TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Cell Mol Immunol. 2013 Mar;10(2):165-75. doi: 10.1038/cmi.2012.58. Epub 2012 Dec 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation / adverse effects
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation* / adverse effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / transplantation
  • Toll-Like Receptor 4 / deficiency*
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / physiology
  • Transplantation, Homologous / adverse effects

Substances

  • Tlr4 protein, mouse
  • Toll-Like Receptor 4