Immunologic aspects of enzyme replacement therapy. An evaluation of the immune response to unentrapped, erythrocyte- and liposome-entrapped enzyme in C3H/HeJ Gush mice.
The ability of autologous erythrocytes and liposomes to provide nonimmunogenic vesicles which protect entrapped enzyme from immunologic surveillance and initiation of an immune response was assessed in C3H/HeJ Gush mice following repeated administration of these vesicles with and without entrapped enzyme. Erythrocyte-entrapped bovine beta-glucuronidase elicited no antibody response detectable by double diffusion, passive hemagglutination, complement-dependent lysis, or time-course experiments. Moreover, erythrocyte entrapment protected the enzyme from circulating antibody in mice previously sensitized with unentrapped enzyme. In contrast, repeated IV injection of negatively-charged liposomes loaded with enzyme induced both humoral and cellular responses. Low levels of antibody to the bovine enzyme were detectable by the double antibody technique; no antibodies to the liposome were detectable by complement lysis. In time-course experiments, significant decreases in tissue recoveries of liposome-entrapped beta-glucuronidase were observed in mice sensitized with enzyme-loaded liposomes compared to the recoveries in unsensitized mice, due in part to the rapid degradation of antigen-antibody complexes. A similarly decreased tissue recovery of liposome-entrapped enzyme was apparent in mice with circulating anti-beta-glucuronidase antibody, indicating the inability of liposomes to protect entrapped protein from immunologic surveillance. The cellular response to the liposome vesicle was characterized by the enhanced phagocytic activity of reticuloendothelial cells in the liver and spleen, and the activation of peritoneal macrophages. These results identify erythrocytes as nonimmunogenic carriers capable of protecting entrapped protein from immunologic surveillance and therefore suitable for enzyme replacement endeavors. However, the demonstration that both buffer- and enzyme-loaded liposomes induce an immune response mandates further investigation of these carriers prior to clinical trials of liposome-entrapped therapeutic agents.
D000818:Animals; D000917:Antibody Formation; D001803:Blood Transfusion; D002417:Cattle; D057487:Enzyme Therapy; D004912:Erythrocytes / Q000378:metabolism*; D005966:Glucuronidase / Q000172:deficiency / Q000627:therapeutic use*; D006386:Hemagglutination Tests; D005779:Immunodiffusion; D007700:Kinetics; D017708:Leukocyte Transfusion; D008081:Liposomes / Q000008:administration & dosage*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D014184:Transplantation, Homologous
D008081:Liposomes; D005966:Glucuronidase