AbstractMultiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system (CNS), characterised by focal areas of demyelination, neuroinflammation and ultimately neurodegeneration. There is an endogenous regenerative process termed remyelination, in which oligodendrocyte progenitor cell populations are recruited to the lesioned area, differentiate into oligodendrocytes and re-wrap myelin sheaths around axons. Unfortunately, remyelination ultimately fails in MS patients, in part due to a failure of oligodendrocyte differentiation, leading to an accumulation of disability and disease progression. Although there is no cure for MS, there has been an expansion in the number of diseases modifying therapies over the last few decades which aim to prevent relapses in MS patients. However, there are currently no approved therapies which aim to promote remyelination in MS patients. Although CD4+ T cells are involved in the pathogenesis of MS, they are also involved in CNS remyelination. Regulatory T cells have been shown to promote oligodendrocyte differentiation and remyelination, however T helper (Th) 17 cells impair endogenous remyelination. The roles of the other CD4+ T cell subsets have not yet been elucidated, and the aim of this PhD thesis was to evaluate the regenerative capacities of other effector T cells in CNS remyelination.
Th1 cells have been implicated in the pathogenesis of MS and in animal models of immune-mediated demyelination, associated with macrophage-induced demyelination in lesions and impaired oligodendrocyte differentiation. Th22 cells are a more recently discovered CD4+ T cells subset, characterised by the secretion of IL-22, which have been detected in the cerebrospinal fluid of MS patients during both relapse and remission phases. Knowledge of the roles of Th22 cells in the CNS is limited, but Th22-secreted factors have been shown to reduce the severity of immune-mediated demyelination in the CNS. The Th22-secreted factor, IL-22, has also shown regenerative effects in other tissues by inducing proliferation of resident stem cell populations. This led to the following hypotheses: 1) Th1 cells negatively impact OPC differentiation and myelination, 2) Th22 cells promote OPC differentiation and myelination, and 3) IL-22 promotes OPC proliferation, differentiation and remyelination.
The results in this PhD thesis show that both Th1 and Th22 cells promote OPC differentiation into oligodendrocytes in vitro through secreted factors. Results suggest that Th1 cells also enhance the rate of myelination, whereas Th22 cells do not impact myelination but decrease the axonal density of organotypic brain slice cultures ex vivo. Interestingly, the re-stimulation of OPC or brain slice cultures with Th1-secreted factors limits the extent of oligodendrocyte differentiation. Recombinant IL-22 does not have any effect on OPC proliferation, differentiation or myelination in vitro or ex vivo. The IL-22 receptor complex was not expressed in the CNS following lysolecithin-induced demyelination, indicating that IL-22 signalling is not relevant in this context. This work further elucidates the regenerative roles of CD4+ T cells in the CNS and opens up different avenues of future research to investigate these further, hopefully for a remyelinating therapy for MS patients.
|Date of Award||Dec 2022|
|Sponsors||Northern Ireland Department for the Economy|
|Supervisor||Denise Fitzgerald (Supervisor), Beckie Ingram (Supervisor) & Yvonne Dombrowski (Supervisor)|
- Multiple sclerosis
- Neurodegenerative diseases
- T cells