Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications.

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 T-cell pathways. While the concept of "T-cell-specific therapy" implies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cell-selective 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.