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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2940-2947
IMMUNOBIOLOGY
CD95 engagement induces disseminated endothelial cell apoptosis
in vivo: immunopathologic implications
Anne Janin,
Christophe Deschaumes,
Marjan Daneshpouy,
Jérôme Estaquier,
Juliette Micic-Polianski,
Premavathy Rajagopalan-Levasseur,
Khadija Akarid,
Nicolas Mounier,
Eliane Gluckman,
Gérard Socié, and
Jean Claude Ameisen
From the EMI-U 9922 INSERM/Université Paris 7, IFR 02, Hôpital Bichat-Claude Bernard, AP-HP, 75877 Paris; EA
2378 Université Paris 7, Department of Pathology, Hôpital
St-Louis, AP-HP, 75475 Paris; and Department of Hematology-Bone Marrow
Transplant, Hôpital St-Louis, AP-HP, 75475 Paris, France.
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-versus-host 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. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an
inhibitor of caspase-8, the upstream caspase coupled to CD95 death
signaling. Vascular lesions are likely to play an important role in the
pathogenesis of allogeneic immune responses and of other diseases
involving circulating CD95L-expressing cells or smCD95L, and the
prevention of CD95-mediated death signaling in endothelial cells may
have therapeutic implications in these diseases.
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