{"id":{"repo_id":"birmingham","oai_identifier":"oai:etheses.bham.ac.uk:544"},"canonical_url":"https://search.dev.ndltd.org/etd/birmingham/oai:etheses.bham.ac.uk:544","repository":{"repo_id":"birmingham","name":"University of Birmingham","base_url":"https://etheses.bham.ac.uk/cgi/oai2"},"display":{"title":"Synthesis of Novel Glycolipid Agonists of the Protein CD1d","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).","abstract_html":"Invariant NKT (iNKT) cells are a subset of T lymphocytes that express an invariant <span class=\"etd-inline-math\">&alpha;</span> <span class=\"etd-inline-math\">&beta;</span> 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. <span class=\"etd-inline-math\">&alpha;</span> <span class=\"etd-inline-math\">&beta;</span>-Galactosyl Ceramide (<span class=\"etd-inline-math\">&alpha;</span> <span class=\"etd-inline-math\">&beta;</span>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-<span class=\"etd-inline-math\"><sub>y</sub></span> (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 <span class=\"etd-inline-math\">&alpha;</span>GalCer, limits the therapeutic potential of this agonist. To address some of these issues, we have also synthesised an <span class=\"etd-inline-math\">&alpha;</span>GalCer analogue, namely Threitol Ceramide (ThrCer), that exhibits attenuated activity relative to <span class=\"etd-inline-math\">&alpha;</span>GalCer. ThrCer is a truncated analogue of <span class=\"etd-inline-math\">&alpha;</span>GalCer that conserves the stereochemistry of the hydroxyl functions present in <span class=\"etd-inline-math\">&alpha;</span>GalCer and that exhibit a much stronger ether bond under acidic hydrolysis linking the sugar moiety with ceramide than the glycosidic bond in <span class=\"etd-inline-math\">&alpha;</span>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 <span class=\"etd-inline-math\">&alpha;</span>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 <span class=\"etd-inline-math\">&alpha;</span>-galactosyl diacylglycerol (<span class=\"etd-inline-math\">&alpha;</span>GalDAG).","abstract_has_math":true,"creators":["Garcia Diaz, Yoel R"],"institution":"University of Birmingham","degree_name":"d_ph","degree_level":"d_ph","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07","date_published":"2010-07","updated_at":"2026-07-24T01:10:58Z","subjects":["QD Chemistry"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.sponsor","label":"Sponsor","values":["na"]},{"key":"dc:creator","label":"Author","values":["Garcia Diaz, Yoel R"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07"]},{"key":"dc:date.issued","label":"Date","values":["2010-07"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["College of Engineering & Physical Sciences","School of Chemistry"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Birmingham"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["http://etheses.bham.ac.uk//id/eprint/544/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["d_ph"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["d_ph"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["QD Chemistry"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://etheses.bham.ac.uk//id/eprint/544/1/garciadiaz10PhD.pdf","http://etheses.bham.ac.uk//id/eprint/544/2/Decl_IS_Garciadiaz10Phd.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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)."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Synthesis of Novel Glycolipid Agonists of the Protein CD1d"]}]}],"canonical_facts":{"dc:contributor.sponsor":["na"],"dc:creator":["Garcia Diaz, Yoel R"],"dc:date":["2010-07"],"dc:date.issued":["2010-07"],"dc:description.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)."],"dc:format":["application/pdf"],"dc:identifier.uri":["http://etheses.bham.ac.uk//id/eprint/544/1/garciadiaz10PhD.pdf","http://etheses.bham.ac.uk//id/eprint/544/2/Decl_IS_Garciadiaz10Phd.pdf"],"dc:publisher.department":["College of Engineering & Physical Sciences","School of Chemistry"],"dc:publisher.institution":["University of Birmingham"],"dc:relation.isreferencedby":["http://etheses.bham.ac.uk//id/eprint/544/"],"dc:subject":["QD Chemistry"],"dc:title":["Synthesis of Novel Glycolipid Agonists of the Protein CD1d"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["d_ph"],"dc:type.qualificationname":["d_ph"]},"updated_at":"2026-07-24T01:10:58Z"}