AMELIORATION OF LYMPHOID HYPERPLASIA AND HYPERGAMMAGLOBULINEMIA IN LUPUS-PRONE MICE (GLD) BY FAS-LIGAND GENE-TRANSFER

We recently demonstrated that the transplantation of wild-type bone ma rrow cells into lupus-prone mice (gld), resulted in the normalization of autoimmune syndromes due to induction of direct elimination of path ogenic cells by apoptosis via Fas/Fas ligand (L) interactions. This fi nding supports the beneficial therapeutic effect of Fas-mediated apopt osis on autoimmunity in gld mice. To further establish the therapeutic effect of Fas-mediated apoptosis on autoimmunity, we investigated the effect of cells transfected with the FasL gene on autoimmune symptoms in gld mice. The FasL transfectants exhibited cytotoxic activity agai nst gld splenocytes via the Fas/FasL system in vitro. In vivo administ ration of irradiated-FasL transfectants induced a reduction in hyperga mmaglobulinemia, the disappearance of lymphoid hyperplasia and of the accumulation of gld cells (B220(+) T-cells). Furthermore, in situ nick end labelling analysis revealed that cells in the spleen and lymph no des frequently underwent apoptosis. These results clearly indicate tha t FasL transfectants induce the apoptosis of the pathogenic cells resp onsible for hypergammaglobulinemia and lymphoid hyperplasia in gld mic e by cell/cell interaction via the Fas/FasL system. Thus, ex vivo gene transfer of FasL may represent a new therapeutic strategy for autoimm unity caused by the FasL dysfunction. (C) 1998 Academic Press.