title: Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation.
abstract: The immune response of hemophilia A patients to administered FVIII is a major complication that obviates this very therapy. We have recently described the use of synthetic, biodegradable nanoparticles carrying rapamycin and FVIII peptide antigens, to induce antigen-specific tolerance. Herein we test the tolerogenicity of nanoparticles that contains full length FVIII protein in hemophilia A mice, focusing on anti-FVIII humoral immune response. As expected, recipients of tolerogenic nanoparticles remained unresponsive to FVIII despite multiple challenges for up to 6 months. Furthermore, therapeutic treatments in FVIII-immunized mice with pre-existing anti-FVIII antibodies resulted in diminished antibody titers, albeit efficacy required longer therapy with the tolerogenic nanoparticles. Interestingly, durable FVIII-specific tolerance was also achieved in animals co-administered with FVIII admixed with nanoparticles encapsulating rapamycin alone. These results suggest that nanoparticles carrying rapamycin and FVIII can be employed to induce specific tolerance to prevent and even reverse inhibitor formation.
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rossi
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Jeongheon
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. Electronic address: david.scott@usuhs.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D004195:Disease Models, Animal; D005169:Factor VIII / Q000008:administration & dosage* / Q000276:immunology; D006467:Hemophilia A / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D053758:Nanoparticles; D020123:Sirolimus / Q000008:administration & dosage* / Q000276:immunology; D014614:Vaccines, Synthetic
chemical_list: D057134:Antibodies, Neutralizing; D007166:Immunosuppressive Agents; D014614:Vaccines, Synthetic; D005169:Factor VIII; D020123:Sirolimus
keywords: FVIII protein; Hemophilia A; Human; Immune tolerance; Nanoparticles; PLGA; Rapamycin