Control of CNS Autoimmunity with Nanoparticles

Background: Multiple sclerosis (MS) is caused by an autoimmune response against the central nervous system (CNS). The immune response is normally controlled by regulatory T cells (Tregs), but Treg deficits characterize autoimmune diseases like MS.  Thus the induction of antigen-specific Tregs is a potential therapeutic approach for autoimmune disorders.  We found that the ligand activated transcription factor aryl hydrocarbon receptor (AHR) controls the differentiation of Treg and pro-inflammatory IL-17-producing Th17 cells.  AHR activation by its mucosal ligand 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) triggers dendritic cells to promote the differentiation of Tregs that suppress experimental autoimmune encephalomyelitis (EAE) , a murine model of MS.  Here we report the use of nanoparticles to co-administer ITE and a peptide containing the encephalitogenic epitope MOG_35-55,to induce tolerogenic DCs and generate CNS-specific Tregs that suppress EAE.

Objectives: To study the use of nanoparticles for the induction of antigen specific tolerance and the arrest of central nervous system (CNS) inflammation.

Methods: We constructed Pegylated gold nanoparticles containing the non-toxic AHR ligand ITE and a peptide coding for the encephalytogenic peptide MOG_35-55.  We studied the effects of the nanoparticles on DCs in culture, and also on the recall response and the development of EAE in mice immunized with MOG_35-55.

Results: Nanoparticles containing ITE and MOG_35-55  induced tolerogenic DCs that showed a reduced ability to drive the polarization of Th1 and Th17 cells, while they promoted the development of FoxP3+ Tregs.  In vivo, nanoparticles containing ITE and MOG_35-55 suppressed the recall response to MOG_35-55, interfering with the differentiation of Th1 and Th17 cells and promoting the differentiation of FoxP3+ Tregs.  Moreover, the administration of nanoparticles containing ITE and MOG_35-55 suppressed the development of EAE.

Conclusions: Nanoparticles are a new tool to reestablish antigen-specific tolerance in MS and other autoimmune disorders.