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(Stroke. 2002;33:2156.)
© 2002 American Heart Association, Inc.

Expedited Publication

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

Hidetaka Takeda, MD, PhD; Maria Spatz, MD; Christl Ruetzler, BA; Richard McCarron, PhD; Kyra Becker, MD John Hallenbeck, MD

From the Stroke Branch (H.T., M.S., C.R., J.H.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md; the Resuscitative Medicine Department (R.M.), Naval Medical Research Center, Silver Spring, Md; and the Department of Neurology (K.B.), Harborview Medical Center, Seattle, Wash. Dr Takeda is now at the Department of Neurology, Keio University School of Medicine, Tokyo, Japan.

Correspondence to John M. Hallenbeck, MD, Stroke Branch, NINDS, NIH, Bldg 36, Room 4A03, 36 Convent Dr, MSC 4128, Bethesda, MD 20892-4128. E-mail Hallenbj{at}ninds.nih.gov

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-ß1–positive splenocyte counts, plasma interferon- 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-ß1–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- 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.

Editorial Comment

Nili Feuerstein, PhD, Guest Editor¹; Steven Goldman, PhD, Guest Editor² Giora Feuerstein, MD, MSc, Guest Editor³

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