Targeted tolerance in multiple sclerosis: development of transgenic T cell receptor-engineered regulatory T cells recognizing myelin basic proteins.

The therapeutic landscape of MS is constantly evolving, and one could pose the question if we still have unmet needs for the treatment of MS? Nevertheless, despite the availability of improved therapies and the significant advances in the understanding of what triggers disease, patients continue to experience relapses and, in some cases, are exposed to potential life-threatening side-effects. Hence, current challenge is to balance the need to modify the underlying disease pathogenesis and the long-term risks. In this perspective, immunemodulatory cell therapy has brought a new hope for a wide spectrum of diseases. Tregs offer the opportunity to target cells that are potentially involved in the disease progress. Nevertheless, whether Tregs act in an antigen-specific manner remains elusive. Hence, despite the potential that Treg therapy holds, 2 there are still some challenges, not in the least to direct the interaction of Tregs with key disease-associated immune cells in an antigen-specific manner. To address these, the following objectives have been set forth in current project proposal: Our first objective is to select antigen-specific effector T cells by means of tetramer analysis, thereby identifying and cloning a myelin-recognizing TCR. Secondly, we will optimize a clinically safe mRNA electroporation protocol to induce expression of mRNA encoding the TCR in freshly-isolated and expanded Tregs from MS patients. Thirdly, we ensure the stability of the phenotype and suppressive function of TCR-engineered Tregs. In doing so, we will deliver in vitro proof-of-concept of the safety of the approach which is especially important when administering the cells in an inflammatory disease-driven microenvironment. Finally, we will investigate if TCR-transgenic Tregs can modulate ongoing disease processes by investigating their effect on the phenotype and function of DCs from healthy volunteers and MS patients. Ultimately, we envisage that this will foster a durable clinical application of this technology without the risk for general immunosuppression.

Keywords:MULTIPLE SCLEROSIS

Disciplines:Autoimmunity, Inflammation, Neurosciences not elsewhere classified, Cell therapy, Immunomodulation therapy