An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis

Biomaterials. 2017 Oct:143:79-92. doi: 10.1016/j.biomaterials.2017.07.029. Epub 2017 Jul 24.

Abstract

Antigen-specific treatments are highly desirable for autoimmune diseases in contrast to treatments which induce systemic immunosuppression. A novel antigen-specific therapy has been developed which, when administered semi-therapeutically, is highly efficacious in the treatment of the mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). The treatment uses dual-sized, polymeric microparticles (dMPs) loaded with specific antigen and tolerizing factors for intra- and extra-cellular delivery, designed to recruit and modulate dendritic cells toward a tolerogenic phenotype without systemic release. This approach demonstrated robust efficacy and provided complete protection against disease. Therapeutic efficacy required encapsulation of the factors in controlled-release microparticles and was antigen-specific. Disease blocking was associated with a reduction of infiltrating CD4+ T cells, inflammatory cytokine-producing pathogenic CD4+ T cells, and activated macrophages and microglia in the central nervous system. Furthermore, CD4+ T cells isolated from dMP-treated mice were anergic in response to disease-specific, antigen-loaded splenocytes. Additionally, the frequency of CD86hiMHCIIhi dendritic cells in draining lymph nodes of EAE mice treated with Ag-specific dMPs was reduced. Our findings highlight the efficacy of microparticle-based drug delivery platform to mediate antigen-specific tolerance, and suggest that such a multi-factor combinatorial approach can act to block autoimmunity.

Keywords: Ag-specific; Drug delivery; EAE; Immunotherapy; Multiple sclerosis; PLGA-microparticles.

MeSH terms

  • Animals
  • Antigens / administration & dosage*
  • Antigens / therapeutic use
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Delayed-Action Preparations / chemistry*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Drug Delivery Systems / methods*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Immune Tolerance / drug effects
  • Immunologic Factors / administration & dosage*
  • Immunologic Factors / therapeutic use
  • Lactic Acid / chemistry*
  • Male
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy / methods
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Polyglycolic Acid / chemistry*
  • Polylactic Acid-Polyglycolic Acid Copolymer

Substances

  • Antigens
  • Delayed-Action Preparations
  • Immunologic Factors
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid