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 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.
Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, 216, Japan.
N M
NM
Hong
K
K
Masuko-Hongo
H
H
Sasakawa
T
T
Kato
T
T
Shirai
K
K
Okumura
K
K
Nishioka
T
T
Kobata
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001327:Autoimmune Diseases / Q000628:therapy*; D053222:Fas Ligand Protein; D005260:Female; D018014:Gene Transfer Techniques; D006942:Hypergammaglobulinemia / Q000628:therapy*; D008177:Lupus Vulgaris / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D008232:Lymphoproliferative Disorders / Q000628:therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D019310:Pseudolymphoma / Q000628:therapy*; D013577:Syndrome; D013601:T-Lymphocytes / Q000502:physiology; D014162:Transfection
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins