Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Abstract

Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

Glatiramer acetate attenuates the activation of CD4+ T cells by modulating STAT1 and −3 signaling in glia

“…Efforts have focused on the understanding MS pathogenesis and the development of effective MS therapeutics. Substantial progress has been made in MS research, and therapeutic options have increased in recent years67. However, the exact molecular mechanisms underlying the onset and progression of MS remain largely unknown and a salient challenge.…”

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].…”

IFN-β differentially regulates the function of T cell subsets in MS and EAE

“…natalizumab, fingolimod) or indirectly via broad effects on the immune system (e.g. glatiramer acetate, interferon beta) [7,8]. Moreover, T cell depletion approaches were also evaluated, unfortunately without success.…”

“…Moreover, T cell depletion approaches were also evaluated, unfortunately without success. Anti-CD3-(Muromonab) and anti-CD4-directed therapies (Priliximab) failed to show efficacy in humans, had limited therapeutic potential and/or exerted serious adverse effects [7]. Since interferon beta (IFN-β) preserves its long-term safety and efficacy, it is widely used as first-line treatment for MS. Meta-analysis of clinical trials indicates that IFN-β reduces MS relapses and attenuates novel inflammatory lesions, although many patients do not respond to the treatment [9].…”