Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.
Cancer Immunol Immunother. 2014 Mar;63(3):235-45. doi: 10.1007/s00262-013-1504-9. Epub 2013 Dec 15.
Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4(-)) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4(+)) versus TLR4(-) mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35-48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4(-) mice. RILD scores of TLR4(+) mice were higher than TLR4(-) mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy.
Toll 样受体 4（TLR4）是乙型肝炎病毒（HBV）感染和肝损伤免疫反应的重要触发因素。HBV 再激活与 TLR4 依赖性免疫反应的作用可能是预防肝癌放疗后放射性肝疾病（RILDs）的关键因素。本研究分为三个阶段。在初级阶段，在不存在或存在 HBV 感染的情况下，用 30Gy 照射突变型 TLR4（TLR4(-)）小鼠的肝脏。后者通过引入质粒 pAAV/HBV 1.2 来完成。在高级阶段，比较正常 TLR4（TLR4(+)）与 TLR4(-)小鼠的 RILDs。在验证阶段，招募了 28 名在肝切除术前行放疗的肝癌患者。使用距肿瘤 35-48Gy 照射的肝活检标本构建组织微阵列。在小鼠和人类中研究了 HBV 再激活、TLR4 表达和 RILDs 的严重程度。与未照射的 TLR4(-)小鼠相比，照射的 TLR4(-)小鼠观察到更多的 HBV 再激活，但没有明显的 RILD。TLR4(+)小鼠的 RILD 评分高于 TLR4(-)小鼠。在人类中，严重的 RILDs往往发生在 TLR4 表达高的患者中，但在 TLR4 表达低或 HBV 表面抗原表达高的患者中则不然。仅在 12 例 HBV 反应性患者中的 2 例中观察到高 TLR4 表达，但在 HBV 非反应性患者中，有 6 例（P <0.03）观察到高 TLR4 表达。总之，RILDs 与高 TLR4 表达相关，而与 HBV 再激活无关，后者在肝癌放疗后 TLR4 表达高的肝脏中受到抑制。
