Antigen-specific tolerization approaches in multiple sclerosis

Abstract

Introduction: Inhibition of self-reactive T cells through induction of antigen-specific immune tolerance holds the promise of effective treatment of autoimmune pathology with few side effects and preservation of normal immune functions. In multiple sclerosis (MS) several approaches have been tested already in clinical trials or are currently ongoing with the aim to inhibit myelin-reactive immune responses. Areas covered: This article provides an overview of the recent and ongoing strategies to inhibit specific immune responses in MS, including different applications of myelin peptide-based approaches, T-cell vaccination, DNA vaccination and antigen-coupled cells. Expert opinion: Despite difficulties in translation of antigen-specific therapies in MS, novel approaches have the potential to effectively induce immune tolerance and ameliorate the disease. To improve efficacy of treatments, future trials should include patients in the early phases of the disease, when the autoimmune response is predominant and immune reactivity still focused. The target antigens are not fully defined yet, and robust immunomonitoring assays should developed to provide mechanistic proof of concept in parallel to showing efficacy with respect to inhibiting inflammatory disease activity in the central nervous system (CNS).

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

“…A limited number of self-reactive T cells escape the thymus and are present in the peripheral T-cell repertoire where they might become activated initiating autoimmune diseases. Inhibition of autoreactive T cells through induction of antigenspecific immune tolerance holds the promise of effective treatment of autoimmune pathology with few side effects and preservation of normal immune functions [110]. In MS, a number of different approaches have already been tested in clinical trials or in currently ongoing trials with the aim of inhibiting myelin-reactive immune responses.…”

“…Different administration routes (intravenously, transdermally, intranasally, orally) have been assessed experimentally [111], and while all of them seem to achieve tolerance induction, different pathways seem to be involved, for example elimination of antigen-specific cells by induction of apoptosis or anergy, or induction of tolerogenic antigenspecific cells [110]. A number of attempts have so far been assessed in human trials.…”

“…Altered peptide ligands (APL) are synthetic peptides derived from MHC-binding antigenic peptide and are modified in order to change MHC-TCR binding characteristics, leading to tolerogenic immune responses to the original peptide [110]. These can either be explained by partial activation of T cells, by induction of suppressive Th2 T cells, or by a direct antagonism of peptide and APL [124][125][126].…”

“…A high frequency of IL-10-secreting cells and an increased expression of FoxP3 in Tregs were observed in treated patients. Most patients remained clinically stable and further clinical studies in patients with RRMS [110], pediatric MS (NCT02200718), and SPMS (NCT02057159) have been announced for 2016 (Table 2).…”

The future of multiple sclerosis treatments

“…Consequently, an alternative treatment approach in MS could aim to selectively restore self-tolerance to auto-antigens via immunization [160] and epitope-specific induction of T cell tolerization [161] or specifically by targeting regulatory T cells (Treg) signaling [162]. Antigen-specific therapies in MS have been reviewed [163,164]. A first phase I trial in humans published in 2013 showed that the antigen-coupled cell tolerization in MS is feasible and safe [165].…”