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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

Authors :
Amy K. Ferketich
Michael A. Caligiuri
Samuel Shin
Seth E. Karol
Noah R. Schwind
Brian Becknell
Bradley W. Blaser
Sameek Roychowdhury
Dennis Chang
Bruce R. Blazar
Donna Frances Kusewitt
Source :
Blood. 108:2463-2469
Publication Year :
2006
Publisher :
American Society of Hematology, 2006.

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/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.

Details

ISSN :
15280020 and 00064971
Volume :
108
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi.dedup.....5abd6b005c3b129d03caaf07843a9fb4
Full Text :
https://doi.org/10.1182/blood-2006-04-019059