Treatment with Multiple-linked Myelin Peptides Encapsulated within Nanoparticles Induces Antigen-specific Tolerance in SJL/J Relapsing-remitting Experimental Autoimmune Encephalomyelitis

Abstract

Abstract Experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a demyelinating disease of the central nervous system (CNS), and serves as a fit-for-purpose pre-clinical model of Multiple Sclerosis (MS). Data show that tolerogenic immune-modifying nanoparticles (TIMPs) encapsulating peptides/proteins is an effective therapeutic that induces antigen-specific tolerance to the encapsulated peptide/protein. The effectiveness of this therapeutic platform has been be demonstrated in multiple mouse models, as well as in a recently completed phase 2 double-blinded placebo-controlled clinical trial for the treatment of celiac disease. While previous EAE studies have utilized single peptides, the present study utilized a polypeptide containing the SJL/J mouse dominant encephalitogenic peptides (PLP139–151, PLP178–191, MBP84–104, and MOG92-10) linked together with intervening capsaicin S cleavage sites. The use of the multiple-linked myelin peptides was produced to achieve broader coverage of myelin-derived epitopes, which will be required for the treatment of MS. The present data show that this multiple-linked myelin peptide emulsified in CFA induced both CD4+ T cell responses and EAE in SJL/J mice similar to PLP139–151/CFA. Our data go on to show that treatment of SJL/J mice with multiple-linked myelin peptide TIMP inhibited both PLP139–151/CFA-induced R-EAE, as well as multiple-linked myelin peptide/CFA-induced EAE. Furthermore, treatment of SJL/J mice with multiple-linked myelin peptide TIMP significantly decreased TH17 cell responses and increased Tr1 cell responses. The present findings suggest that utilizing multiple-linked peptides may be clinically translatable for the treatment of autoimmune disease.