Fas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versushost disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-␣, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-␣. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. IntroductionThe Fas (CD95) protein is a cell surface receptor belonging to the tumor necrosis factor (TNF) receptor family that transduces death signaling on engagement by multimeric Fas ligand (CD95L), either in its membrane-bound form or in its soluble form resulting from cleavage by a putative metalloproteinase. 1,2 Apoptosis induced by inappropriate or excessive expression of CD95L has been proposed as an important pathogenic mechanism in several diseases, involving various organs, tissues, and cell types, and including acute hepatitis, 1,3,4 acute graft-versus-host disease (aGVHD), 5-7 organspecific autoimmune diseases, 8,9 allergic 10 and toxic 11 cutaneous diseases, systemic tissue damage caused by lymphomas and leukemias, 12 and tumor progression. 13 On the other hand, systemic CD95 engagement induced in the mouse by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause tissue damage in a limited range of organs, that is, the liver and the lymphoid organs, through apoptosis induction in only 3 cell types, specifically, hepatocytes, 3,14-16 hepatic sinusoidal endothelial cells, 14,17 and lymphocytes. 16,18 A possible explanation for this discrepancy may be that several diseases in which a role for CD95L-induced apoptosis has been proposed in fact require additional facilitating or effector mechanisms that are not induced in these murine models of systemic CD95 engagement. Alternately, these murine models may involve apoptosis induction in additional cell types and tissues that have not yet been identified. The latter possibility could be consistent with 2 previous reports of sinusoidal endothelial cell death in the hemorrhagic liver of mice injected with agonistic CD95-specific antibodies. 14,17 Although this may be an indirect consequence of the com...