Anastastios Karadimitris, MD, PhD

CD1d-restricted, GPI-specific T cells in paroxysmal nocturnal hemoglobinuria
Pubmed Author Name: 
Karadimitris, A
Original Research Center: 
Imperial College London

Our proposed research addresses one of the main and unresolved issues in the biology of paroxysmal nocturnal hemoglobinuria (PNH) and idiopathic aplastic anemia (IAA). Both disorders are considered to have an autoimmune mechanism involving auto-reactive T cells targeting hematopoietic stem cells (HSC) leading to their profound depletion. It is widely documented that the pathogenesis of IAA and PNH overlap to a great extent, with up to 50% of patients with IAA developing a PNH clone or bonafide PNH and a subgroup of patients with PNH evolving into IAA. The proposed work has the potential to unravel novel cellular and molecular mechanisms that underpin HSC depletion in PNH and IAA, with wider implications for both the hematology and immunology scientific communities.

First Year Report: 

Paroxysmal nocturnal Haemoglobinuria (PNH) is a bone marrow failure  disease in which there is a severe depletion of haematopoietic stem cells (HSC). This is compounded by exquisite sensitivity of red blood cells to the destructive effect of a complex molecular machine called complement, hence the anaemia and the propensity to developing blood clots. Eculizumab prevents the deleterious effects of complement, improves the anaemia and protects from blood clots.

However how depletion of HSC comes about is not known. We previously suggested that self-aggressive  T cells carrying a molecule called invariant T cell receptor (iTCR) can target a molecule called GPI and this interaction might be responsible for depletion of HSC. Towards addressing this idea we have employed advanced genetic tools to generate T cells that carry the candidate iTCR as well as haematopoietic cells in which presence of GPI and of CD1d, another molecule that the iTCR is expected to interact with on the target cells, has been altered.
With these at hand we will be able to determine whether the iTCR-carrying T cells can target and harm haematopoietic cells that express CD1d and GPI but not  cells that don’t express either or both. The outcome of these experiments will be crucial for understanding how depletion of HSC in PNH comes about.