TY - JOUR
T1 - Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells
AU - Curti, Antonio
AU - Pandolfi, Simona
AU - Aluigi, Michela
AU - Isidori, Alessandro
AU - Alessandrini, Isabella
AU - Chiodoni, Claudia
AU - Testoni, Nicoletta
AU - Colombo, Mario P.
AU - Baccarani, Michele
AU - Lemoli, Roberto M.
PY - 2005/12
Y1 - 2005/12
N2 - Objective. Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. Materials and Methods. AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. Results. Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14- AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14--derived AML-DCs restored optimal interferon-γ (IFN-γ) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14- cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14--derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-γ, thus maintaining a Th1 cytokine profile. Conclusion. IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.
AB - Objective. Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. Materials and Methods. AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. Results. Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14- AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14--derived AML-DCs restored optimal interferon-γ (IFN-γ) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14- cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14--derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-γ, thus maintaining a Th1 cytokine profile. Conclusion. IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.
UR - http://www.scopus.com/inward/record.url?scp=28844475121&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28844475121&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2005.08.005
DO - 10.1016/j.exphem.2005.08.005
M3 - Article
C2 - 16338495
AN - SCOPUS:28844475121
VL - 33
SP - 1521
EP - 1530
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 12
ER -