Induction of Mucosal Tolerance to E-Selectin Prevents Ischemic and Hemorrhagic Stroke in Spontaneously Hypertensive Genetically Stroke-Prone Rats

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Abstract
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. 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. 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. The novel findings in this study support further investigation of immunologic tolerance as applied to the prevention of stroke.