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Featured APS New Member


Dr. Maria Grazia Roncarolo has made outstanding contributions to translational research in the fields of immunology and gene therapy. Her translational research studies have led to greater understanding of the mechanisms underlying immune tolerance and have been of paramount importance to the development of novel therapies for pediatric patients with genetic and acquired diseases of the hematopoietic and immune systems.

She contributed to the elucidation of the mechanisms underlying the induction and breaking of tolerance in stem cell transplantation/organ grafts/autoimmune diseases and gene therapy. Specifically, she discovered a new subset of human T regulatory cells with immune regulatory and suppressor functions, named Type 1 (Tr1) cells.

She established that these cells were present in tolerant pediatric patients following hematopoietic stem cell transplantation. Subsequently, she isolated these cells from both mice and man, demonstrating that they are responsible for induction and maintenance of tolerance to allo- and self-antigens and food- and environmental- antigens. Recently, she discovered that the surface molecules CD49b and LAG3 are specific biomarkers for this subset of T regulatory cells, which allows for their isolation for therapeutic purposes and in vivo tracking in patients. She was the principal investigator of the first clinical trial using these ex-vivo generated donor-derived Tr1 cells to prevent the occurrence of severe graft-versus-host disease in leukemia patients undergoing haploidentical hematopoietic stem cell transplantation. She is currently initiating a new trial to use the T-allo10 drug product, which contains Tr1 cells to prevent graft-versus-host disease in children receiving HLA mismatched hematopoietic stem cell transplantation.

Dr. Roncarolo also discovered that Rapamycin favors expansion of another subset of human T regulatory cells, CD25+FOXP3+ Treg cells, allowing for their therapeutic use. She further demonstrated that treatment with Rapamycin and IL-10 induces tolerance in vivo by promoting differentiation of Tr1 cells and expansion of CD25+FOXP3+ T regulatory cells. She showed that specific Ag-targeting to the hepatocytes results in immunological tolerance mediated by CD25+FOXP3+ T regulatory cells. She showed that in vivo gene therapy which specifically targets self-antigens to hepatocytes results in immunological tolerance mediated by CD25+FOXP3+ T regulatory cells. She also showed that effector T cells which are responsible for immune mediated diseases can be converted into T regulatory cells by lentiviral vector mediated gene transfer of the human IL-10 or foxp3 genes.

Parallel to her studies on immunological tolerance, Dr. Roncarolo has investigated the pathological mechanisms responsible for genetic diseases of the hematopoietic and immune system in order to design therapies that will ultimately cure afflicted children. She made major contributions to the design and execution of the first successful trial for in utero fetal stem cell transplantation to cure primary immune deficiencies and of the first in utero trial using maternal haploidentical hematopoietic stem cells to cure SCID-X1 deficient patients.

Dr. Roncarolo was the principal investigator for the first successful gene therapy trial for Severe Combined Immunodeficiency (SCID) patients lacking adenosine deaminase (ADA), a purine metabolism disorder that results in severe immunodeficiency and death. In this trial, she introduced a new therapeutic conditioning regimen for the host, which favored the outgrowth of the gene corrected cells, resulting in the most successful clinical outcome for this formerly non-treatable genetic disease. Based on these results, gene therapy for ADA-SCID has obtained Orphan drug status from both the FDA and EMEA and recently has received European Commission approval to market under the name of Strimvelis. This is the first stem cell gene therapy product that has received market authorization.

The use of conditioning in ADA-SCID patients represented a breakthrough in the field of gene therapy which enabled the use of conditioning in more complex and non-immunological genetic diseases, such as metabolic diseases and genetic blood disorders.

Dr. Roncarolo was the principal investigator for the first lentiviral-vector based gene therapy trial for patients with Wiskott-Aldrich syndrome, which demonstrated safety and efficacy of this therapy.

She Is currently developing new gene therapy approaches to treat patients with genetic autoimmune diseases due to immune dysregulation and T regulatory cell abnormalities, such as IPEX syndrome.

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