Chen Yong, Ruetzler Christl, Pandipati Sruthi, Spatz Maria, McCarron Richard M, Becker Kyra, Hallenbeck John M
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15107-12. doi: 10.1073/pnas.2436538100. Epub 2003 Nov 26.
We have demonstrated that induction of mucosal tolerance to E-selectin, a cytokine-inducible adhesion molecule restricted to activating blood vessels, prevents ischemic and hemorrhagic stroke in spontaneously hypertensive, genetically stroke-prone (SHR-SP) rats. We now examine whether mucosal tolerance to E-selectin has protective effects in ischemic brain damage after permanent middle cerebral artery occlusion (MCAO) in SHR-SP rats and whether these effects are related to generation of regulatory T cells. Rats were exposed to intranasal administration of E-selectin every other day for 10 days (single tolerization group) or on two tolerization schedules separated by 11 days (booster tolerization group). Control groups received PBS on corresponding schedules. MCAO was performed 48 h after the last dose of E-selectin or PBS. There were 45.8% and 37.9% (P < 0.05) decreases of infarction volume in the E-selectin booster group compared with the PBS group at 6 and 48 h, respectively. Single tolerization with E-selectin had only a slight trend toward a decrease in infarction volume (6.3%). CD8-positive cells were decreased in brains of E-selectin booster animals (46.6%, P < 0.01) compared with controls; splenocyte-culture supernatant levels of IL-10 were increased (59.3%, P < 0.05) in E-selectin booster animals. A decrease of infarction volume (34%, P < 0.05) was also observed in SHR-SP rats subjected to MCAO after adoptive transfer of splenocytes from E-selectin-tolerized compared with PBS-tolerized donors. The results indicate that, in addition to preventing stroke, mucosal tolerance to E-selectin is cytoprotective. Thus, immunomodulation targeted to activated blood vessel segments can both reduce stroke occurrence and attenuate brain damage if a stroke supervenes.
我们已证明，诱导对E-选择素的黏膜耐受可预防自发性高血压、遗传性易中风（SHR-SP）大鼠的缺血性和出血性中风，E-选择素是一种细胞因子诱导的黏附分子，仅限于激活血管。我们现在研究对E-选择素的黏膜耐受在SHR-SP大鼠永久性大脑中动脉闭塞（MCAO）后对缺血性脑损伤是否具有保护作用，以及这些作用是否与调节性T细胞的产生有关。大鼠每隔一天经鼻给予E-选择素，共10天（单次耐受组），或按两个耐受方案给药，间隔11天（加强耐受组）。对照组按相应方案给予PBS。在最后一剂E-选择素或PBS后48小时进行MCAO。与PBS组相比，E-选择素加强组在6小时和48小时时梗死体积分别减少了45.8%和37.9%（P<0.05）。E-选择素单次耐受仅使梗死体积有轻微下降趋势（6.3%）。与对照组相比，E-选择素加强组动物大脑中的CD8阳性细胞减少（46.6%，P<0.01）；E-选择素加强组动物脾细胞培养上清液中IL-10水平升高（59.3%，P<0.05）。与PBS耐受供体相比，将E-选择素耐受的脾细胞过继转移给接受MCAO的SHR-SP大鼠后，也观察到梗死体积减少（34%，P<0.05）。结果表明，除预防中风外，对E-选择素的黏膜耐受具有细胞保护作用。因此，针对激活血管段的免疫调节既能减少中风的发生，又能在中风发生时减轻脑损伤。
