Therapeutics/pharmacology

Oral

Generation of Human Alloantigen-specific Regulatory T Cells by il-10 Gene Transfer

Wednesday, June 14
6:15 PM - 7:45 PM

Regulatory T cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate Graft-versus Host Disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In a clinical trial aimed at promoting immune-reconstitution in the absence of GvHD, we demonstrated the safety and feasibility of Type 1 regulatory T (Tr1) cell-infusion after allo-HSCT. Tr1 cells are generated in vitro in an antigen-specific manner with recombinant IL-10 or DC-10; however, this cell product still contains effector T cells that may limit the efficacy of Tr1 cells. We developed a method to generate a homogeneous population of Tr1-like (CD4IL-10) cells by lentiviral vector-mediated human IL-10 (LV-IL-10) gene transfer. Here, we show the generation of human alloantigen-specific (allo)-CD4IL-10 cells by LV-10 gene transfer. Allo-CD4IL-10 cells were generated by transducing naïve or total CD4+ T cells with LV-IL-10 following a second stimulation with allogeneic mature DC. Allo-CD4IL-10 cells secreted high levels of IL-10 upon allo-specific stimulation, displayed an anergic and suppressive phenotype, released Granzyme-B, and selectively eliminated myeloid leukemic cell lines in vitro. Allo-CD4IL-10 cells can be differentiated starting from naïve or total CD4+ T cells, this latter leading to a sufficient number of allo-CD4IL-10 cells suitable for cell-based therapy. In vivo testing of this allo-specific CD4IL-10 cells in humanized model of GvHD are ongoing. These results represent the first step towards the development of allo-specific Tr1-like cells by IL-10 gene transfer and will contribute to broaden the use of Tr1-based immunotherapy to induce tolerance after transplantation.

Grazia Locafaro

Junior PostDoc
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute

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    Grazia Andolfi

    San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy

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      Luca Cesana

      San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy

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        Maria-Grazia Roncarolo

        Professor
        Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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          Silvia Gregori

          Group Leader
          San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy

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            Generation of Human Alloantigen-specific Regulatory T Cells by il-10 Gene Transfer



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