IL-7 and IL-15 allow the generation of suicide gene modified alloreactive self-renewing central memory human T lymphocytes

Shin Kaneko, Sara Mastaglio, Attilio Bondanza, Maurilio Ponzoni, Francesca Sanvito, Luca Aldrighetti, Marina Radrizzani, Seta Catamancio Simona La, Elena Provasi, Anna Mondino, Toshiro Nagasawa, Katharina Fleischhauer, Vincenzo Russo, Catia Traversari, Fabio Ciceri, Claudio Bordignon, Chiara Bonini

Research output: Contribution to journalArticlepeer-review

Abstract

Long-term clinical remissions of leukemia, after allogeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective suicide in donor T cells is a current gene therapy approach to abrogate GVHD. Unfortunately, genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (TEM) phenotype of gene-modified lymphocytes and may limit antileukemia effect.We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (TCM) phenotype. To this, we generated suicide gene-modified TCM lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, suicide gene-modified TCM cells selfrenewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only suicide gene-modified T cells cultured with IL-7 and IL-15 persisted, differentiated in TEM cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the suicide gene machinery. These results warrant the use of suicide gene-modified TCM cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer.

Original languageEnglish
Pages (from-to)1006-1015
Number of pages10
JournalBlood
Volume113
Issue number5
DOIs
Publication statusPublished - Jan 29 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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