Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes

Attilio Bondanza, Veronica Valtolina, Zulma Magnani, Maurilio Ponzoni, Katharina Fleischhauer, Mark Bonyhadi, Catia Traversari, Francesca Sanvito, Salvatore Toma, Marina Radrizzani, Simona La Seta-Catamancio, Fabio Ciceri, Claudio Bordignon, Chiara Bonini

Research output: Contribution to journalArticlepeer-review

Abstract

In allogeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the herpes simplex virus-thymidine kinase (TK) suicide gene confers selective sensitivity to the prodrug ganciclovir (GCV). In patients, the infusion of TK+ lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of antihost reactivity for a GvL effect, while controlling GvHD. Because activation required for genetic modification with RV may reduce antihost reactivity, we investigated the requirements for maximizing the potency of human TK+ lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM) TK + lymphocytes, the addition of CD28 costimulation through cell-sized beads resulted in the generation of central memory (CM) TK+ lymphocytes. In a quantitative model for GvHD using nonobese diabetic/severely combined immunodeficient mice, CM TK+ lymphocytes were more potent than EM TK+ lymphocytes. GCV administration efficiently controlled GvHD induced by CM TK+ lymphocytes. These results warrant the clinical investigation of CM suicide gene-modified human T lymphocytes for safe and effective allo-HCT.

Original languageEnglish
Pages (from-to)1828-1836
Number of pages9
JournalBlood
Volume107
Issue number5
DOIs
Publication statusPublished - Mar 1 2006

ASJC Scopus subject areas

  • Hematology

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