Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.674805
Title: Pathophysiology and novel therapeutic approaches in autoimmune Addison's disease
Author: Gan, Earn Hui
ISNI:       0000 0004 5370 0588
Awarding Body: University of Newcastle upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2015
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Abstract:
Autoimmune Addison’s disease (AAD) is a debilitating condition and affected patients rely on lifelong steroid replacement. Despite treatment, many patients have increased morbidity and mortality. The disease’s rarity has precluded large scale genomic or cellular studies in humans, resulting in an incomplete picture of the pathophysiology of AAD. This thesis details my research on the pathophysiology and novel therapeutic approaches in AAD. I performed two candidate gene studies on susceptibility alleles that have been implicated in other autoimmune diseases to explore potential causal pathways of these genetic determinants in AAD. The common variant 307*Ser allele of CD226 gene was found to contribute to AAD susceptibility as part of autoimmune polyendocrinopathy type 2. Two genetic variants from a panel of rare and functionally defective variants in the sialic acid acetylesterase (SIAE) gene were identified but they were not significantly associated with AAD. I explored new therapeutic approaches in AAD using a therapeutic regimen of parenteral ACTH1-24. This study demonstrated the presence of residual adrenal function in patients with established AAD, which was remediable to ACTH1-24 therapy. Clinical remission was induced in 2 of 13 study participants. However, some patients developed cutaneous reaction following ACTH1-24 injection, with one failing to sustain clinical remission. I proceeded to investigate the potential immunologic effects induced by ACTH therapy using ELISA and immunoblotting methods. Auto-reactivity against ACTH1-24 and ACTH 1-39 was detected, which could account for the side effects and treatment resistance observed. Finally, I attempted to characterise adrenocortical progenitor cells through cell cultures, immunocytochemistry and flow cytometry. A mesenchymal stem cell-like (MSC) population was isolated from human adrenals for the first time. My studies have advanced knowledge relevant to regenerative medicine approaches to adrenal failure, and the finding of residual adrenal function in some Addison’s disease patient opens an important therapeutic window for this condition.
Supervisor: Not available Sponsor: Medical Research Council (MRC) ; Society for Endocrinology
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.674805  DOI: Not available
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