Investigating immunomodulation and promotion of remyelination by regulatory T cells, in response to nalfurafine treatment.
Authors:   , Kiernan Mackenzie 
Published: January 2025

<p><strong>Multiple sclerosis (MS) is a chronic inflammatory condition characterised by the targeted destruction of the protective myelin sheath surrounding nerve cells in the central nervous system (i.e. demyelination). In demyelinating diseases, the process of remyelination is either impaired or the rate of myelin production fails to compensate for its depletion. This prolonged demyelination with inadequate remyelination results in symptoms of MS including visual disturbances, cognitive impairment, fatigue, and paralysis. The current treatment options are limited to immunomodulatory agents and generalised symptom management, which do not directly support remyelination. Our research is focused on developing therapeutics to promote remyelination and recovery in MS.</strong></p><p>The kappa opioid receptor (KOR) agonist, nalfurafine, has been shown to promote functional recovery and remyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of demyelination. Previous work conducted by the La Flamme research group indicated that nalfurafine-mediated benefit in control of EAE disease may be regulatory T cell (Treg)-dependent. Tregs play a regulatory role in the immune system by suppressing T cell responses and promoting immune resolution. Research has shown that Treg abundance and/or function is impaired in several chronic inflammatory conditions including MS. More recently, studies have identified that Tregs are involved in the remyelination process by contributing to both inflammatory resolution and promoting the differentiation of the cells which provide the myelin sheaths (i.e., oligodendrocyte precursor cells).</p><p>The in vitro assessment of nalfurafine on Treg function demonstrated an enhancement in Treg expansion and proliferation. Furthermore, we revealed that nalfurafine may also augment the suppressive capacity of Tregs, both in vitro and in vivo. We have demonstrated that in vivo neutralisation of regulatory T cell function with anti-CD25 antibody treatment abolished nalfurafine-mediated recovery from disease and hindered spinal cord remyelination. Through the selective genetic deletion of the kappa opioid receptor on regulatory T cells, we have shown that FoxP3+ regulatory T cells are crucial for nalfurafine-mediated remyelination and recovery from EAE, and that this protective effect is mediated through the kappa opioid receptor on regulatory T cells specifically. We subsequently utilised human PBMCs in vitro to assess the immune-related changes occurring as a result of nalfurafine treatment. We observed similar immune profiles in these human PBMCs, following nalfurafine treatment, as we do in murine splenocytes. Most notably, an increase in regulatory T cells was observed. Given the essential role of Tregs in nalfurafine-mediated remyelination and recovery from animal models of MS, these results suggest that nalfurafine may provide additional benefit by supporting the protective functions of Tregs in MS.</p><p>This study was pivotal in assessing the potential of using nalfurafine in the treatment of MS, and provides a promising rationale for its translation to the clinic. Moreover, this research contributes to the understanding and development of therapeutics targeted at promoting remyelination within the central nervous system, which would directly address the cause of disability in MS – demyelination.</p>