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Title: Mechanisms of action of peptide immunotherapy for type 1 diabetes : characterising T-cells induced or modified by proinsulin C19-A3
Author: Liu, Yuk-Fun
ISNI:       0000 0004 6498 3034
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Peptide immunotherapy (PIT) is a specific immunomodulatory treatment aiming to tip the balance from pro8inflammatory attack to restoration of immune tolerance. It has been successfully translated into clinical practice in the field of allergy, stimulating ongoing research in autoimmune diseases including type 1 diabetes. The safety and mechanistic effects of proinsulin C198A3 (PI C198A3), a HLA8DR4 restricted, naturally processed and presented peptide, was assessed through a multicentre placebo controlled double8blind clinical trial of 2 or 4 weekly intradermal doses of 10µg peptide for 6 months, with a 6 month follow8up period. Overall, treatment was well tolerated with no evidence of local or systemic hypersensitivity or disease acceleration. In some PIT8treated subjects there was retention of C8peptide. To address the question of whether and how PIT impacts upon immune function, over the 6 month treatment period, T cell receptor (TCR) clonotyping and gene expression analysis were performed on peptide8specific activated CD4 T8cells. TCR β8chain clonotyping revealed shared β8chain clonotypes between patients; however, these were not apparently linked to peptide immunotherapy. Gene expression changes were explored but no antigen8 specific changes related to treatment identified. This study concludes that peptide immunotherapy using PI C198A3 is a safe and well8 tolerated treatment in newly8diagnosed adults with type 1 diabetes; deployment of novel mechanistic studies to examine alterations in antigen8specific effector CD4 T cells do not reveal any linked changes in TCR or gene expression.
Supervisor: Peakman, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available