Article

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

Experimental Hematology Unit, Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, San Raffaele Scientific Institute, Milano, Italy.
Blood (impact factor: 9.9). 11/2008; 113(5):1006-15. DOI:10.1182/blood-2008-05-156059 pp.1006-15
Source: PubMed

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.

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    Article: Impact of γ-chain cytokines on EBV-specific T cell cultures.
    Anna Merlo, Riccardo Turrini, Cristina Trento, Paola Zanovello, Riccardo Dolcetti, Antonio Rosato
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    Journal of Translational Medicine 01/2010; 8:121. · 3.41 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

abrogate GVHD
 
activation-induced cell death
 
allogeneic hematopoietic
 
alloreactive memory T cells able
 
alloreactive response
 
antileukemia effectors
 
CD28 costimulation
 
central memory
 
current gene therapy approach
 
detrimental graft-versus-host disease
 
donor T cells
 
effector memory
 
gene-modified lymphocytes segregates
 
genetic modification
 
humanized mouse model
 
Long-term clinical remissions
 
safe exploitation
 
selective suicide
 
suicide gene machinery
 
suicide gene-modified T(CM)