Paroxysmal Nocturnal Haemoglobinuria
The focus of Dr Karadimitris's research is on two areas:
-
Role of lipid specific T cells in the pathogenesis of haematological disorders with initial focus on acute graft versus host disease (aGVHD)
-
Paroxysmal Nocturnal Haemoglobinuria; acquired and inherited
CD1d is a nonpolymorphic antigen presenting molecule which, instead of peptides, presents glycolipids to T cells. A relatively well characterised subset of CD1d-restrcited T cells is that of NK T cells. NKT cells are thought to modulate a variety of immune responses including tumour responses, autoimmunity and infection. We are currently studying the potential modulatory effect of NK T cells on the immune responses involved in the pathogenesis of aGVHD. In addition, we are exploring the potential role of glycolipids as histocompatibility antigens.
Paroxysmal Nocturnal Haemoglobinuria (PNH), is an acquired clonal disorder of the haemopoietic stem cell (HSC). The genetic lesion is mutation(s) affecting the X-linked gene PIG-A. Current pathogenetic models predict that autoreactive T cells target normal (non-mutated) HSCs sparing mutated HSCs. In this context, PNH HSC cells expand and supply the periphery with mature blood cells which at various proportions lack surface expression of glycosylphosphatidylinositol (GPI)-linked proteins. In fact, it is the synthesis of GPI that is disrupted as a result of the mutation(s). We are currently investigating the potential role of CD1d-restricted, GPI-specific T cells in the pathogenesis of PNH. As well as using conventional techniques, we also study lipid specific T cell responses using CD1d/glycolipid tetrameric complexes (see figure).
Specificity of CD1d/aGalCer tetramers.
a-d). Va24+/Vb11+ T cells were expanded after stimulation of PBMC with a-GalCer and were stained with CD1d tetramers and antibodies shown in the figure. Cells in panel (c) were first incubated with unlabelled anti-Va24 and anti-Vb11 antibodies, and subsequently stained with FITC-conjugated anti-Va24 antibody and CD1d/a-GalCer tetramer. All density plots were gated on the CD3+ Propidium iodide- cells; (e) CD4+ CD1d/a-GalCer tetramer+ cells were sorted from an in vitro expanded a-GalCer stimulated T cell line containing 0.59% positive cells. Enrichment for NKT cells was confirmed after two rounds of stimulation using anti-Va24 and anti-Vb11 antibodies.
