Prevention of EAE by PEGylated Antigenic Peptides

Abstract

AbstractThe treatment of autoimmune disorders such as multiple sclerosis (MS) so far relies largely on the use of non-specific immunosuppressive drugs, which are not able to cure the disease. Presently, approaches to induce antigen-specific tolerance e.g. by peptide-based tolerogenic “inverse” vaccines regain interest. We previously have shown that coupling of peptides to carriers can enhance their capacity to induce regulatory T cells in vivo. We here investigated in an experimental autoimmune encephalomyelitis (EAE) model for chronic MS (MOG C57BL/6) whether the tolerogenic potential of immunodominant myelin T cell epitopes can be improved by conjugation to the synthetic carrier polyethylene glycol (PEG). Indeed, preventive administration of the PEGylated antigenic peptide could almost completely protect mice from EAE development, which was accompanied by reduced immune cell infiltration in the central nervous system (CNS). Depletion of Tregs abrogated the protective effect indicating that Tregs play a crucial role in induction of antigen-specific tolerance in EAE. Treatment during the acute phase was safe and did not induce immune activation. However, treatment at the peak of disease was not affecting the disease course, suggesting that either induction of Tregs is not occurring in the highly inflamed situation, or that the immune system is refractory to regulation in this condition. Thus, PEGylation of antigenic peptides is an effective and feasible strategy to improve tolerogenic (Treg-inducing) peptide-based vaccines, but application in overt disease might require modifications or combination therapies that simultaneously suppress effector mechanisms.