Peripheral Immune Phenotyping in Multiple Sclerosis: Immunomodulatory Treatment Effects and Treatment Response Biomarkers

Abstract

Disease modifying therapies (DMTs) used in the treatment of relapsing remitting multiple sclerosis (RRMS) have broad effects on the immune system that are incompletely understood. There is great heterogeneity in treatment response to most DMTs. However, biomarkers predicting treatment response are lacking. In this thesis, the peripheral immune changes induced by treatment with two DMTs, fingolimod (FTY) and dimethyl fumarate (DMF), are examined in detail by immune phenotyping using multicolour flow cytometry. Chapter 3 presents a longitudinal study of T cell subsets in patients commencing treatment with DMF. Differential losses of T cell subsets are found, including relative changes in regulatory and effector subsets potentially relevant to the mechanism of action of DMF. DMF-induced lymphopaenia is further studied in an in vitro culture system. The study results suggest that differential susceptibility of distinct T cell subsets to DMF-induced apoptosis may underly differential T cell losses seen in treated patients. In Chapter 4, the effects of FTY on peripheral T cell subsets and the reversibility of these effects is explored in patients ceasing FTY treatment. Long-lasting alterations in circulating T cell subsets are documented, indicating that FTY-induced changes in the peripheral immune repertoire may persist beyond the time taken for clinical laboratory measures to normalise. Chapter 5 presents a longitudinal study of a broad range of immune cell subsets in patients commencing FTY. Changes in potentially disease-relevant immune cell subsets not previously examined in FTY-treated patients are documented. Using magnetic resonance imaging (MRI) and clinical information to assess disease activity in these patients, potential immune biomarkers of FTY treatment response are uncovered. This thesis expands on our understanding of the effects of MS DMTs on the peripheral immune repertoire and highlights the utility of immune phenotyping in exploring DMT mechanisms of action and treatment response biomarkers.