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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 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 Citation Map 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  |  Table of Contents  |  Next Article  GENE THERAPY IL-7 and IL-15 allow the generation of suicide gene–modified alloreactive self-renewing central memory human T lymphocytes Shin Kaneko1,2, Sara Mastaglio1, Attilio Bondanza1,3, Maurilio Ponzoni4, Francesca Sanvito4, Luca Aldrighetti5, Marina Radrizzani6, Simona La Seta-Catamancio6, Elena Provasi1, Anna Mondino1, Toshiro Nagasawa2, Katharina Fleischhauer7, Vincenzo Russo1, Catia Traversari6, Fabio Ciceri1,3,8, Claudio Bordignon6,8, and Chiara Bonini1,3,8 1 Experimental Hematology Unit, Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, San Raffaele Scientific Institute, Milano, Italy; 2 Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan; 3 Hematology and BMT Unit, Department of Oncology, 4 Department of Pathology, and 5 Liver Unit, Department of Surgery, San Raffaele Scientific Institute, Milano, Italy; 6 MolMed SpA, Milano, Italy; 7 Unit of Molecular Immunology of Transplantation Immunohematology and Transfusion Medicine Service, San Raffaele Scientific Institute, Milano, Italy; and 8 Hematology, Università Vita-Salute San Raffaele, Milano, Italy 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 self-renewed 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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