Our proposed research addresses one of the main and unresolved issues in the biology of paroxysmal nocturnal hemoglobinuria paroxysmal nocturnal hemoglobinuria: (par-uk-SIZ-muhl nok-TURN-uhl hee-muh-gloe-buh-NYOOR-ee-uh) A rare and serious blood disease that causes red blood cells to break apart. Paroxysmal means sudden and irregular. Nocturnal means at night. Hemoglobinuria means hemoglobin in the urine. Hemoglobin is the red part of red blood cells. A… (PNH) and idiopathic idiopathic: Usually refers to any condition with no known cause. aplastic anemia aplastic anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… (IAA). Both disorders are considered to have an autoimmune mechanism involving auto-reactive T cells targeting hematopoietic stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… (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 clone: To make copies. Bone marrow stem cells clone themselves all the time. The cloned stem cells eventually become mature blood cells that leave the bone marrow and enter the bloodstream. 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.
Paroxysmal nocturnal Haemoglobinuria (PNH) is a bone marrow failure bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… disease in which there is a severe depletion of haematopoietic stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… (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 Eculizumab: Eculizumab (Soliris ®) is given as an IV into a vein at the doctor’s office or at a special center. The procedure usually takes about 35 minutes. You will probably get an IV once a week for the first 4 weeks. Starting in the 5th week, you will get a slightly higher dose of Soliris every 2 weeks. … 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
T cell:
see lymphocyte
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.