title: Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease.
abstract: Development of unwanted immune responses against therapeutic proteins is a major clinical complication. Recently, we have shown that exposure of Factor VIII in the presence of phosphatidylserine (PS) induces antigen-specific hyporesponsiveness to Factor VIII rechallenge, suggesting that PS is not immune suppressive, but rather immune regulatory in that PS converts an immunogen to a tolerogen. Since PS is exposed in the outer leaflet during apoptosis, we hypothesize that PS imparts tolerogenic activity to this natural process. Thus, immunization with PS containing liposomes would mimic this natural process. Here, we investigate the immune regulatory effects of PS in inducing tolerance toward recombinant human acid alpha-glucosidase (rhGAA). rhGAA was found to complex with PS liposomes through hydrophobic interactions, and incubation PS-rhGAA with dendritic cells resulted in the increased secretion of transforming growth factor-β. Immunization with PS-rhGAA or O-phospho-L-serine-rhGAA led to a reduction in anti-rhGAA antibody response which persisted despite rechallenge with free rhGAA. Importantly, the titer levels in a majority of these animals remained unchanged after rechallenge and can be considered nonresponders. These data provide evidence that PS liposomes can be used to induce tolerance toward therapeutic proteins, in general.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Schneider
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214. Electronic address: svb@buffalo.edu.
authors.forename: Sathy V
authors.initials: SV
authors.lastname: Balu-Iyer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007114:Immunization / Q000379:methods; D000071497:Immunogenicity, Vaccine / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009930:Organic Chemicals / Q000008:administration & dosage / Q000276:immunology; D010718:Phosphatidylserines / Q000008:administration & dosage / Q000276:immunology*; D000520:alpha-Glucosidases / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D009930:Organic Chemicals; D010718:Phosphatidylserines; C029248:Tolerogen; C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: biotechnology; immunology; liposomes; phospholipids; protein delivery