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Lipid antigens and immunoregulatory iNKT cells in the prevention and treatment of type 1 diabetes and related autoimmune diseases

Reddington, Faye (2008)
Ph.D. thesis, University of Birmingham.

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Invariant natural killer T (iNKT) cells constitute an important regulatory arm of the immune system. Defects in the number and activities of iNKT cells have been linked to the development of autoimmune diseases. The glycoprotein CD1d plays an integral part in the recognition and presentation of lipid antigens such as α-galactosylceramide (α-GalCer) to iNKT cells, producing a variety of anti-inflammatory (T\(_H\)2) cytokines, such as interleukin-4 (IL-4), and pro-inflammatory (T\(_H\)1) cytokines, such as interferon-γ (IFN-γ). A decreased number of iNKT cells and defects in their capacity to produce T\(_H\)2 cytokines is associated with autoimmune diseases, such as type 1 diabetes (T1D). α-GalCer stimulates both T\(_H\)1 and T\(_H\)2 responses. Some analogues of α-GalCer preferentially induce the production of T\(_H\)2 cytokines, highlighting the possibility that such compounds could have therapeutic potential with regards to T\(_H\)1 cell-mediated autoimmune diseases, such as T1D and SLE. A library of α-GalCer analogues was synthesised and their ability to modulate immune responses analysed. Altering the length of the phytosphingosine chain in α-GalCer analogues was shown to drastically affect the T\(_H\)1:T\(_H\)2 response, with truncated phytosphingosine chains of 9 carbons skewing the response towards a predominantly T\(_H\)2 response. Substituting the galactose sugar head for glucose (α-GlcCer) or L-fucose (α-L-FucCer) also elicited differences in the immunological profile of α-GalCer analogues, with lymphocytic proliferation being greatest in the galactose analogue, followed by L-fucose, followed by a glucose analogue. These differences in activity were also mirrored in the cytokine responses of the analogues, suggesting the C4’ hydroxyl group plays a key part in antigen recognition and activity. Analogues incorporating 2 double bonds in the \(N\)-acyl chain exhibited T\(_H\)2 cytokine profiles on a par with α-GalCer, yet dramatically decreased T\(_H\)1 responses were observed. They also considerably delayed the clinical presentation of glucosuria in NOD mice. These results have provided important insights into the nature of antigen binding with CD1d, recognition of the antigen by iNKT cell receptors, and how such factors play a role in skewing the immune response, thus highlighting areas where structural diversity could be introduced in order to exploit immunomodulating potential, and find a possible prophylactic therapy for the prevention and treatment of autoimmune diseases, such as T1D.

Type of Work:Ph.D. thesis.
Supervisor(s):Besra, Gurdyal S.
School/Faculty:Schools (1998 to 2008) > School of Biosciences
Keywords:Glycolipid, autoimmune disease, type 1 diabetes, CD1, CD1d, Th1, Th2, Wittig reaction, glycosylation, phytosphingosine, iNKT cell
Subjects:RC Internal medicine
QP Physiology
Institution:University of Birmingham
Library Catalogue:Check for printed version of this thesis
ID Code:146
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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