It has been a long-standing dogma that host sensitization against fully-vascularized organ allografts occurs peripherally within the graft itself. In this report we show that donor-derived MHC class II-positive (Ia+) DL migrate rapidly out of mouse cardiac allografts into the recipients' spleens where they home to the peripheral white pulp and associate predominantly with CD4+ T lymphocytes. This provides a novel route for central sensitization against fully vascularized allografts, and most likely represents a pathway by which immune responses are generated against antigens on blood-borne DL emigrating from peripheral tissues.