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 （Th 1） development was obviously attenuated compared with TLR4＋/＋ mice dendritic cells, and the levels of interferon-T （IFN-γ） and IL-IO, 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.
Yi ZhaoQiuyan LiuLi YangDonghua HeLijuan WangJun TianYi LiFuming ZiHanying BaoYang YangYuanyuan ZhengJimin ShiXingkui XueZhen Cai
