Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects.
Interleukin-18 (IL-18) is a unique cytokine that modulates both T(H)1/T(H)2 responses, but its ability to modulate diseases through induction of T(H)2 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 gamma (IFN-gamma) 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-gamma 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.
Reddy
Pavan
P
Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, MI 48109-0942, USA.
Teshima
Takanori
T
Hildebrandt
Gerhard
G
Williams
Debra L
DL
Liu
Chen
C
Cooke
Kenneth R
KR
Ferrara
James L M
JL
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050800:STAT6 Transcription Factor; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects; D014019:Tissue Donors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology / Q000379:methods
D020382:Interleukin-18; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma