Fc{gamma}Rs Modulate Cytotoxicity of Anti-Fas Antibodies: Implications for Agonistic Antibody-Based Therapeutics

• Published in: The Journal of immunology (1950) 2003-07, Vol.171 (2), p.562-568
• Main Authors: Xu, Yuanyuan, Szalai, Alexander J, Zhou, Tong, Zinn, Kurt R, Chaudhuri, Tandra R, Li, Xiaoli, Koopman, William J, Kimberly, Robert P
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

Development of anti-Fas Abs to treat diseases with insufficient Fas-mediated apoptosis has been limited by concern about hepatotoxicity. We report here that hepatotoxicity elicited by anti-Fas Ab Jo2 is dependent on Fc[gamma]RIIB. Thus, following Jo2 treatment, all Fc[gamma]RIIB super(-/-) mice survived while 80% of wild-type and all FcR-[gamma] super(-/-) mice died from acute liver failure. Microscopic examination suggests that Fc[gamma]RIIB deficiency protects the hepatic sinusoidal endothelium, a cell type that normally coexpresses Fas and Fc[gamma]RIIB. In vitro studies showed that Fc[gamma]RIIB, but not Fc[gamma]RI and Fc[gamma]RIII, on neighboring macrophages substantially enhanced Jo2 mediated apoptosis of Fas expressing target cells. However, Fc[gamma]RI and Fc[gamma]RIII appeared essential for apoptosis-inducing activity of a non-hepatotoxic anti-Fas mAb HFE7A. These findings imply that by interacting with the Fc region of agonistic Abs, Fc[gamma]Rs can modulate both the desired and undesired consequences of Ab-based therapy. Recognizing this fact should facilitate development of safer and more efficacious agonistic Abs.