Current status of the immunomodulation and immunomediated therapeutic strategies for multiple sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and CD4(+) T cells form the core immunopathogenic cascade leading to chronic inflammation. Traditionally, Th1 cells (interferon-γ-producing CD4(+) T cells) driven by interleukin 12 (IL12) were considered to be the encephalitogenic T cells in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Currently, Th17 cells (Il17-producing CD4(+) T cells) are considered to play a fundamental role in the immunopathogenesis of EAE. This paper highlights the growing evidence that Th17 cells play the core role in the complex adaptive immunity of EAE/MS and discusses the roles of the associated immune cells and cytokines. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS discussed in this paper.

Figure 1

Current schedule of T-helper-cell differentiation. When naïve CD4⁺TCRαβ ⁺ T lymphocytes, classified by their low expression of CD44, absence of CD25, and high levels of CD62L, encounter their cognate antigens, they can differentiate into several previously identified effector subsets. It is likely that several “master” transcription factors, individually required for T-cell differentiation towards one of the end effector stages, are initially expressed upon engagement of the TCR with costimulatory receptors. Each transcription factor drives a specific set of genes required for lineage commitment and the expression of signature cytokines and negatively affects alternative pathways. However, the local microenvironment is the driving force that determines the outcome of the differentiation course. Th1 cells are established in the presence of IFNγ and IL12 and signaling via STAT1 and STAT4, resulting in the expression of the master transcription factor T bet. Th2 cells depend on IL4 and STAT6 for the increased expression of GATA3, whereas the simultaneous presence of TGFβ results in the development of Th9 cells, utilizing an undefined master transcription factor. The presence of TGFβ, with IL2 signaling via STAT5, is known to generate, at least in vitro, inducible Treg, which utilize FOXP3 like those Treg generated in the thymus. Again, it is TGFβ in combination with IL6 signaling via STAT3 that drives the expression of RORγt, resulting in the differentiation of Th17 cells. However, the initiation of the developmental program of these T helper subsets may not be completed in the presence of only these driving cytokines. Several additional factors may be required for their subsequent functional maturation or may be responsible for the fine tuning of their effector phases. Several of these factors are indicated, together with the characteristic cytokine profiles of each subset (adapted from [54]).

Figure 2

Multiple sclerosis immunopathogenesis and therapeutic targets. Immature dendritic cells (DCs) are central players in the innate immune response and are involved in the maintenance of peripheral tolerance by promoting the suppressor Treg and anti-inflammatory Th2-cell responses. Abnormally activated (mature) antigen-presenting DCs can be found in patients with multiple sclerosis (MS). This activation results in the increased production of proinflammatory cytokines, which lead to the aberrant activation of Th1 and Th17 proinflammatory responses. Activated encephalitogenic adaptive immune effectors (such as Th1 cells, Th17 cells, CD8⁺ cells, and B cells) express surface molecules that allow them to penetrate the blood-brain barrier and to enter the central nervous system (CNS). The presence of autoreactive immune effectors, together with abnormally activated CNS astrocytes and microglia, leads to the increased production of reactive oxygen species, excitotoxicity, autoantibody production, and direct cytotoxicity, which are all involved in the demyelination and axonal and neuronal damage that is present in patients with MS. Potential therapeutic interventions at different levels of the immunopathological cascade are shown in the filled yellow boxes (cytotoxic T lymphocytes [CTL]; interferon γ [IFNγ]; IL2 receptor [IL2R]; major histocompatibility complex class II [MHC II]; matrix metalloproteinases [MMPs]; nitric oxide [NO]; oligodendrocyte [ODG]; sphingosine 1-phosphate receptor [S1PR]; transforming growth factor β [TGFβ]; tumor necrosis factor [TNF]; regulatory T cells [Treg]; vascular cellular adhesion molecule 1 [VCAM1]; very late antigen 4 [VLA-4] (This figure was adapted and partly revised from [55].).