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Front Immunol. 2014 Jan 31;5:16. doi: 10.3389/fimmu.2014.00016. eCollection 2014.

Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells.

Author information

1
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy , Milan , Italy.
2
Hematology and BMT Unit, San Raffaele Hospital , Milan , Italy.
3
TcLand Expression S. A. , Nantes , France.
4
Miltenyi Biotec GmbH , Bergisch-Gladbach , Germany.
5
MRC Center for Transplantation, King's College London , London , UK.
6
Unit of Immunohaematology and Transfusion Medicine Service, San Raffaele Hospital , Milan , Italy.
7
Center for Statistics in Biomedical Sciences, San Raffaele Scientific Institute , Milan , Italy.
8
MolMed SpA , Milan , Italy.
9
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy , Milan , Italy ; Vita-Salute San Raffaele University , Milan , Italy.

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-Vβ 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.

KEYWORDS:

IL-10; T regulatory type 1 cells; cell therapy; haploidentical; hematopoietic stem cell transplantation; tolerance

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