Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512380
Title: Synthesis of Novel Glycolipid Agonists of the Protein CD1d
Author: Garcia Diaz, Yoel R.
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2010
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Abstract:
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).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.512380  DOI: Not available
Keywords: QD Chemistry
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