Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation.
Administration of IL-11 prevented lethal graft-versus-host disease (GVHD) in a murine bone marrow transplant (BMT) model (B6 --> B6D2F1) across MHC and minor H antigen barriers (survival at day 50: 90 vs 20%, P < 0.001). Surpisingly, IL-11 administration polarized the donor T cell cytokine responses to host antigen after BMT with a 50% reduction in IFNgamma and IL-2 secretion and a 10-fold increase in IL-4. This polarization of T cell responses was associated with reduced IFNgamma serum levels and decreased IL-12 production in mixed lymphocyte cultures (MLC). In addition, IL-11 prevented small bowel damage and reduced serum endotoxin levels by 80%. Treatment with IL-11 also reduced TNFalpha serum levels and suppressed TNFalpha secretion by macrophages to LPS stimulation in vitro. IL-11 thus decreased GVHD morbidity and mortality by three mechanisms: (a) polarization of donor T cells; (b) protection of the small bowel; and (c) suppression of inflammatory cytokines such as TNFalpha. We conclude that brief treatment with IL-11 may represent a novel strategy to prevent T cell-mediated inflammatory processes such as GVHD.
Hill
G R
GR
Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cooke
K R
KR
Teshima
T
T
Crawford
J M
JM
Keith
J C
JC
Brinson
Y S
YS
Bungard
D
D
Ferrara
J L
JL
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D016764:Cell Polarity; D002478:Cells, Cultured; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007371:Interferon-gamma / Q000097:blood; D017370:Interleukin-11 / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis; D007421:Intestine, Small / Q000187:drug effects; D008070:Lipopolysaccharides / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D017370:Interleukin-11; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma