Rosario Notaro, MD | Aplastic Anemia and MDS International Foundation

Rosario Notaro, MD

Lead Photo
The role of GPI-reactive T cells in the pathogenesis of acquired aplastic anemia
Original Research Center: 
Istituto Toscano Tumori, Florence, Italy
Pubmed Author Name: 
Notaro, Rosario
Current Position/Title: 
Deputy Director, Core Research Laboratory

Aplastic anemia and Paroxysmal Nocturnal Hemoglobinuria (PNH) are two serious blood disorders that share one important feature:  the bone marrow cannot always keep up with the body’s needs for blood cells.  We call this feature bone marrow failure (BMF); it means that there may be anemia, low white cells (particularly neutropenia, entailing the risk of infection), low platelets (with risk of bleeding).  Recently we have analyzed in depth a type of lymphocyte cells called T cells in patients with PNH, and we have found that they have an excess of a very rare subset of T cells that are able to recognize a specific glycolipid molecule (a molecule that contains both a sugar moiety and a fat moiety) – we have called them GPI-reactive T cells.  We now plan to investigate whether GPI-reactive T cells are also increased in aplastic anemia.  Our findings would corroborate the notion that these cells are prime movers of the disease and therefore may make it possible to develop new forms of treatment. 

2013
First Year Report: 

In the first year of this project we have started to investigate the presence of CD1d restricted GPI-reactive T cells in aplastic anemia.  We have found that GPI-reactive cells were present in 8 out of 10 aplastic anemia patients, but in follow-up with these patients there was a lower frequency of those cells.  It is possible that the frequency of the GPI-reactive T cells, which are likely responsible for the auto-immune attack to the normal (GPI+) hematopoiesis, is affected by the immunosuppressive treatments. We will test this possibility by studying the samples from the patients we have already studied at diagnosis.

Our starting hypothesis was that GPI-reactive T cells should more likely be present in aplastic anemia patients with a substantial proportion of GPI-negative (PNH) blood cells.  Thus is was unexpected and very interesting that we found a high frequency of GPI-reactive  T cells in all aplastic anemia patients without detectable PNH blood cells.  This preliminary observation, if confirmed in a larger number of such aplastic anemia patients, suggests that the GPI-reactive T cells are implicated in the pathogenesis of most cases of both aplastic anemia and PNH.  These findings support the view that there is more than a close link between aplastic anemia and PNH; in fact they suggest that in most cases aplastic anemia and PNH are just different clinical presentations of the same disease.  In both aplastic anemia and PNH, GPI-reactive T cells could be responsible for the auto-immune attack targeting the GPI+ hematopoiesis, thus the emergence of GPI-negative clones depends only on the “degree” of staminality of pre-existent PIG-A mutated hematopoietic stem cells

In the second year of this project we will study the possible variation of the frequency of GPI-reactive T cells upon immunosuppressive treatments during the follow-up with the patients we have already studied at diagnosis.  In addition, we are collecting samples from a new series of aplastic anemia patients at diagnosis and during their follow-up.

Final Report: 

Aplastic anemia (AA) and Paroxysmal nocturnal hemoglobinuria (PNH) are two blood disorders that share one important feature called bone marrow failure: the bone marrow cannot keep up with the body’s needs for blood cells. It means that there may be anemia, low white cells (entailing the risk of infection), low platelets (with risk of bleeding).

Recently we have studied a type of lymphocytes called T cells in patients with PNH, and we have found that they have an excess of a very rare subset of T cells that are able to recognize a specific glycolipid molecule (GPI): we have called these lymphocytes “GPI-­‐reactive T cells”. The GPI-­‐reactive T cells could be responsible for the bone marrow failure because they should be able to attack/destroy the normal blood marrow cells that display on their surface the GPI molecules.

The aim of this project was to investigate whether GPI-­‐reactive T cells are also increased in AA. During the two years of this project, studying a large number of patients (both AA and PNH) and healthy controls, we have found that GPI-­‐reactive T cells, detected with different techniques, are present and increased in the large majority (more than 70%) of patients with AA. These findings corroborate the notion that AA and PNH are two side of the same disease and that GPI-­‐reactive T cells could be the prime responsible for the bone marrow failure typical of these disease. In this respect, a very intriguing observation is that the number of these GPI-­‐ reactive T cells is reduced by the immunosuppression that is used to treat most of AA patients.

Current Institution: 
Istituto Toscano Tumori, Florence, Italy