T he ability of circulating white blood cells to enter inflamed tissues is mediated by specific cell adhesion molecules thought to be expressed in a programmed and sequential manner to form an "adhesion cascade." Because of the complexity of this process, it is becoming increasingly important to develop in vivo models. Two major problems have limited the utility of current animal models. The first is the inability of many of the antibodies developed against cell adhesion molecules in human cell culture models to cross-react in animals. The second is the uncertainty in extrapolating animal (particularly rodent) findings to humans. To circumvent these problems, full thickness human skin grafts were transplanted onto immunodeficient (severe combined immunodeficient) mice. After 4-6 wk, the transplanted skin grafts closely resembled normal skin histologically and maintained their human vasculature as determined by immunohistochemical staining with human-specific endothelial cell markers. Intradermal injection of tumor necrosis factor-alpha resulted in the reversible upregulation of the leukocyte-endothelial adhesion molecules E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, and in an active inflammatory reaction with migration of murine leukocytes into cytokine-injected areas. These results indicate that the severe combined immunodeficient mouse/human skin transplant model provides a useful in vivo system in which to study human endothelium during the process of inflammation.