Development of the lymphocyte-homing modulator against hepatitis

T细胞介导的免疫反应在包括自身免疫性肝炎在内的多种肝损伤中起关键作用。向小鼠注射刀豆蛋白A （Con A）可模拟T细胞介导的肝炎的组织学和病理表型。器官移植中宿主免疫控制的最新进展包括鞘氨醇-1-磷酸（S1P）受体激动剂的开发，如FTY720，它改变淋巴细胞归巢，但不抑制宿主的一般免疫。在此，我们研究了新的S1P受体激动剂KRP-203对Con a诱导的肝损伤模型的影响。在BALB/c小鼠正常肝淋巴细胞中，FTY720和KRP203均能促进淋巴细胞从肝脏向次级淋巴结的隔离，显著减少肝淋巴细胞数量（p<0.05）。基于这一观察，KRP203被应用于Con - a诱导的肝炎模型。KRP203可显著降低Con a处理的肝脏中CD4^+淋巴细胞的数量（p<0.05），并成功降低血清转氨酶升高（p=0.017），从而保护小鼠免受Con a诱导的肝损伤。有趣的是，这种归巢调节较少发生在通过趋化因子受体CXCR4的天然肝T细胞归巢中。因此，S1P受体激动剂优先靶向CXCR4^+CD4^+外周血T淋巴细胞，抑制Con - a诱导的肝炎的发生，提示其治疗T细胞介导的肝损伤的有效性。

T cell-mediated immune responses play a critical role in a variety of liver injuries including autoimmune hepatitis. Injection of concanavalin A (Con A) into mice mimics the histological and pathological phenotype of T cell-mediated hepatitis. Recent advances in host immune control of organ transplantation include the development of sphingosine-1-phosphate (S1P) receptor agonists such as FTY720, which alter lymphocyte homing but do not suppress host general immunity. Herein we examined the effect of the new S1P receptor agonist KRP-203 on the Con A-induced liver damage model. In normal liver lymphocytes of BALB/c mice, both FTY720 and KRP203 promoted lymphocyte sequestering from the liver to secondary lymph nodes and significantly reduced the number of liver lymphocytes (p<0.05). Based on this observation, KRP203 was employed in the Con A-induced hepatitis model. KRP203 markedly reduced the number of CD4^+ lymphocytes that infiltrate Con A-treated liver (p<0.05) and successfully reduced serum transaminase elevation (p=0.017), therefore protecting mice from Con A-induced liver injury. Interestingly this homing modulation less occur in natural hepatic T cell homing through the chemokine receptor, CXCR4. Therefore, S1P receptor agonists preferentially target CXCR4^+CD4^+ peripheral blood T lymphocytes and suppress the occurrence of Con A-induced hepatitis, suggesting their therapeutic usefulness against T cell-mediated hepatic injury.