TY - JOUR
T1 - Critical role of TLR9 in acute graft-versus-host disease
AU - Calcaterra, Claudia
AU - Sfondrini, Lucia
AU - Rossini, Anna
AU - Sommariva, Michele
AU - Rumio, Cristiano
AU - Ménard, Sylvie
AU - Balsari, Andrea
PY - 2008/11/1
Y1 - 2008/11/1
N2 - Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9-/-) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4-/-) mice. The reduced mortality and morbidity in TLR9 -/- mice related with reduced stimulatory activity of TLR9 -/- spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9+/+ into TLR9 -/- and TLR9-/- into TLR9+/+ chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9+/+ cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.
AB - Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9-/-) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4-/-) mice. The reduced mortality and morbidity in TLR9 -/- mice related with reduced stimulatory activity of TLR9 -/- spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9+/+ into TLR9 -/- and TLR9-/- into TLR9+/+ chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9+/+ cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.
UR - http://www.scopus.com/inward/record.url?scp=58749110721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58749110721&partnerID=8YFLogxK
M3 - Article
C2 - 18941203
AN - SCOPUS:58749110721
VL - 181
SP - 6132
EP - 6139
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -