Evidence for the involvement of CD44 in endothelial cell injury and induction of vascular leak syndrome by IL-2

At sites of chronic inflammation seen during infections, autoimmunity, graf t-vs-host response, and cytokine therapy, endothelial cell injury is known to occur, the exact mechanism of which is unknown. In the current study we used IL-2-induced vascular leak syndrome (VLS) as a model to investigate wh ether cytotoxic lymphocytes use CD44 in mediating endothelial cell injury. Administration of IL-2 to wild-type mice triggered significant VLS in the l ungs and liver. In contrast, in CD44 knockout (KO)mice, IL-2-induced VLS wa s markedly reduced in the lungs and liver. IL-2-treated wild-type and CD44 KO mice had similar levels of perivascular infiltration with lymphocytes in the lungs and liver. This suggested that the decrease in VLS seen in CD44 KO mice was not due to the inability of lymphocytes to migrate to these org ans. Ultrastructural studies demonstrated extensive endothelial cell damage in the lungs and liver of IL-2-treated wild-type, but not CD44 KO, mice. M oreover, CD44-KO mice exhibited a marked decrease in IL-2-induced lymphokin e-activated killer cell activity. The induction of VLS was dependent on the expression of CD44 on immune cells rather than endothelial cells because a doptive transfer of CD44(+), but not CD44(-) spleen cells along with IL-2 i nto CD44 KO mice triggered VLS, The IL-2-induced VLS was blocked by adminis tration of F(ab')(2) of Abs against CD44, The current study demonstrates th at CD44 plays a key role in endothelial cell injury. Blocking CD44 in vivo may offer a novel therapeutic approach to prevent endothelial cell injury b y cytotoxic lymphocytes in a variety of clinical disease models.