Development of Peptides to Target Antigen Presenting Cells for Controlling the Immune Response in Experimental Autoimmune Encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human disease multiple sclerosis (MS). In EAE and MS, the immune system recognizes proteins of the myelin sheath as antigenic, and an inflammatory reaction is initiated within the central nervous system (CNS), leading to demyelination of the axons. Current therapies for the treatment of MS are generally non-specific and weaken the global immune system, thus making the individual susceptible to opportunistic infections. The objective of this project is to develop peptides that target myelin-specific antigen presenting cells (APC) in order to modulate the immune response towards the myelin sheath. Bifunctional peptide inhibitors (BPI) are molecules composed of an antigenic peptide and an adhesion peptide that are designed to target the major histocompatibility class-II molecule and adhesion receptors, respectively, on the surface of APC. The simultaneous binding to both receptors on the APC is proposed to hinder the delivery of activation signals to T cells and, therefore, attenuate the inflammatory T cell response. In this study, PLP-BPI, a well-studied BPI molecule, was tested as a peptide vaccine in preventing the onset of EAE as well as for its role in providing protection against blood-brain barrier breakdown during disease. Next, a novel BPI molecule known as PLP-B7AP, which targets costimulatory molecules, was developed and tested for the first time in suppressing EAE. Finally, to provide protection against the diverse pool of antigenic proteins of the myelin sheath, BPI molecules targeting other myelin antigens as well as a multivalent BPI molecule were developed. These novel peptides have consistently demonstrated a shift towards an immuno-tolerant state accompanied by significant suppression of EAE.