Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats

Background and Purpose-Inflammatory and immune mechanisms can precipitate cerebrovascular thrombosis and hemorrhage Immunologic tolerance can be induced to a specific antigen by intranasal instillation of that antigen Lymphocytes tolerized in this way provide local immunosuppression on restimulation with the same antigen This study tests whether tolerization of lymphocytes to E selectin can suppress local vessel activation and prevent stroke Methods-Spontaneously hypertensive genetically stroke prone rats (n = 113) were distributed among the following studies comparison of ischemic infarcts/intraparenchymal hemorrhages after single or repetitive tolerization schedules with ovalbumin E selectin or PBS comparison of E selectin tolerization- and PBS tolerization-induced suppression of delayed type hypersensitivity in animals subsequently sensitized to E selectin and comparison of PBS- ovalbumin- and E selectin-tolerized groups (after intravenous lipopolysaccharide to activate vessels) regarding transforming growth factor beta1-positive splenocyte counts plasma interferon gamma levels anti human E selectin antibodies endothelial intercellular adhesion molecule 1 and anti-endothelial cell antibodies Results-Nasal instillation of E selectin which is specifically expressed on activated endothelium potently inhibited the development of ischemic and hemorrhagic strokes in spontaneously hypertensive stroke prone rats with untreated hypertension Repeated schedules of tolerization were required to maintain the resistance to stroke Suppression of delayed type hypersensitivity to E selectin and increased numbers of transforming growth factor beta1-positive splenocytes showed that intranasal exposure to E selectin induced immunologic tolerance E selectin tolerization also reduced endothelial activation and immune responses after intravenous lipopolysaccharide as shown by marked suppression of intercellular adhesion molecule 1 expression anti-endothelial cell antibodies on luminal endothelium and plasma interferon gamma levels compared with the control condition Conclusions-The novel findings in this study support further investigation of immunologic tolerance as applied to the prevention of stroke.