An investigation of novel therapeutic strategies for the treatment of multiple sclerosis and autoimmunity

Abstract

Autoimmune disease is characterised by the development of abnormal immune responses directed against antigenic components of the host i.e. self-antigen. Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease directed against an unknown antigen in the central nervous system. This leads to focal demyelinating lesions and axonal damage. MS is caused by a complex interplay between multiple genetic and environmental risk factors and its incidence is increasing in both developed and developing countries worldwide. Current disease-modifying therapies non-specifically suppress components of the inflam- mation in MS. They are effective but with significant adverse events. There is an unmet need for safe targeted immunotherapies and for treatments that actively promote remyelination. This thesis examines two potential novel therapeutic strategies in autoimmunity and MS. The first approach arose from the observation, by previous research at GSK, that there is a population of CD4+ lymphocytes with apparent constitutive pSTAT1 expression independent of any stimulus and refractory to JAK-1 inhibition. This pSTAT1hi population had been found to be enriched in patients with systemic lupus erythematosus. The starting hypothesis of this thesis was that these cells might be pathogenic in autoimmune disease. However, following deep FACS phenotyping of this lymphocyte subset, the constitutive pSTAT1hi population was demonstrated to be an artefact of non-specific antibody binding, resulting in termination of this project. The remainder of the thesis focuses on the immunological effects of bexarotene. This retinoid X receptor agonist is currently being tested in a phase II clinical trial for its ability to promote remyelination [“CCMR One” trial]. Here, we focused on the ability of bexarotene to modulate the human Th17/iTreg axis in vitro, owing to literature reporting that RXR ligands augment RAR agonists’ effect on murine Th17/iTreg cells. We show that bexarotene promotes the differentiation of human Foxp3+ iTregs from naive CD4+ T cells independent of RAR engagement, whilst concomitantly inhibiting the differentiation of Th17 cells and their secretion of IL-17a. Bexarotene was not found to alter the methylation status of the Treg-specific demethylated region, with iTregs remaining fully methylated within this study. Next, I examined the peripheral blood of patients receiving six months of oral bexarotene treatment within the CCMR One trial. There was no change in serum IL-17a, the frequency of CD25hi CD127 Foxp3+ Tregs, nor in the secretion of IL-17a from effector T cells. Mirroring the data in vitro, no change was observed in the TSDR methylation status of Tregs isolated from these patients. Taken together, these results demonstrate the ability for RXR-specific ligands to modulate the Th17/iTreg axis in favour of iTreg differentiation in vitro, and thus their potential in the treatment of those autoimmune diseases which are driven by a failure of self-tolerance and imbalance of Tregs and inflammatory Teffectors.