Hong N M, Masuko-Hongo K, Sasakawa H, Kato T, Shirai T, Okumura K, Nishioka K, Kobata T
Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, 216, Japan.
J Autoimmun. 1998 Aug;11(4):301-7. doi: 10.1006/jaut.1998.0204.
We recently demonstrated that the transplantation of wild-type bone marrow cells into lupus-prone mice (gld), resulted in the normalization of autoimmune syndromes due to induction of direct elimination of pathogenic cells by apoptosis via Fas/Fas ligand (L) interactions. This finding supports the beneficial therapeutic effect of Fas-mediated apoptosis 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 against gld splenocytes via the Fas/FasL system in vitro. In vivo administration of irradiated-FasL transfectants induced a reduction in hypergammaglobulinemia, 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 nodes frequently underwent apoptosis. These results clearly indicate that FasL transfectants induce the apoptosis of the pathogenic cells responsible for hypergammaglobulinemia and lymphoid hyperplasia in gld mice by cell/cell interaction via the Fas/FasL system. Thus, ex vivo gene transfer of FasL may represent a new therapeutic strategy for autoimmunity caused by the FasL dysfunction.
我们最近证明，将野生型骨髓细胞移植到狼疮易感小鼠（gld）体内，可使自身免疫综合征恢复正常，这是由于通过Fas/Fas配体（L）相互作用诱导致病性细胞通过凋亡直接清除。这一发现支持了Fas介导的凋亡对gld小鼠自身免疫的有益治疗作用。为了进一步确定Fas介导的凋亡对自身免疫的治疗效果，我们研究了用FasL基因转染的细胞对gld小鼠自身免疫症状的影响。FasL转染细胞在体外通过Fas/FasL系统对gld脾细胞表现出细胞毒性活性。体内给予经辐照的FasL转染细胞可导致高球蛋白血症减轻、淋巴组织增生消失以及gld细胞（B220+T细胞）积聚减少。此外，原位缺口末端标记分析显示，脾脏和淋巴结中的细胞频繁发生凋亡。这些结果清楚地表明，FasL转染细胞通过Fas/FasL系统的细胞/细胞相互作用诱导gld小鼠中导致高球蛋白血症和淋巴组织增生的致病性细胞凋亡。因此，FasL的体外基因转移可能代表了一种针对由FasL功能障碍引起的自身免疫的新治疗策略。
