The present invention provides a method for reducing stroke-related tissue damage by treating a mammal with E-selectin. Preferably, this treatment induces E-selectin tolerance in the mammal. Another aspect of the invention is a method for inducing E-selectin tolerance in a mammal through intranasal administration of E-selectin, preferably including booster administrations. The present methods are especially adapted for use in patients at increased risk of stroke or who may become at increased risk of stroke.