Novel Approaches in the Immunotherapy of Multiple Sclerosis: Cyclization of Myelin Epitope Peptides and Conjugation with Mannan

Abstract

Multiple Sclerosis (MS) is a serious autoimmune disease. The patient in an advanced state of the disease has restrained mobility and remains handicapped. It is therefore understandable that there is a great need for novel drugs and vaccines for the treatment of MS. Herein we summarise two major approaches applied for the treatment of the disease using peptide molecules alone or conjugated with mannan. The first approach focuses on selective myelin epitope peptide or peptide mimetic therapy alone or conjugated with mannan, and the second on immune-therapy by preventing or controlling disease through the release of appropriate cytokines. In both approaches the use of cyclic peptides offers the advantage of increased stability from proteolytic enzymes. In these approaches, the synthesis of myelin epitope peptides conjugated to mannan is of particular interest as this was found to protect mice against experimental autoimmune encephalomyelitis, an animal model of MS, in prophylactic and therapeutic protocols. Protection was peptide-specific and associated with reduced antigen-specific T cell proliferation. The aim of the studies of these peptide epitope analogs is to understand their molecular basis of interactions with human autoimmune T-cell receptor and a MS-associated human leucocyte antigen (HLA)-DR2b. This knowledge will lead the rational design to new beneficial non-peptide mimetic analogs for the treatment of MS. Some issues of the use of nanotechnology will also be addressed as a future trend to tackle the disease. We highlight novel immunomodulation and vaccine-based research against MS based on myelin epitope peptides and strategies developed in our laboratories.

Development of Methamphetamine Conjugated Vaccine through Hapten Design: In Vitro and In Vivo Characterization

“…One can further optimize antibody responses by using self-adjuvanting tricomponent vaccines that include antigen-glycoprotein-universal T helper epitope PADRE and Pam 3 CysSer adjuvant [51][52][53] or the use of nanoparticles [54][55][56]. Previous research on the efficacy and stability of relevant candidate MS vaccine using oxidized mannan conjugated with antigenic epitope peptide MOG35-55 is in line with and supports the findings of this study [57,58].…”

Integration: Gospel for immune bioinformatician on epitope-based therapy

“…On the other hand, autoimmune diseases arise from immune responses to self-antigens and reflect a breakdown in immunological tolerance ( 54 ). Most classical autoimmune diseases have associations with genes in the MHC-II region ( 55 ), leading to the production of autoantibodies ( 56 ) or the activation of CTL cells ( 57 ) to autoantigens. Therefore, pathognomonic autoimmune diseases need to be specifically designed according to the disease mechanism and site of immunoreaction.…”

Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel

“…For example, peptide epitopes of myelin basic protein have been conjugated to R-Man to decrease the proliferation of autoreactive T cells and ameliorate symptoms of multiple sclerosis. 12,13 O-Man, on the other hand, has been conjugated to Mucin 1 for cancer immunotherapy applications to promote cellular immunity to tumor cells and prevent adenocarcinoma reoccurrence. 14,15 Conversely, the combination of Mucin poor immunological response with no substantial formation of cellular immunity, demonstrating the differing biological responses to R-Man and O-Man.…”

“…These mannan bioconjugates can be used in their oxidized form or can be reduced after conjugation, converting aldehydes to hydroxyl groups, to prevent further reactivity. For example, peptide epitopes of myelin basic protein have been conjugated to R-Man to decrease the proliferation of autoreactive T cells and ameliorate symptoms of multiple sclerosis. , O-Man, on the other hand, has been conjugated to Mucin 1 for cancer immunotherapy applications to promote cellular immunity to tumor cells and prevent adenocarcinoma reoccurrence. , Conversely, the combination of Mucin 1 and R-Man lead to a poor immunological response with no substantial formation of cellular immunity, demonstrating the differing biological responses to R-Man and O-Man . These two forms of mannan can be purposefully used to leverage their specific functional properties and control the type of immune response generated.…”