute GVHD, yet the mechanism by which it impacts this lethal process remains unclear. Using the well-described and clinically relevant C57BL/6 
B6D2F1 murine model of acute GVHD, we demonstrate that in trans presentation of IL-15 by donor bone marrow-derived cells is required for the rapid onset of acute GVHD. Recipients of IL 15-/- C57BL/6 bone marrow cells show diminished type 1 polarization of T cells yet there is no decrease in donor T cell reconstitution. A molecular basis for these findings is provided with the observation that expression of T-bet, the master control gene for type 1 T cell functions, is necessary for IL-15-mediated acute GVHD lethality. Finally, we demonstrate that in the absence of donor-derived IL-15, the GVT effect is maintained. These findings thus establish a mechanism by which endogenous donor-derived IL-15 impacts the pathobiology of acute GVHD and GVT activity.
