Tolerogenic vaccines for Multiple sclerosis

Abstract

Tolerogenic vaccines represent a new class of vaccine designed to re-establish immunological tolerance, restore immune homeostasis, and thereby reverse autoimmune disease. Tolerogenic vaccines induce long-term, antigen-specific, inhibitory memory that blocks pathogenic T cell responses via loss of effector T cells and gain of regulatory T cell function. Substantial advances have been realized in the generation of tolerogenic vaccines that inhibit experimental autoimmune encephalomyelitis in a preclinical setting, and these vaccines may be a prequel of the tolerogenic vaccines that may have therapeutic benefit in Multiple Sclerosis. The purpose here is to provide a snapshot of the current concepts and future prospects of tolerogenic vaccination for Multiple Sclerosis, along with the central challenges to clinical application.

Keywords: T lymphocytes; autoimmune disease; experimental autoimmune encephalomyelitis; immune; multiple sclerosis; myelin; neuroantigen; therapy; tolerance; vaccine.

Figure 1. Hypothetical model of action for tolerogenic vaccines. Natural homeostatic mechanisms of self tolerance are noted in blue. Endogenous myelin autoantigens and other crossreactive self antigens shape development of the T cell repertoire so that conventional T cells recognize “self” with an efficiency that is below the threshold necessary to drive differentiation of memory/ effector subsets. Endogenous myelin autoantigens also promote the differentiation of regulatory T cell subsets. Together, the two mechanisms (low efficacy recognition of self by conventional T cells and active, dominant inhibitory action of regulatory T cells) prevent differentiation of myelin-specific T cells into memory or effector subsets and thereby prevent autoimmune disease. The mechanism of ‘molecular mimicry’ is represented in red. A crossreactive foreign antigen from a recurrent or chronic infectious pathogen drives crossreactive clones with sufficiently high efficacy to override homeostatic regulatory mechanisms. These high efficiency foreign ‘mimic’ antigens drive the differentiation of myelin-crossreactive T cells into memory/ effector subsets. The potential consequence is the initiation of a potentially self-sustaining autoimmune response against myelin and induction of MS. A potential beneficial effect is that these crossreactive clones may eliminate or suppress the etiological infection and thereby clear the antigenic stimulus of the autoimmune disease. The proposed action of tolerogenic vaccines is represented in green. Tolerogenic vaccines are postulated to reinforce myelin-specific regulatory T cell subsets and cause anergy/ apoptosis of myelin-reactive naïve and memory/ effector T cell subsets, even in the midst of an inflammatory environment. Arrowheads represent stimulatory interactions. Spherical line-ends represent inhibitory actions.