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Novel glycolipids in CD1d-mediated immunity: synthesis of new agonists of CD1d

Wonjo, Justyna (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

The glycolipid α-galactosyl ceramide, α-GalCer, has been shown to stimulate the proliferation of murine spleen cells and activate the immune system. Stimulation occurs through binding of the glycolipid to the protein CD1d. Subsequent presentation of the CD1d−glycolipid complex to invariant Natural Killer T cells (iNKT cells) initiates the proliferation of a host of cytokines leading to an immune response The therapeutic potential of α-GalCer is currently being explored; however the induction of both Th1 and Th2 cytokines by this agent is likely to limit its therapeutic application. Significantly, analogues of α-GalCer have been shown to induce iNKT cell-derived cytokines more selectively through a skewed Th1-Th2 response. To date, very few alterations around the amide bond have been explored. To investigate its importance in iNKT cell stimulation, a range of α-GalCer and threitol ceramide (ThrCer) analogues has been synthesised in which the amide functionality in these two leads has been replaced with different carbonyl functional groups. These compounds have been tested for iNKT cell induction and in particular their Th1/Th2 response, which determined their therapeutic potential. Labelled derivatives of α-GalCer and ThrCer have also been designed and synthesised to find application in lipid trafficking studies.

Type of Work:Ph.D. thesis.
Supervisor(s):Cox, Liam and Besra, Gurdyal S.
School/Faculty:Colleges (2008 onwards) > College of Engineering & Physical Sciences
Department:School of Chemical Sciences
Subjects:QD Chemistry
QR180 Immunology
Institution:University of Birmingham
ID Code:3551
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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