Therapeutic targeting of oligodendrocytes in an agent-based model of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease in which misdirected, persistent activity of the immune system degrades the protective myelin sheaths of nerve axons. Historically, treatment of MS has relied on disease-modifying therapies that involve immunosuppression, such as targeting of the blood-brain barrier (BBB) to restrict lymphocyte movement. New therapeutic ideas in the development pipeline are instead designed to promote populations of myelin producing cells, oligodendrocytes, by exploiting their innate resilience to the stressors of MS or restoring their numbers. Given the significant advancements made in immunological disease understanding due to mathematical and computational modelling, we sought to develop a platform to (1) interrogate our understanding of the neuroimmunological mechanisms driving MS development and (2) examine the impact of different therapeutic strategies. To this end we propose a novel, open-source, agent-based model of lesion development in the CNS. Our model includes crucial populations of T cells, perivascular macrophages, and oligodendrocytes. We examine the sensitivity of the model to key parameters related to disease targets and conclude that lesion stabilisation can be achieved when targeting the integrated stress response of oligodendrocytes. Most significantly, complete prevention of lesion formation is observed when a combination of approved BBB-permeability targeting therapies and integrated-stress response targeting therapies is administered, suggesting the potential to strike a balance between a patients immune inflammation and their reparative capacity. Given that there are many open questions surrounding the etiology and treatment of MS, we hope that this malleable platform serves as a tool to test and generate further hypotheses regarding this disease. Author summaryMultiple sclerosis is a disease that is not yet fully understood and has no cure. Some patient phenotypes see little benefit from current therapeutic interventions besides symptomatic treatment. Typically, MS studies have focused on the prevention of damage to brain tissue. As such, there are unanswered questions about how to reverse the damage in the brain and spinal cord of MS patients caused by immune cells. In light of this there is an urgent need for mathematical modelling of new therapeutic strategies - some of which remain to be clinically examined - shifting the attention from the targeting of aberrant immune activity to the upregulation of resident, reparative cells called oligodendrocytes. Here, we have developed a mathematical model to probe the potential benefits of oligodendrocyte targeted therapies in silico. We focus on T cells as damaging agents and monitor oligodendrocyte function in response to their activity. We show that oligodendrocytes strongly influence the tissues ability to stabilise and even recover under persistent, harmful immune activity. In practice, these therapies could hold the potential to unlock neuroprotection by means of enhanced remyelination.