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.