Fc gamma Rs modulate cytotoxicity of anti-Fas antibodies: implications for agonistic antibody-based therapeutics.
Development of anti-Fas Abs to treat diseases with insufficient Fas-mediated apoptosis has been limited by concern about hepatotoxicity. We report here that hepatotoxicity elicited by anti-Fas Ab Jo2 is dependent on FcgammaRIIB. Thus, following Jo2 treatment, all FcgammaRIIB(-/-) mice survived while 80% of wild-type and all FcR-gamma(-/-) mice died from acute liver failure. Microscopic examination suggests that FcgammaRIIB deficiency protects the hepatic sinusoidal endothelium, a cell type that normally coexpresses Fas and FcgammaRIIB. In vitro studies showed that FcgammaRIIB, but not FcgammaRI and FcgammaRIII, on neighboring macrophages substantially enhanced Jo2 mediated apoptosis of Fas expressing target cells. However, FcgammaRI and FcgammaRIII appeared essential for apoptosis-inducing activity of a non-hepatotoxic anti-Fas mAb HFE7A. These findings imply that by interacting with the Fc region of agonistic Abs, FcgammaRs can modulate both the desired and undesired consequences of Ab-based therapy. Recognizing this fact should facilitate development of safer and more efficacious agonistic Abs.
Xu
Yuanyuan
Y
Division of Clinical Immunology and Rheumatology, Department of Medicine and Laboratory for MultiModality Imaging Assessment, University of Alabama, Birmingham, AL 35294, USA. yuanyuan.ma@ccc.uab.edu
Szalai
Alexander J
AJ
Zhou
Tong
T
Zinn
Kurt R
KR
Chaudhuri
Tandra R
TR
Li
Xiaoli
X
Koopman
William J
WJ
Kimberly
Robert P
RP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity*; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D024201:Bystander Effect / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D003601:Cytotoxicity Tests, Immunologic; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007262:Infusions, Intravenous; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D019014:fas Receptor