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

Reddington, Faye (2008). Lipid antigens and immunoregulatory iNKT cells in the prevention and treatment of type 1 diabetes and related autoimmune diseases. University of Birmingham. Ph.D.

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Abstract

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:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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