Targeted Therapy of Multiple Sclerosis: A Case for Antigen-Specific Tregs

Abstract

Multiple sclerosis is an autoinflammatory condition that results in damage to myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing-remitting disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting potential to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

Keywords: T cell receptor; adoptive T cell therapy; autoimmunity; immunotherapy; multiple sclerosis; regulatory T cells.

Figure 1

The beneficial immunosuppressive and tissue repair mechanisms of actions of T_reg cells in multiple sclerosis. In lymphoid organs, resting T_reg cells will be activated by the cognate antigen presented by Antigen-Presenting Cells (APCs) and elicit immunosuppressive functions, including APC suppression through (i) dampening the costimulatory molecules CD80/86 by CTLA4 binding; (ii) the production of anti-inflammatory cytokines, such as IL-10 and TGF-β; and (iii) scavenging signals and metabolites essential to the survival and functionality of pro-inflammatory cells, as well as suppressing B cell effector functions for high-affinity antibody production [28]. On the other hand, once attracted to the inflammatory CNS, T_reg cells can produce IL-10 and AIM2, which dampens the neuroinflammation, and CCN3, which potentiates oligodendrocyte differentiation for remyelination. The figure was produced by Biorender.com.

Figure 2

Summary of T_reg-based therapy. Several promising sources, including the T_reg cells extracted from the peripheral blood (PB) or umbilical cord blood (UCB) or developed from the fibroblast-to-induced pluripotent stem (iPS) cell developmental pathway. The figure was produced by Biorender.com.