Dual peptide nanoparticle platform for enhanced antigen-specific immune tolerance for the treatment of experimental autoimmune encephalomyelitis

Abstract

Current therapeutic strategies for autoimmune diseases such as multiple sclerosis (MS) are directed towards nonspecific immunosuppression, which has severe side effects. The induction of antigen-specific tolerance has become an ideal therapy for autoimmune diseases. In this study, we have constructed a dual peptide nanoparticle platform, including the antigen peptide of the primary signal and inhibitory peptide of the co-stimulatory signal, for T-cell activation and to trigger antigen-specific immune tolerance to treat experimental autoimmune encephalomyelitis (EAE), a murine model for MS. The peptide LABL binding with ICAM-1 was encapsulated in PLGA nanoparticles and the antigenic peptide MOG_35–55-KKK was then covalently bonded to the surface of the PLGA nanoparticles. In this way, peptide-loaded PLGA nanoparticles (NPs_LABL+MOG) were developed. When the dual peptide nanoparticles were administered intravenously either prophylactically or therapeutically to MOG_35–55-immunized mice, it completely prevented the occurrence of EAE in the prophylactic therapy trial and decreased inflammatory cell infiltration and the demyelination of the nerve myelin in the spinal cord in both prophylactic and therapeutic trials. In therapeutic experiments especially, the dual peptide nanoparticles a showed stronger inhibitory effect on EAE than the MOG peptide nanoparticles alone. Mechanistically, the dual peptide nanoparticles reduced MHC II and the co-stimulatory molecule CD86 expression of dendritic cells (DCs) on the surface and induced abortive T-cell activation, which eventually led to a decreased infiltration of Th1 and Th17 cells in the central nervous system and showed antigen-specific immune tolerance. The dual peptide nanoparticles have great potential for the treatment of autoimmune diseases by inducing immune tolerance.