Silvia Gregori

Mechanisms of peripheral tolerance

SR-Tiget Unit
Silvia Gregori, Group Leader

The Unit major interests are in the field of immunological tolerance, key mechanisms responsible for maintaining tissue homeostasis and to avoid adverse immune responses in several circumstances including allogeneic bone marrow or solid organ transplantation, autoimmune diseases, allergy, and gene therapy. The Group is aim at studying the mechanisms responsible for the induction and maintenance of peripheral tolerance by regulatory cells (Dendritic Cells (DC) and T cells) and immune-regulatory factors such as the non-classical HLA- class I molecule HLA-G.

In the past years we elucidated the mechanisms underlying the induction and functions of T regulatory type 1 (Tr1) cells, an inducible subset of CD4+ T regulatory cells characterized by the co-expression of CD49b and LAG-3, the ability to secrete IL-10 and to suppress T cell responses in vitro and in vivo via IL-10 and TGF-Beta secretion. We identified and characterized a new subset of tolerogenic DC, termed DC-10 that are present in vivo and can be differentiated in vitro in the presence of IL-10, which promote Tr1 cell differentiation in vitro. Moreover, we defined that the IL-10-dependent ILT4/HLA-G pathway is the peculiar molecular mechanisms responsible for the induction of Tr1 cells via DC-10. These studies have been instrumental to the definition of a modified protocol for the induction of Tr1 cells for cell therapy currently under clinical development. For the first time we showed that specific killing of myeloid cells represents an additional mechanism of suppression mediated by Tr1 cells. In collaboration with the Group of Prof. Maria Grazia Roncarolo we also contributed to the definition of a new protocol for the induction of Tr1 cells in vitro for cell therapy using lentiviral vector-mediated IL-10 gene transfer into CD4+ T cells and to the discovery of specific biomarkers of Tr1 cells, which allows their identification and isolation. The Group aims at combining bench and clinical studies (in patients treated with hematopoietic stem cell transplantation or with autoimmune diseases, or women with reproductive pathologies) to generate findings to support clinical translation, specifically of cell therapy approaches.

The Group of Prof. Maria Grazia Roncarolo, External Supervisor of the SR-Tiget Research Project: Cell and Gene Therapy for Immune Tolerance, has pioneered in the discovery of Tr1 cells and in the develop protocols to restore or promote antigen-specific tolerance by cell therapy after allograft transplantation, in autoimmunity, and in allergy, or by in vivo gene therapy approaches. In the first case the goal is the development of cell therapy protocols designed to reduce the risk of Graft-versus host disease (GvHD) after hematopoietic stem cell transplantation adult, or rejection after organ transplantation, or to restore tolerance in autoimmune diseases. In the second case the aim of the project is the definition of innovative strategies focused induction of transgene-specific tolerance through the use of modified lentiviral vectors (for further information, please visit the SR-Tiget Research Project: Cell and Gene Transfer Immune Tolerance web pages).

The Group of Dr. Rosa Bacchetta, External Supervisor of the SR-Tiget Research Project: Autoimmune Genetic Diseases, aims at understanding the pathogenesis of genetic diseases characterized by loss of immune tolerance in human subjects and at defining novel cell/gene transfer based therapies to re-establish immune regulation. The group starts from the patients to study the biology of diseases and to search for new biomarkers, and to develop strategies to modulate the disrupted mechanisms and to provide new therapies for the benefit of the patients). Innovative basic research on immune dysregulation includes studying the epigenetic control of adaptive immune cell development and function, genomics, transcriptome analysis and proteomics and functional reverse-genetics studies (for further information, please visit the SR-Tiget Research Project: Autoimmune Genetic Disease web pages).

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