LENTIVIRAL-MEDIATED FOXP3 GENE TRANSFER TO CONVERT AUTOLOGOUS CD4+ T CELLS INTO TREG CELLS, SUITABLE AS CELL THERAPY PRODUCTS
Thymic-derived T-regulatory (Treg) cells are important for the induction of self-tolerance and the control of autoimmunity. CD4+ T cells can be converted into Treg cells after lentivirus-mediated FOXP3 gene transfer, resulting in a CD4Foxp3 T cell population with stable phenotype and suppressive function. We aim to applying this FOXP3 gene transfer strategy for the development of Treg cell based adoptive therapy, as polyclonal or auto-antigen-specific Treg cells by may contribute to the clinical remission of patients with immune disorders of different origins.
GENE CORRECTED AUTOLOGOUS HSPCS FOR THE TREATMENT OF IPEX SYNDROME
The prototypical genetic autoimmune disease is IPEX (immune-dysregulation polyendocrinopathy-enteropathy- X-linked) syndrome. IPEX syndrome is caused by mutations in the FOXP3 gene and subsequent dysfunction of regulatory T cells and autoimmune manifestations. Without treatment, IPEX can be fatal within the first years of life. Current treatment options include immunosuppression, which is only partially effective, and allogeneic hematopoietic stem cell transplantation (HSCT), which is limited by lack of suitable donors and toxicity related to pre-transplant conditioning. To address the current limitations, we propose autologous hematopoietic stem and progenitor cell (HSPCs) transplantation for IPEX, whereby patient HSPCs are gene corrected ex vivo using CRIPSR and reinfused into the patients. Gene corrected HSPCs maintaining endogenous FOXP3 regulation would provide long term repair of abnormalities in all lymphocyte lineages of affected patients. The results from this project will provide the preclinical basis for new CRIPSR-based therapeutic cure for IPEX.
IMMUNOLOGICAL DESCRIPTION OF PRIMARY IMMUNODEFICIENCY AND IMMUNE DYSEGULATION
We aim at developing advanced diagnostics and treatments for patients with primary diseases of the immune system, by rational understanding of the immune pathologic pathways affected by the gene mutations. We work in the development of critical immunological tests needed for rapid phenotyping and functional system-level analysis of the different immune cells and their interactions.
PHENOTYPIC CHARACTERIZATION OF CD4+ T CELLS BY MASS CYTOMETRY
Elucidating the interrelationship between CD3+ CD4+ T helper and T regulatory cell populations is critical to provide a deeper understanding of the immune system, which will pave the way for a comprehensive analysis in immune-mediated diseases.
In the Roncarolo/Bacchetta Lab, by evaluating the differential expression of transcription factors, chemokine-, activation-, and inhibitory-receptors, among others, using Cytometry by time-of-flight (CyTOF) we aim at characterizing each human Th, Treg, and Tr1 cell populations in healthy human blood and in patients with immune dysregulation, referred by the Center of Genetic Immune Diseases.