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 journalArticle

87 Citations (Scopus)

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

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Gene therapy
T-cells
Thymidine Kinase
Graft vs Host Disease
Lymphocytes
Grafts
Genetic Therapy
Suicide
T-Lymphocytes
Data storage equipment
Ganciclovir
Cell Transplantation
Leukemia
Genes
Transplants
Prodrugs
Simplexvirus
T-Cell Antigen Receptor
Viruses
Chemical activation

ASJC Scopus subject areas

  • Hematology

Cite this

Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes. / Bondanza, Attilio; Valtolina, Veronica; Magnani, Zulma; Ponzoni, Maurilio; Fleischhauer, Katharina; Bonyhadi, Mark; Traversari, Catia; Sanvito, Francesca; Toma, Salvatore; Radrizzani, Marina; La Seta-Catamancio, Simona; Ciceri, Fabio; Bordignon, Claudio; Bonini, Chiara.

In: Blood, Vol. 107, No. 5, 01.03.2006, p. 1828-1836.

Research output: Contribution to journalArticle

Bondanza, A, Valtolina, V, Magnani, Z, Ponzoni, M, Fleischhauer, K, Bonyhadi, M, Traversari, C, Sanvito, F, Toma, S, Radrizzani, M, La Seta-Catamancio, S, Ciceri, F, Bordignon, C & Bonini, C 2006, 'Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes', Blood, vol. 107, no. 5, pp. 1828-1836. https://doi.org/10.1182/blood-2005-09-3716
Bondanza A, Valtolina V, Magnani Z, Ponzoni M, Fleischhauer K, Bonyhadi M et al. Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes. Blood. 2006 Mar 1;107(5):1828-1836. https://doi.org/10.1182/blood-2005-09-3716
Bondanza, Attilio ; Valtolina, Veronica ; Magnani, Zulma ; Ponzoni, Maurilio ; Fleischhauer, Katharina ; Bonyhadi, Mark ; Traversari, Catia ; Sanvito, Francesca ; Toma, Salvatore ; Radrizzani, Marina ; La Seta-Catamancio, Simona ; Ciceri, Fabio ; Bordignon, Claudio ; Bonini, Chiara. / Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes. In: Blood. 2006 ; Vol. 107, No. 5. pp. 1828-1836.
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