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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-08-2566.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2877-2885
TRANSPLANTATION
Pretreatment of donors with interleukin-18 attenuates acute
graft-versus-host disease via STAT6 and preserves graft-versus-leukemia
effects
Pavan Reddy,
Takanori Teshima,
Gerhard Hildebrandt,
Debra L. Williams,
Chen Liu,
Kenneth R. Cooke, and
James
L.M. Ferrara
From the Departments of Internal Medicine and
Pediatrics, University of Michigan Cancer Center, Ann Arbor, MI; and
the Department of Pathology, University of Florida College of Medicine,
Gainesville, FL.
Interleukin-18 (IL-18) is a unique cytokine that modulates
both TH1/TH2 responses, but its ability to
modulate diseases through induction of TH2 cytokines is
unclear. It has been shown to play an important role in allogeneic bone
marrow transplantation (BMT). Because immune responses of
allogeneic BM donors may affect acute graft-versus-host disease (GVHD),
we investigated the effect of pretreating BM transplant donors with
IL-18 on the severity of acute GVHD using a well-characterized
experimental BMT model (BALB/c B6). Pretreatment of allogeneic BM
transplant donors with IL-18 significantly improved survival (80% vs
0%; P < .001), and reduced clinical, biochemical, and
pathologic indices of acute GVHD in BM transplant recipients. IL-18
pretreatment was associated with reduced interferon  (IFN-) and greater IL-4 secretion by donor T cells after BMT. Acute
GVHD mortality was reduced when IL-18 was administered to donors
deficient in IFN- and signal transducer and activator of
transcription 4 (STAT4) but not STAT6 signaling molecules, suggesting a critical role for STAT6 signaling in IL-18's protective effect. IL-18 treatment did not alter donor CD8+ cytotoxic
T-lymphocyte (CTL) activity and preserved graft-versus-leukemia (GVL)
effects after allogeneic BMT (70% vs 10%; P < .01).
Together these data illustrate that pretreatment of donors with IL-18
prior to allogeneic BMT attenuates acute GVHD in a STAT6-dependent
mechanism while preserving GVL effects.
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