Leukocyte immunoglobulin-like receptors are a family of inhibitory and activating receptors found on a wide variety of immune cells, and are thought to play a significant role in determining immune responses. Their known ligands are HLA Class I molecules; HLA-G is the prototypic ligand which has high affinity for two inhibitory members of the family and mediates its immunosuppressive functions through them. The hypothesis of this study is that polymorphisms in the non-coding regions are likely to influence both the expression and response of the LILRs to various stimuli. Published data supports this view in that polymorphisms in the LILRs are associated with various immunologically mediated diseases. In addition, these molecules represent a potential target for therapeutic manipulation and attempts to develop a therapy using this route were undertaken. Expression levels of various LILR molecules on APCs at baseline and after stimulation have shown significant variation between subjects. Genomic variation in the promoter regions of LILRB2 was established by sequencing. The relationship between LILRB2 SNPs and cell expression levels was tested both directly and in a luciferase assay, but no significant associations were found. Engagement of LILRB2 by monoclonal antibodies was shown to affect TLR-induced cytokine secretion, but no relationship was found between LILRB2 expression levels and the effect on cytokine secretion. A synthetic construct (the “G-body”) utilising the LILR-HLA-G interaction has been developed for testing as a potential therapeutic molecule. This construct comprises two functional domains – an anti-HLA class I domain and an HLA-G domain. This construct would be expected to modulate allogeneic responses by localisation of an immunosuppressive signal (HLA-G) to the allogeneic HLA molecule; and (ii) potentially masking the allogeneic HLA class I molecule. Testing has shown that the construct suppresses lymphocyte proliferation with enhancement of this effect dependent on the presence of allogeneic HLA class I.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634183 |
| Date | January 2013 |
| Creators | Yong, Patrick |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/a-study-of-the-variation-of-leukocyte-immunoglobulin-like-receptors-on-antigen-presenting-cells(a79cecd9-abf2-4828-a70d-29c3dcc797e4).html |
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