MODULATION OF ADHESION MOLECULES BY CYTOKINES IN-VIVO USING HUMAN SEVERE COMBINED IMMUNODEFICIENT (SCID) MOUSE CHIMERAS/

Endothelial cell-leukocyte interactions involve multiple cell adhesion molecules acting in a programmed and sequential manner to create a le ukocyte-endothelial cell adhesion cascade. To understand this process fully, in vivo models are needed. To accomplish this, we have transpla nted pieces of normal human tissues onto immunodeficient mice to creat e chimeric animals. In one model, human skin is grafted and closely re sembles normal skin histologically. The grafts retain their human vasc ulature and show low baseline expression of E-selectin, vascular cell adhesion molecule-1, and intercellular cell adhesion molecule-1. After intradermal injection of human cytokines, these cell adhesion molecul es are markedly upregulated and an active inflammatory reaction ensues , with migration of murine leukocytes. Intravenous injection of an ant ihuman E-selectin antibody completely inhibits leukocyte accumulation induced by tumor necrosis factor-or but only partially inhibits leukot riene B4-induced inflammation. In a second model, human bronchus was s uccessfully transplanted heterotopically into severe combined immunode ficient mice. Injection of tumor necrosis factor induced upregulation of E-selectin, intercellular-cell adhesion molecule-1, and vascular ce ll adhesion molecule-1 in the submucosal microvessels, with slightly d ifferent kinetics than in the skin. In conclusion, human-severe combin ed immunodeficient chimeric mice represent a useful model system to st udy the regulation and function of human cell adhesion molecules in an in vivo setting.