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

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 selecti...

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Bibliographic Details
Published in:Blood 2009-01, Vol.113 (5), p.1006-1015
Main Authors: Kaneko, Shin, Mastaglio, Sara, Bondanza, Attilio, Ponzoni, Maurilio, Sanvito, Francesca, Aldrighetti, Luca, Radrizzani, Marina, La Seta-Catamancio, Simona, Provasi, Elena, Mondino, Anna, Nagasawa, Toshiro, Fleischhauer, Katharina, Russo, Vincenzo, Traversari, Catia, Ciceri, Fabio, Bordignon, Claudio, Bonini, Chiara
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Death - genetics
Cell Death - immunology
Cell Differentiation - genetics
Cell Differentiation - immunology
Cells, Cultured
Genes, Transgenic, Suicide - genetics
Genes, Transgenic, Suicide - immunology
Graft vs Host Disease - genetics
Graft vs Host Disease - immunology
Graft vs Host Disease - therapy
Hematologic and hematopoietic diseases
Humans
Immunologic Memory - genetics
Interleukin-15 - immunology
Interleukin-15 - pharmacology
Interleukin-2 - genetics
Interleukin-2 - immunology
Interleukin-7 - immunology
Interleukin-7 - pharmacology
Isoantigens - genetics
Isoantigens - immunology
Lymphocyte Activation
Medical sciences
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - therapy
Stem Cell Transplantation
T-Lymphocytes - immunology
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-05-156059