NEW IMMUNOGENETIC PARAMETERS FOR IMPROVING THE CURE OF INBORN GENETIC DISEASES BY ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

For many genetic disorders of the blood system leading to life-threatening immune defects or persistent anemia, stable transfer of blood stem cells carrying the gene missing or defective in the patient by bone marrow transplantation (BMT) from healthy family or volunteer unrelated donors, is the only possible cure. The success of this powerful therapeutic tool is however hampered by the frequent onset of rejection, especially in patients with genetic disorders of red blood cells who have a fully functioning immune system. Over recent years, accumulating evidence has been obtained to show that the immune response is regulated by a number of genes with inter-individual sequence variability, called polymorphic genes. The emerging scenario suggests that each individual has a unique immunological risk profile determined by genetic imprinting. The final goal of this project is to characterize a panel of polymorphic genes involved in the immune response to BMT, in order to allow us to predict each patient’s immunological risk profile by screening for these genes. To this end, we will characterize the immune related gene profile of patients undergoing BMT for beta-thalassemia, a frequent inherited genetic disorder affecting the red blood system, and correlate our findings with the onset of rejection, as well as with immune function in experimental laboratory models. These studies will be performed by a joint effort of three participating centers from Milan, Rome and Cagliari, leaders in the field who together perform over eighty BMT for beta-thalassemia every year, in a governmental program aimed at the cure of this disease in Middle Eastern countries. The expected data will allow us to set up an “Immune Response Genotyping Array” for risk prediction of the immune response not only in the context of BMT but also of other clinical settings such as gene therapy of inherited diseases, solid organ transplantation, autoimmunity and cancer.