Journal Article

Peptide-Conjugated Nanoparticles Reduce Positive Co-stimulatory Expression and T Cell Activity to Induce Tolerance

Shea, Lonnie D., Kuo, Robert, Saito, Eiji, Miller, Stephen D.

2017

Overview

Targeted approaches to treat autoimmune diseases would improve upon current therapies that broadly suppress the immune system and lead to detrimental side effects. Antigen-specific tolerance was induced using poly(lactide-co-glycolide) nanoparticles conjugated with disease-relevant antigen to treat a model of multiple sclerosis. Increasing the nanoparticle dose and amount of conjugated antigen both resulted in more durable immune tolerance. To identify active tolerance mechanisms, we investigated downstream cellular and molecular events following nanoparticle internalization by antigen-presenting cells. The initial cell response to nanoparticles indicated suppression of inflammatory signaling pathways. Direct and functional measurement of surface MHC-restricted antigen showed positive correlation with both increasing particle dose from 1 to 100 μg/mL and increasing peptide conjugation by 2-fold. Co-stimulatory analysis of cells expressing MHC-restricted antigen revealed most significant decreases in positive co-stimulatory molecules (CD86, CD80, and CD40) following high doses of nanoparticles with higher peptide conjugation, whereas expression of a negative co-stimulatory molecule (PD-L1) remained high. T cells isolated from mice immunized against myelin proteolipid protein (PLP139–151) were co-cultured with antigen-presenting cells administered PLP139–151-conjugated nanoparticles, which resulted in reduced T cell proliferation, increased T cell apoptosis, and a stronger anti-inflammatory response. These findings indicate several potential mechanisms used by peptide-conjugated nanoparticles to induce antigen-specific tolerance. Peptide-conjugated nanoparticles induce antigen-specific tolerance in models of autoimmunity. Kuo et al. investigated cellular and molecular mechanisms of antigen-presenting cells following nanoparticle internalization. Increasing peptide conjugation and delivering higher nanoparticle doses both contributed to enhanced antigen presentation, as well as reductions in co-stimulatory expression and effector T cell responses.

• Publisher: Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
• Subject: Animals / Antigen presentation / Antigen-presenting cells / Antigen-Presenting Cells - drug effects / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - pathology / antigen-specific tolerance / Antigens - chemistry / Antigens - immunology / Antigens - pharmacology / Apoptosis / Autoimmune diseases / B7-1 Antigen - genetics / B7-1 Antigen - immunology / B7-2 Antigen - genetics / B7-2 Antigen - immunology / CD40 antigen / CD40 Antigens - genetics / CD40 Antigens - immunology / CD80 antigen / CD86 antigen / Cell proliferation / Cytokines / Delayed-Action Preparations - administration & dosage / Delayed-Action Preparations - chemistry / Dendritic cells / Disease / Encephalomyelitis, Autoimmune, Experimental - genetics / Encephalomyelitis, Autoimmune, Experimental - immunology / Encephalomyelitis, Autoimmune, Experimental - pathology / Encephalomyelitis, Autoimmune, Experimental - therapy / Female / Gene Expression / Immune system / immune tolerance / Immune Tolerance - drug effects / Immunoconjugates - chemistry / Immunoconjugates - metabolism / Immunoconjugates - pharmacology / Immunological tolerance / Inflammation / Internalization / Localization / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Mice / Mice, Inbred C57BL / Multiple sclerosis / Myelin / Myelin proteolipid protein / Myelin Proteolipid Protein - chemistry / Myelin Proteolipid Protein - immunology / Myelin Proteolipid Protein - pharmacology / Nanoparticles / Nanoparticles - administration & dosage / Nanoparticles - chemistry / Original / Ovalbumin - chemistry / Ovalbumin - immunology / Ovalbumin - pharmacology / Particle Size / PD-L1 protein / Peptides / PLG nanoparticles / PLGA / Poly(lactide-co-glycolide) / Polyglactin 910 - chemistry / Polyglactin 910 - metabolism / Primary Cell Culture / Proteolipid protein / Spleen - drug effects / Spleen - immunology / Spleen - pathology / Studies / T cell receptors / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - pathology / tolerance induction mechanism / Transcription factors