TY - JOUR
T1 - 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
AU - Blaser, Bradley W.
AU - Schwind, Noah R.
AU - Karol, Seth
AU - Chang, Dennis
AU - Shin, Samuel
AU - Roychowdhury, Sameek
AU - Becknell, Brian
AU - Ferketich, Amy K.
AU - Kusewitt, Donna F.
AU - Blazar, Bruce R.
AU - Caligiuri, Michael A.
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2006-04-019059
DO - 10.1182/blood-2006-04-019059
M3 - Article
C2 - 16757683
AN - SCOPUS:33749353281
SN - 0006-4971
VL - 108
SP - 2463
EP - 2469
JO - Blood
JF - Blood
IS - 7
ER -