title: TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
abstract: Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4(-/-)) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4(-/-) mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4(+/+)) mice. In addition, histopathological analyses revealed that in TLR4(-/-)→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4(+/+), TLR4(-/-) mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4(-/-) mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4(+/+) mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4(-/-)→BALB/c than in TLR4(+/+)→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.
authors.affiliation: Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Donghua
authors.initials: D
authors.lastname: He
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Fuming
authors.initials: F
authors.lastname: Zi
authors.forename: Hanying
authors.initials: H
authors.lastname: Bao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jimin
authors.initials: J
authors.lastname: Shi
authors.forename: Xingkui
authors.initials: X
authors.lastname: Xue
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4