Cell death and immune regulation: in vivo application of a novel agonistic monoclonal antibody for death receptor Fas

Abstract

Fas (CD95/Apo-1) is a cell surface death receptor belonging to the tumor necrosis factor receptor super family. Fas can transduce an apoptosis-inducing signal in cells when stimulated by Fas ligand (FasL) or by agonistic anti-Fas monoclonal antibodies. Mice with Fas-defective lymphoproliferation and with FasL-defective generalized lymphoproliferative disease (gld) mutations develop autoimmune disease and lymphoadenopathy, indicating that the death receptor Fas is a functional molecule in eliminating either autoreactive peripheral T lymphocytes and B lymphocytes or tumor cells. On the contrary, Fas has been also regarded to work as an inducer of tissue damage in fulminant hepatitis, graft-versus-host disease and tissue-specific autoimmune disease. In vivo stimulation of Fas by administration of different agonistic anti-mouse Fas monoclonal antibodies (mAbs) also induces opposite biological effects in mice. Administration of antimouse Fas mAb Jo2 killed mice within 5 hours by causing fulminant hepatitis with hemorrhage, while administration of antimouse Fas mAb RK8 to FasL-deficient MRL-gld/gld mice, which never kills mice, not only reduced the autoimmune symptoms including nephritis, arthritis and vasculitis, but also reduced lymphoadenopathy. I shall propose a strategy for therapeutic use of a novel agonistic anti-Fas monoclonal antibody HFE-7A for autoimmune disease including rheumatoid arthritis and other diseases including cancer. Antihuman Fas mAb HFE7A, which cross-reacts with Fas of various mammals, ranging from humans to mice, can induce apoptosis in vitro both in human and mouse Fas-expressing T-cell lines. Moreover, HFE7A shows very interesting in vivo effects of inducing Fas-mediated apoptosis in lymphocytes including mouse thymocytes and abnormal gld T cells and for inhibiting Fas-mediated fulminant hepatitis induced by Jo2. Not only mice, but also monkeys given a high dose of HFE7A never showed liver injury. In vivo therapeutic effects of humanized anti-Fas mAb HFE7A against human rheumatoid arthritis and human adult T-cell leukemia in SCID mice will be also summarized.