Therapeutic effect of an anti-Fas ligand mAb on lethal graft-versus-host disease.
Several anti-Fas ligand (FasL) inhibitory mAb (FLIM) were raised and characterized in this study. One, FLIM58, showed more potent neutralizing activity than Fas-Fc, the previously established artificial neutralizing agent for FasL. Several murine models of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation have been used to show that both FasL and perforin, the major effector molecules of cytotoxic T lymphocytes, are involved in this disease. In our GVHD model, FasL rather than perforin was associated with lethality. Administration of FLIM58 or Fas-Fc reduced the weight loss and mortality caused by GVHD, although other signs of GVHD, such as skin lesions, lymphoid hypoplasia and mononuclear cell infiltration in the liver, did not improve significantly. FLIM58 was more effective than Fas-Fc in reducing mortality. Our results demonstrated that neutralizing agents for FasL are therapeutic for lethal GVHD.
Miwa
K
K
Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan.
Hashimoto
H
H
Yatomi
T
T
Nakamura
N
N
Nagata
S
S
Suda
T
T
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D006224:Cricetinae; D003412:Cricetulus; D053222:Fas Ligand Protein; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007116:Immunization, Passive; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins; D054353:Perforin