Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Roberto A. Maldonado, Robert A. LaMothe, Joseph D. Ferrari, Ai Hong Zhang, Robert J. Rossi, Pallavi N. Kolte, Aaron P. Griset, Conlin O'Neil, David H. Altreuter, Erica Browning, Lloyd Johnston, Omid C. Farokhzad, Robert Langer, David W. Scott, Ulrich H. Von Andrian, Takashi Kei Kishimoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

355 Scopus citations

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.

Original languageEnglish
Pages (from-to)E156-E165
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number2
DOIs
StatePublished - 13 Jan 2015
Externally publishedYes

Keywords

  • Anti-drug antibodies
  • Immune tolerance
  • Immunotherapy
  • Nanoparticles
  • Rapamycin

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