Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T Cells

Rosa Bacchetta, Barbarella Lucarelli, Claudia Sartirana, Silvia Gregori, Maria T. Lupo Stanghellini, Patrick Miqueu, Stefan Tomiuk, Maria Hernandez-Fuentes, Monica E. Gianolini, Raffaella Greco, Massimo Bernardi, Elisabetta Zappone, Silvano Rossini, Uwe Janssen, Alessandro Ambrosi, Monica Salomoni, Jacopo Peccatori, Fabio Ciceri, Maria Grazia Roncarolo

Research output: Contribution to journalArticlepeer-review

Abstract

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 type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vß repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders.

Original languageEnglish
Article numberArticle 16
JournalFrontiers in Immunology
Volume5
Issue numberJAN
DOIs
Publication statusPublished - 2014

Keywords

  • Cell therapy
  • Haploidentical
  • Hematopoietic stem cell transplantation
  • IL-10
  • T regulatory type 1 cells
  • Tolerance

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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