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, Michael A. Caligiuri

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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 interleukin 15 (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/63 → 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.

Original languageEnglish (US)
Pages (from-to)2463-2469
Number of pages7
JournalBlood
Volume108
Issue number7
DOIs
StatePublished - Oct 1 2006

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