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Synthesis of Novel Glycolipid Agonists of the Protein CD1d

Garcia Diaz, Yoel R (2010)
Ph.D. thesis, University of Birmingham.

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Invariant NKT (iNKT) cells are a subset of T lymphocytes that express an invariant \(\alpha\) \(\beta\) T cell receptor (TCR) as well as an NK1.1 marker. They play an important role in autoimmune diseases, such as type I diabetes and lupus. In contrast to conventional CD4+ and CD8+ T lymphocytes that recognise foreign peptides bound to the major histocompatibility complex (MHC) class I or MHC class II, iNKT cells recognise a range of foreign lipids and glycolipids bound to CD1d proteins. \(\alpha\) \(\beta\)-Galactosyl Ceramide (\(\alpha\) \(\beta\)GalCer), originally isolated from a marine sponge, is a powerful agonist of CD1d capable of triggering an immune response that results in the proliferation of a range of regulatory cytokines, including IFN-\(_y\) (Th1), as well as IL-4 (Th2). This mixed cytokine response (i.e. Th1 and Th2), combined with the “unresponsive state” of iNKT cells after activation with \(\alpha\)GalCer, limits the therapeutic potential of this agonist. To address some of these issues, we have also synthesised an \(\alpha\)GalCer analogue, namely Threitol Ceramide (ThrCer), that exhibits attenuated activity relative to \(\alpha\)GalCer. ThrCer is a truncated analogue of \(\alpha\)GalCer that conserves the stereochemistry of the hydroxyl functions present in \(\alpha\)GalCer and that exhibit a much stronger ether bond under acidic hydrolysis linking the sugar moiety with ceramide than the glycosidic bond in \(\alpha\)GalCer. We have labelled ThrCer with a biotin residue and with a 14C radiolabel, and our collaborators have used these derivatives to show that ThrCer behaves similarly to \(\alpha\)GalCer in endogenous lipid trafficking and its tissue distribution in vivo. We have also made advances towards the stereoselective synthesis of recently discovered natural agonists of iNKT cells from pathogenic origin, namely \(\alpha\)-galactosyl diacylglycerol (\(\alpha\)GalDAG).

Type of Work:Ph.D. thesis.
School/Faculty:Colleges (2008 onwards) > College of Engineering & Physical Sciences
Department:School of Chemistry
Subjects:QD Chemistry
Institution:University of Birmingham
ID Code:544
This unpublished thesis/dissertation is copyright of the author and/or third parties.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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