Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats.
OBJECTIVE
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.
Takeda
Hidetaka
H
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md 20892-4128, USA.
Spatz
Maria
M
Ruetzler
Christl
C
McCarron
Richard
R
Becker
Kyra
K
Hallenbeck
John
J
D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D019040:E-Selectin / Q000008:administration & dosage / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology*; D007322:Instillation, Drug; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D009297:Nasal Mucosa / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D016896:Treatment Outcome
D019040:E-Selectin; D008070:Lipopolysaccharides; D010047:Ovalbumin