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IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes.
- Source :
-
Blood [Blood] 2009 Jan 29; Vol. 113 (5), pp. 1006-15. Date of Electronic Publication: 2008 Oct 31. - Publication Year :
- 2009
-
Abstract
- 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 (T(EM)) phenotype of gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (T(CM)) phenotype. To this, we generated suicide gene-modified T(CM) 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 T(CM) 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 T(EM) 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 T(CM) cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer.
- Subjects :
- Animals
Cell Death genetics
Cell Death immunology
Cell Differentiation genetics
Cell Differentiation immunology
Cells, Cultured
Genes, Transgenic, Suicide genetics
Graft vs Host Disease genetics
Graft vs Host Disease therapy
Humans
Interleukin-15 immunology
Interleukin-2 genetics
Interleukin-2 immunology
Interleukin-7 immunology
Isoantigens genetics
Isoantigens immunology
Lymphocyte Activation
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasms genetics
Neoplasms immunology
Neoplasms therapy
Genes, Transgenic, Suicide immunology
Graft vs Host Disease immunology
Immunologic Memory genetics
Interleukin-15 pharmacology
Interleukin-7 pharmacology
Stem Cell Transplantation
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 113
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 18978209
- Full Text :
- https://doi.org/10.1182/blood-2008-05-156059