Critical Role of TLR9 in Acute Graft-versus-Host Disease

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 o...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2008-11, Vol.181 (9), p.6132-6139
Main Authors: Calcaterra, Claudia, Sfondrini, Lucia, Rossini, Anna, Sommariva, Michele, Rumio, Cristiano, Menard, Sylvie, Balsari, Andrea
Format: Article
Language:English
Subjects:
Acute Disease
Adoptive Transfer
Animals
Bone Marrow Transplantation - immunology
Cells, Cultured
Coculture Techniques
Female
Graft vs Host Disease - genetics
Graft vs Host Disease - immunology
Graft vs Host Disease - mortality
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Radiation Chimera - genetics
Radiation Chimera - immunology
Severity of Illness Index
Survival Analysis
Toll-Like Receptor 9 - deficiency
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - physiology
Transplantation, Homologous
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.181.9.6132