The innate immune system in multiple sclerosis - role in neuroinflammation and implications for therapy

Abstract

Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative condition of the central nervous system (CNS). MS pathology is driven by antigen-specific immune activity, where peripheral immune cells infiltrate the CNS and mount an immune response targeting myelin. Adaptive contributions to this process have been well-studied and are the main target of existing MS therapies. In contrast, the myriad roles of innate immunity in MS neuroinflammation remain relatively poorly understood, in part due to the multi-faceted nature of these cells and their phenotypic complexity.

This thesis investigates the use of liposomes-a drug vehicle characteristically taken up by phagocytic innate cells-as a delivery platform for MS therapeutics. This was achieved using mouse experimental autoimmune encephalomyelitis (EAE) models, which are commonly used to mimic MS neuroinflammation. Using a liposomal formulation of existing MS therapeutic mitoxantrone (MTX) as proof-of-concept, MTX-loaded liposomes possessed enhanced efficacy in comparison to freely delivered drug. Moreover, the liposome formulation examined displayed CNS-penetrance during neuroinflammation, and displayed strong preferential interaction with a specific myeloid population which could be depleted during treatment.

Further, this thesis examines myeloid cell, particularly dendritic cell (DC), heterogeneity in MS. These cells, critical in the activation and modulation of antigen-specific immunity as seen in MS, comprise multiple ontogenetically distinct subsets and a spectrum of activation states. How this complexity reflects in MS is still unclear. Here, high-parameter flow cytometry was used to characterise DC subsets and functional phenotypes in blood of people with MS (PwMS) relative to non-MS controls.

These data delineate innate complexity in neuroinflammation through characterisation of DC populations and phenotypes which have previously not been analysed in PwMS, further adding to our knowledge of how these complex cells behave in this context. Further, these data demonstrate the utility of liposomes as a treatment platform in neuroinflammation, and how these vehicles may be leveraged to target innate immunity.