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Interleukin-10-anergized T-cell infusion provides immune reconstitution without severe graft-versus-host disease after haploidentical hematopoietic stem cell transplantation

ABSTRACT: 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/µl 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).

ORGANISM(S): Homo sapiens  

SUBMITTER: Barbarella Lucarelli   Rosa Bacchetta  Silvia Gregori  Patrick Miqueu  Maria T Stanghellini  Stefan Tomiuk  Fabio Ciceri  Monica Salomoni  Uwe Janßen  Claudia Sartirana  Maria-Grazia Roncarolo  Jacopo Peccatori  Massimo Bernardi  Raffaella Greco  Silvano Rossini  Elisabetta Zappone  Alessandro Ambrosi 

PROVIDER: E-GEOD-21885 | ArrayExpress | 2015-12-14



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T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory  ...[more]

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