Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines

Abstract

Autoimmune T and B cell responses to CNS antigen(s) are thought to drive the pathogenesis of multiple sclerosis (MS), and thus are logical targets for therapy. Indeed, several immunomodulatory agents, including IFN-␤1b, IFN-␤1a, glatiramer acetate, and mitoxantrone, have had beneficial clinical effects in different forms of MS. However, because the available treatments are only partially effective, MS therapy needs to be further improved. Selective (antigen-specific) immunotherapies are especially appealing because in theory they combine maximal efficacy with minimal side effects. Indeed, several innovative immunotherapies have been successfully applied in experimental autoimmune encephalomyelitis. For example, autoreactive T cells can be selectively targeted by means of antigen, T cell receptor, or activation markers. However, experimental autoimmune encephalomyelitis is far from being a perfect approximation of MS because MS is more heterogeneous and the target antigen(s) is (are) not known. Further advances in MS therapy will depend on our growing understanding of the pathogenesis of this still incurable disease.

The molecular basis of neurodegeneration in multiple sclerosis

“…While clinical disease is highly variable between patients with relapsing MS, the clinical course of the disease is surprisingly uniform in patients who have entered the progressive phase. Furthermore, onset of steady disease progression, both in patients with primary or secondary progressive disease, occurs around the same age (age [40][41][42][43][44][45][46][47][48][49][50], irrespective of previous disease severity or course [21,22].…”

“…Thus, when searching medical databases for publications of the last decades related to the pathogenesis of MS, the vast majority of the respective studies describe disease mechanisms in EAE animals. This approach was in part highly valuable, as it uncovered basic mechanisms of immune surveillance of the CNS and the molecular events that allow leukocytes to pass the blood brain barrier and to induce brain inflammation [30,35,46]. Furthermore, it shed light on different pathways of tissue injury triggered by immune reactions in the CNS.…”

Instant effect of soluble antigen on effector T cells in peripheral immune organs during immunotherapy of autoimmune encephalomyelitis

“…It is important to note that high-dose treatment with a particular autoantigen is a negative therapy, one aimed at deleting specific T cells from the immune repertoire. Thus, so long as the identification of individual autoantigens remains an unsolved problem, therapeutic concepts that promote bystander suppression of undefined autoimmune effector T cells, like treatment with APLs, promise a clear advantage (41).…”

Alteration of T helper cell subsets in the optic nerve of experimental autoimmune encephalomyelitis

“…In the present study we take advantage of EAE, model of lesions located predominantly in the optic nerve, to observe the role of the main four T helper cell subsets Th1, Th2, Th17 and Treg during different stages of disease. MS is an autoimmune disease of the CNS that perhaps is mediated in part by T cells (16). Historically, Th1 and Th2 cells have been characterized as two classic CD4 + T cell subsets that secrete pro-inflammatory cytokines, such as IFN-Á, or anti-inflammatory cytokines, such as IL-4, IL-5, IL-10 and IL-13, respectively.…”

“…Development of ON after induction of EAE suggests an autoimmune origin of the optic nerve inflammation observed in MS. Previous studies have demonstrated that MS is an autoimmune disease of the central nervous system (CNS) that appears to be mediated in part by T cells (16). Some studies have shown that regulatory T cells (Treg) play a critical role in the progression of the disease (17).…”