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.
Keywords:
anti-drug antibodies; immune tolerance; immunotherapy; nanoparticles; rapamycin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens / administration & dosage*
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Antigens / chemistry*
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CD4-Positive T-Lymphocytes / immunology
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Disease Models, Animal
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Encephalomyelitis, Autoimmune, Experimental / therapy
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Factor VIII / immunology
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Female
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Hemocyanins / administration & dosage
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Hemophilia A / immunology
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Hemophilia A / therapy
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Humans
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Hypersensitivity, Delayed / immunology
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Hypersensitivity, Delayed / therapy
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Immune Tolerance*
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Immunity, Humoral
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Immunosuppression Therapy / methods*
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Immunosuppressive Agents / administration & dosage
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Lactic Acid / chemistry
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Mice
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Mice, Inbred BALB C
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Nanocapsules / administration & dosage
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Nanocapsules / chemistry
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Nanoparticles / administration & dosage
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Nanoparticles / chemistry*
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Oligodeoxyribonucleotides / administration & dosage
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology
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Peptides / administration & dosage
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Peptides / chemistry
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Peptides / immunology
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Polyglycolic Acid / chemistry
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Polylactic Acid-Polyglycolic Acid Copolymer
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Proteins / administration & dosage
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Proteins / chemistry
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Proteins / immunology
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Recombinant Proteins / immunology
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Sirolimus / administration & dosage
Substances
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Antigens
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CPG-oligonucleotide
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Immunosuppressive Agents
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Nanocapsules
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Oligodeoxyribonucleotides
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Peptide Fragments
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Peptides
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Proteins
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Recombinant Proteins
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ovalbumin (325-339)
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Polylactic Acid-Polyglycolic Acid Copolymer
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Polyglycolic Acid
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Lactic Acid
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Factor VIII
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Ovalbumin
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Hemocyanins
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keyhole-limpet hemocyanin
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Sirolimus