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Blood, 29 January 2009, Vol. 113, No. 5, pp. 1006-1015. Prepublished online as a Blood First Edition Paper on October 31, 2008; DOI 10.1182/blood-2008-05-156059. This Article Full Text (PDF) All Versions of this Article: blood-2008-05-156059v1 113/5/1006    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kaneko, S. Articles by Bonini, C. Search for Related Content PubMed PubMed Citation Articles by Kaneko, S. Articles by Bonini, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 30, 2008 Accepted October 2, 2008 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, Simona La Seta-Catamancio, Elena Provasi, Anna Mondino, Toshiro Nagasawa, Katharina Fleischhauer, Vincenzo Russo, Catia Traversari, Fabio Ciceri, Claudio Bordignon, and Chiara Bonini Experimental Hematology Unit, Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy Hematology and BMT Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy Department of Pathology, San Raffaele Scientific Institute, Milan, Italy Liver Unit, Department of Surgery, San Raffaele Scientific Institute, Milan, Italy MolMed SpA, Milan, Italy Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan Unit of Molecular Immunology of Transplantation Immunohematology and Transfusion Medicine Service, San Raffaele Scientific Institute, Milan, Italy Hematology, Universita Vita-Salute San Raffaele, Milan, Italy * Corresponding author; email: bondanza.attilio{at}hsr.it. Long-term clinical remissions of leukemia, after allogeneic hematopoietic transplantation, depend on alloreactive memory T-cells able to self-renew and differentiate into anti-leukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GvHD). Induction of a selective suicide program in donor T-cells is a current gene therapy approach to abrogate GvHD. Unfortunately, genetic modification reduces alloreactivity of human lymphocytes. This associates with an effector memory (TEM) phenotype of gene-modified lymphocytes and may limit their anti-leukemia 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 co-stimulation and culture with IL-2, IL-7 or a combination of IL-7 and IL-15. In vitro, suicide gene-modified TCM were capable to self-renew upon alloantigen stimulation and resisted activation-induced cell death. In a fully humanized mouse model, only suicide gene-modified T-cells cultured with IL-7 and IL-15 persisted, differentiated in TEM 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 cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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