AbstractDespite significant advances in the efficacy of immunotherapies that target increasingly specific inflammatory elements critical to the development of the disease, there remains a significant therapeutic shortfall for sufferers of Multiple Sclerosis (MS). The pathophysiological disconnect between inflammation and the neurodegeneration that ultimately underlines disability is well described and continues to limit the success of increasingly potent immunosuppression.
Neuroprotection, immunomodulation and cell replacement, all demonstrable properties of adult multipotent mesenchymal stem cells (MSCs) offer further therapeutic potential that may help to address both the inflammatory disease component and the neuronal loss that underscores disability. Much work has been done over the last decade and more to elucidate these properties with the accumulation of a critical body of evidence enabling translation to clinical trials including in Bristol.
Animal models of inflammatory neurological pathology have yielded many clues to the mode of activity of MSCs. Detailed knowledge of their pathophysiological role in man however is lacking.
This thesis was principally directed towards supporting and refining the imminent translational study. The aim of this work was twofold; to identify stem cell populations with proven advantageous properties in the bloodstream and in the brains of individuals with MS and interrogation of Neurophysiological outcome measures as a surrogate for disability measures.
Stem cells of the bone marrow niche were identified in patients undergoing clinical relapse, as well as in those taking commonly prescribed disease modifying therapies. Whilst MSCs were readily identified in bone marrow samples, they were not detectable in peripheral blood at current technological thresholds. Cells expressing markers commonly expressed by MSCs were also identified in postmortem brain tissue from individuals with active MS, suggesting possible central nervous system infiltration. Finally evoked potential-based composite scores were demonstrated to correlate with clinical disability scoring methods both in crosssectional and to a lesser extent longitudinal analysis.
|Date of Award||19 Jun 2018|
|Supervisor||Neil Scolding (Supervisor) & Alastair Wilkins (Supervisor)|