Toll样受体(toll like receptors,TLRs)识别各自的配体,是机体抵抗感染性疾病和肿瘤的第一道防线。TLRs主要在固有性免疫系统细胞表面表达,一些非免疫细胞也表达TLRs;不同TLRs定位于不同的细胞。TLRs信号转导通路分为MyD88依赖性和MyD88非依赖性两种。已证实几种TLRs的激动剂具有抗肿瘤作用,肿瘤细胞表面TLRs的活化也可能对肿瘤生长产生影响。近年来TLRs在血液系统恶性肿瘤如多发性骨髓瘤、白血病和淋巴瘤方面的研究已取得一定进展,多发性骨髓瘤、白血病细胞表达多种TLRs,TLRs激动剂能诱导多发性骨髓瘤细胞发生免疫逃逸,最近白血病的免疫治疗方案中已包含TRLs激动剂,TRLs激动剂用于淋巴瘤的治疗目前正在进行临床试验。
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
