title: Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance.
abstract: Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Maldonado
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Robert A
authors.initials: RA
authors.lastname: LaMothe
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ferrari
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rossi
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Pallavi N
authors.initials: PN
authors.lastname: Kolte
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Griset
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Conlin
authors.initials: C
authors.lastname: O'Neil
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: David H
authors.initials: DH
authors.lastname: Altreuter
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Erica
authors.initials: E
authors.lastname: Browning
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472;
authors.forename: Lloyd
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; King Abdulaziz University, Jeddah 22254, Saudi Arabia;
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; The David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139;
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115-6017; and The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA 02139.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.affiliation: Selecta Biosciences, Inc., Watertown, MA 02472; kkishimoto@selectabio.com.
authors.forename: Takashi Kei
authors.initials: TK
authors.lastname: Kishimoto
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D005169:Factor VIII / Q000276:immunology; D005260:Female; D006433:Hemocyanins / Q000008:administration & dosage; D006467:Hemophilia A / Q000276:immunology / Q000628:therapy; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000628:therapy; D007108:Immune Tolerance; D056724:Immunity, Humoral; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage
chemical_list: D000941:Antigens; C408982:CPG-oligonucleotide; D007166:Immunosuppressive Agents; D053769:Nanocapsules; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D011994:Recombinant Proteins; C438947:ovalbumin (325-339); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005169:Factor VIII; D010047:Ovalbumin; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; D020123:Sirolimus
keywords: anti-drug antibodies; immune tolerance; immunotherapy; nanoparticles; rapamycin