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Title: Investigation of the role of antagonism of the Interleukin-7 Receptor in the treatment of Multiple Sclerosis in humans and in vitro differences between genetically stratified subjects based on Interleukin-7 receptor genotype
Author: Kousin-Ezewu, Onajite
ISNI:       0000 0004 7972 9805
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Multiple Sclerosis is an autoimmune disease mediated by activated lymphocytes entering the central nervous system. Treatments with the greatest efficacy either prevent the entry of activated lymphocytes, or deplete the lymphocyte population, before allowing lymphocyte reconstitution. IL-7Rα was identified by genetic studies in MS pathogenesis and is involved in the homeostasis and proliferation of lymphocytes. This thesis investigates the role of antagonism of IL-7Rα in the treatment of MS in humans and in vitro differences between genetically stratified subjects based on IL-7Rα genotype. It also explores the role for biomarkers during reconstitution of lymphocytes after Alemtuzumab treatment in MS, in which IL-7Rα plays a major role. Chapter 3 describes the prematurely aborted clinical trial of subjects with an IL-7Rα antagonist. This first-time-in-human trial demonstrated the drug was safe and well tolerated in this limited cohort of subjects. Chapter 4 investigated the differences between individuals based on IL-7Rα genotype with in vitro IL-7Rα antagonism and stimulation. It demonstrated greater activation through IL-7Rα in individuals with the protective genotype. Differences in negative feedback mechanisms of IL-7Rα were explored. Chapter 5 investigated the tolerability of palifermin, a keratinocyte growth factor, with alemtuzumab, which was well tolerated as part of a dose escalation sub-study of the CAMTHY trial. The main CAMTHY trial investigated if palifermin could cause increased thymic lymphopoiesis, offsetting the IL-7 driven homeostatic proliferation of lymphocytes and secondary autoimmunity associated with alemtuzumab. Chapter 6 investigated the use of CD4+ lymphocytes as a biomarker for relapses after Alemtuzumab treatment. This contradicted the findings of a previously published paper, using a much larger cohort of patients in Cambridge. This work underlines the importance of IL-7 in the pathogenesis and treatment of MS. It points towards the IL-7Rα pathway as a future avenue for biomarkers and novel treatments for MS.
Supervisor: Coles, Alasdair Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Interleukin-7 ; Multiple Sclerosis ; Alemtuzumab ; CAMTHY ; Interleukin-7 Receptor