A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease

ACS Nano. 2014 Mar 25;8(3):2148-60. doi: 10.1021/nn405033r. Epub 2014 Feb 27.

Abstract

Targeted immune tolerance is a coveted therapy for the treatment of a variety of autoimmune diseases, as current treatment options often involve nonspecific immunosuppression. Intravenous (iv) infusion of apoptotic syngeneic splenocytes linked with peptide or protein autoantigens using ethylene carbodiimide (ECDI) has been demonstrated to be an effective method for inducing peripheral, antigen-specific tolerance for treatment of autoimmune disease. Here, we show the ability of biodegradable poly(lactic-co-glycolic acid) (PLG) nanoparticles to function as a safe, cost-effective, and highly efficient alternative to cellular carriers for the induction of antigen-specific T cell tolerance. We describe the formulation of tolerogenic PLG particles and demonstrate that administration of myelin antigen-coupled particles both prevented and treated relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a CD4 T cell-mediated mouse model of multiple sclerosis (MS). PLG particles made on-site with surfactant modifications surpass the efficacy of commercially available particles in their ability to couple peptide and to prevent disease induction. Most importantly, myelin antigen-coupled PLG nanoparticles are able to significantly ameliorate ongoing disease and subsequent relapses when administered at onset or at peak of acute disease, and minimize epitope spreading when administered during disease remission. Therapeutic treatment results in significantly reduced CNS infiltration of encephalitogenic Th1 (IFN-γ) and Th17 (IL-17a) cells as well as inflammatory monocytes/macrophages. Together, these data describe a platform for antigen display that is safe, low-cost, and highly effective at inducing antigen-specific T cell tolerance. The development of such a platform carries broad implications for the treatment of a variety of immune-mediated diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens / immunology*
  • Brain / drug effects
  • Brain / immunology
  • Brain / metabolism
  • Cytokines / biosynthesis
  • Drug Carriers / chemistry*
  • Drug Carriers / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Immunosuppression / methods*
  • Lactic Acid / chemistry
  • Lactic Acid / metabolism
  • Maleates / chemistry
  • Mice
  • Nanoparticles / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology
  • Peptide Fragments / therapeutic use
  • Polyethylenes / chemistry
  • Polyglycolic Acid / chemistry
  • Polyglycolic Acid / metabolism
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Recurrence
  • Safety
  • Spinal Cord / drug effects
  • Spinal Cord / immunology
  • Spinal Cord / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology

Substances

  • Antigens
  • Cytokines
  • Drug Carriers
  • Maleates
  • Peptide Fragments
  • Polyethylenes
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • poly(methyl vinyl ether-co-maleic anhydride)