Lethal effect of the anti-Fas antibody in mice

Abstract

During mammalian development, many cells are programmed to die most mediated by apoptosis. The Fas antigen coded by the structural gene for mouse lymphoproliferation mutation (lpr), is a cell surface protein belonging to the tumour necrosis factor/nerve growth factor receptor family, and mediates apoptosis. The Fas antigen messenger RNA is expressed in the thymus, liver, heart, lung and ovary. We prepared a monoclonal antibody against mouse Fas antigen, which immunoprecipitated the antigen (M(r) 45K) and had cytolytic activity against cell lines expressing mouse Fas antigen. We report here that staining of mouse thymocytes with the antibody indicated that thymocytes from the wild-type and lprcg mice expressed the Fas antigen, whereas little expression of the Fas antigen was found in lpr mice. Intraperitoneal administration of the anti-Fas antibody into mice rapidly killed the wild-type mice but neither lpr nor lprcg mice. Biochemical, histological and electron microscope analyses indicated severe damage of the liver by apoptosis. These findings suggest that the Fas antigen is important in programmed cell death in the liver, and may be involved in fulminant hepatitis in some cases.

JNK activation is not required for Fas-mediated apoptosis

“…To determine whether the Fas signalling pathway led to the activation of JNK in the IL-3 dependent cell line BAF3, we exposed these cells to the agonistic antibody Jo2 immobilized on tissue culture plates (Ogasawara et al, 1993). Fas crosslinking in these cells increased JNK1 and JNK2 phosphorylation ( Figure 1a).…”

Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways

“…Mice usually die within 6 h of receiving a lethal dose of anti-Fas antibody, and Fas lpr / lpr mice that do not have functional Fas are completely resistant to this treatment [11]. The major organ affected is the liver and the massive hepatocyte apoptosis is responsible for the animal death [11].…”

“…Mice usually die within 6 h of receiving a lethal dose of anti-Fas antibody, and Fas lpr / lpr mice that do not have functional Fas are completely resistant to this treatment [11]. The major organ affected is the liver and the massive hepatocyte apoptosis is responsible for the animal death [11]. Furthermore, isolated hepatocytes are susceptible to anti-Fas antibody induced apoptosis in vitro, demonstrating the direct cytotoxic effects of Fas activation in this type of cells [12].…”

In vitro and in vivo delivery of novel anticancer fusion protein MULT1E/FasTI via adenoviral vectors

“…5,9,24 The failure of some tumor cells to die following drug treatment and their resultant resistance to these drugs is due to their failure to undergo apoptosis, as tumors cells have defects in triggering mechanisms of their own death by apoptosis. 26 The toxic side effects observed from the use of FasL or agonistic anti-Fas antibodies in vivo, resulting in a fatal hepatic damage with symptoms similar to fulminant hepatitis 27,28 has encouraged a shift of focus to therapies that would enhance apoptosis by using Fas ligand independent activation of Fas. 26 Therefore, our fusion protein MULT1E/FasTI may be both novel and useful as it combines two different functionalities together into one functional protein.…”