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Tolerogenic Dendritic Cells Engineered with IL-10 and Antigen Control Pathogenic T Cell Responses and Promote Type 1 T Regulatory Cells

ABSTRACT: Dendritic cells (DC) play a critical role in the maintenance of tissue homeostasis and in promoting tolerance, thus acting as regulatory cells. Tolerogenic DC (tolDC) represent the cells of choice to fulfill the goal of restoring antigen (Ag)-specific tolerance since they can dampen Ag-specific T cell responses, induce pathogenic T cell exhaustion, and Ag-specific regulatory T cells. Here we efficiently generate tolDC by genetic engineering of monocytes with bidirectional lentiviral vectors co-encoding for immunodominant Ag-derived peptides (Ovalbumin or Matrix Protein 1, Insulin and Gliadin) in combination with IL-10 (DCIL-10/Ag). DCIL-10/Ag secrete high amounts of IL_x0002_10 in the absence of pro-inflammatory cytokines and efficiently modulate Ag-specific CD4+ and CD8+ T cell activation and proliferation in vitro in healthy subjects and Celiac Disease patients. DCIL-10/Ag promote Ag-specific CD49b+LAG-3 + T cells, which display the type 1 T regulatory (Tr1) cell gene signature in vitro. In vivo administration of DCIL-10/Ag promote Ag-specific Tr1 cells and prevent type 1 diabetes development in two murine models of disease. In conclusion, we generate an innovative approach based on the use of autologous engineered DC, which effectively modulate pathogenic CD4+ and CD8+ T cell responses in vitro and in vivo by promoting Ag_x0002_specific Tr1 cells suitable for cell-based therapy for restoring tolerance in T cell mediated diseases

ORGANISM(S): Homo sapiens

PROVIDER: GSE199425 | GEO | 2023/05/02

REPOSITORIES: GEO

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Project description:Regulatory T cells restore tolerance in preclinical models of immune-mediated diseases and are therefore a promising alternative to conventional immune-suppression for preventing graft-versus-host disease (GvHD) in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Adaptive CD4+ Type 1 regulatory T (Tr1) cells specific for alloantigens are induced in vitro by interleukin-10 (IL-10). Therefore, we evaluated whether infusion of Tr1 cells could promote immune-competence to foreign antigens and long-term alloantigen-specific tolerance. In this phase 1-2 trial, we performed adoptive transfer with IL-10-induced alloantigen-specific Tr1 cells (IL-10-DLI), without immune-suppression, in patients with high-risk hematopoietic malignancies transplanted with CD34+ cells from haploidentical donors. Donor T cells, primed ex vivo with host antigen-presenting-cells and IL-10, are anergic towards host-HLA antigens and contain host-specific Tr1 cells but also memory T cells able to respond to pathogens. Nineteen patients were enrolled in the trial. Twelve received IL-10-DLI. Seven were not evaluable because of early death/relapse, whereas five immune-reconstituted (>100/Âµl CD3+ T cells) at median day 28 after IL-10-DLI. T-cell counts and function progressively normalized in patients who received 105 CD3+ T cells/kg, whereas a higher dose (3x105 CD3+ T cells/kg) caused acute grade III GvHD in one patient. Four patients are alive, in disease remission and immune-suppression-free at a median follow-up of 3.3 years, three of them were analyzed by microarrays; their T-cell receptor repertoire and gene expression profiles are comparable to those of healthy subjects. Cell therapy with IL-10-DLI is feasible, safe, and provides immune-competence. This trial is the first step towards widespread use of Tr1 cells as adjuvant treatment in allogeneic HSCT (IS/11/6172/8309/8391). Keywords: classification of clinical samples Whole blood samples of three healthy donors and three different patients collected at various time points after hematopoietic stem cell transplantation (HSCT) before and after the subsequent administration of IL-10 anergized T cells were analysed on a custom Agilent 8x15K 60mer oligonucleotide microarray encomprising 4610 probes in triplicates. The microarray is dedicated to transplantation research and was designed based on current literature and published and unpublished data provided by the RISET consortium. For the probe selection procedure we specially focused on the detection of multiple transcript variants of a gene, on optimized hybridization properties of the probes, and on the avoidance of crosshybridization. The RISET 1.0 platform (GPL10370) is a precursor of the RISET 2.0 microarray (GPL8136).

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Tolerogenic Dendritic Cells Engineered with IL-10 and Antigen Control Pathogenic T Cell Responses and Promote Type 1 T Regulatory Cells

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