Effects of anti-Fas antibodies on lymphocytes and other organs: preparation of original and new monoclonal antibodies and amelioration of systemic autoimmune disease

Fifteen and ten years have passed since original anti-human Fas mAb CH-11 with associated apoptosis-inducing activity was prepared in 1984 and reported in 1989, respectively. Fas antigen (FS-7 cell-associated cell surface antigen) has been shown to be a cell surface receptor molecule (Fas) which can introduce apoptosis-inducing signals into Fas-bearing cells. Studies on lpr (lymphoproliferation) and gld (generalized lymphoproliferative disease) mice, which are loss-of-function mutant mice of Fas and Fas ligand (FasL), respectively, show that these mutations are responsible for the early onset of systemic autoimmune disease in MRL mice, suggesting that autoreactive immunocytes are eliminated by the function of Fas/FasL system ("physiological function" of Fas). Fas/FasL system, however, plays an important role in not only prevention but also aggravation of autoimmune disease. Fas/FasL was shown to be involved in the mechanisms responsible for tissue disruption in autoimmune diseases ("pathological function" of Fas). Studies on the in vivo administration of anti-mouse Fas mAbs, Jo2 and RK-8, emphasized pathological and physiological functions of Fas, respectively: Jo2 induces fulminant hepatitis and RK-8 ameliorates systemic autoimmune disease without the induction of fulminant hepatitis. The different in vivo effects of Jo2 and RK-8 coincide well with different target cell specificity of these mAbs in vitro. Similarly, I observed different target cell specificity on anti-human Fas mAbs. In this review, I propose new strategy of therapeutic use of anti-Fas mAb as specific suppressor for activated immune system on autoimmune disease and other diseases.