In vitro analysis of the antileukemic effect of tumor necrosis factor-alpha gene therapy with myeloid progenitor cells: the role of dendritic cells.
We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) gene therapy with transgene-expressing myeloid progenitor cells (32DTNF-alpha) is effective in inhibiting the progression of leukemia with a lethal dose of murine 32Dp210 myeloid leukemia cells. Because TNF-alpha has been shown to induce the activation and maturation of dendritic cells (DCs), we investigated the effect of TNF-alpha secreted by transduced cells (32DTNF-alpha cells) on the activation of DCs and their role in the production of antileukemic cytotoxic T lymphocytes (CTLs). We demonstrate that administration of 32DTNF-alpha cells to the mice enhances the allo-stimulatory capacity of the splenic (CD11c+) and bone marrow-derived DCs in both mixed leukocyte response and CTL development. The enhanced allo-stimulatory capacity of splenic DCs from mice injected with 32DTNF-alpha cells correlated with increase in the cell-surface expression of the costimulatory molecules CD40, CD80, CD86, and major histocompatibility complex (MHC) class II molecules (I-Ak), and production of interleukin-12 (IL-12). Furthermore, administration of 32DTNF-alpha cells during immunization with irradiated 32Dp210 leukemia cells augmented the capacity of splenic DCs to stimulate antileukemic CTL response in spleen cells. Collectively, these data suggest that in vivo production of TNF-alpha by transduced cells enhances the phenotypic and functional activation of DCs, resulting in induction of a stronger antileukemic cytotoxic T-cell immune response.
Xu
Yong X
YX
Oncology Research Laboratory, Henry Ford Health System, Detroit, MI, USA.
Deeb
Dorrah
D
Gao
Xiaohua
X
Janakiraman
Nalini
N
Chapman
Robert A
RA
Gautam
Subhash C
SC
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D039521:CD11c Antigen / Q000096:biosynthesis; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000096:biosynthesis; D007938:Leukemia / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D015854:Up-Regulation
D039521:CD11c Antigen; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D013936:Thymidine