title: 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.
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.
authors.affiliation: The Ohio State University, Comprehensive Cancer Center, A458 Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210-1214. michael.caligiuri@osumc.edu.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Blaser
authors.forename: Noah R
authors.initials: NR
authors.lastname: Schwind
authors.forename: Seth
authors.initials: S
authors.lastname: Karol
authors.forename: Dennis
authors.initials: D
authors.lastname: Chang
authors.forename: Samuel
authors.initials: S
authors.lastname: Shin
authors.forename: Sameek
authors.initials: S
authors.lastname: Roychowdhury
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: Amy K
authors.initials: AK
authors.lastname: Ferketich
authors.forename: Donna F
authors.initials: DF
authors.lastname: Kusewitt
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000378:metabolism; D020350:Graft vs Tumor Effect; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D019409:Interleukin-15