Grauer, Oliver and Poeschl, Peter and Lohmeier, Annette and Adema, Gosse J. and Bogdahn, Ulrich (2007) Toll-like receptor triggered dendritic cell maturation and IL-12 secretion are necessary to overcome T-cell inhibition by glioma-associated TGF-beta 2. JOURNAL OF NEURO-ONCOLOGY, 82 (2). pp. 151-161. ISSN 0167-594X, 1573-7373
Full text not available from this repository. (Request a copy)Abstract
Malignant gliomas are able to secrete large amounts of immunosuppressive cytokines like transforming growth factor beta 2 (TGF-beta 2) and regularly escape from immune surveillance. Many strategies have been developed to induce potent anti-glioma responses, among those the use of dendritic cells (DC) as therapeutic vaccines. Here, we report that both mature DC and IL-12 secretion are necessary to overcome T-cell inhibition by TGF-beta 2. Flow cytometric analyses showed that TGF-beta 2 does not suppress the upregulation of MHC (major histocompatibility complex) class II molecules and the T cell stimulatory capacity of human DC that were stimulated with a strong cytokine cocktail containing tumor necrosis factor alpha (TNF-alpha), IL-1 beta, IL-6 and prostaglandin E2 (PGE(2)). Moreover, TGF-beta 2 signaling studies revealed that these cytokine-matured DC become unresponsive to TGF-beta 2. Although both mature and immature DC expressed comparable amounts of the TGF-beta receptor type II, Smad2 phosphorylation and subsequent upregulation of Smad7 was inhibited in mature DC, but not immature DC. However, further analysis revealed that mature DC alone are not sufficient to mediate full T cell activation in the presence of TGF-beta 2, unless IL-12 is added to the DC/T-cell coculture. Finally, we demonstrate that MHC class II expression and IL-12 secretion by DC are not disturbed by TGF-beta 2 after DC stimulation with a modified maturation cocktail containing the Toll-like receptor (TLR)-ligands Poly I:C or R848, TNF-alpha, IL-1 beta and INF-gamma. These data imply that mature DC retaining their capacity to produce IL-12 are of favorable use in glioma immunotherapy and suggest that TLR triggering of DC plays an important role to elicit a strong immune response in the immunosuppressive environment of malignant gliomas.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED PROTEIN-KINASE; CLASS-II TRANSACTIVATOR; CENTRAL-NERVOUS-SYSTEM; TGF-BETA; IMMUNE-RESPONSES; CUTTING EDGE; IFN-GAMMA; SIGNAL-TRANSDUCTION; LARGE NUMBERS; HUMAN BLOOD; dendritic cell; glioma; maturation; IL-12; TGF-beta 2; Toll-like receptor |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Dec 2020 14:45 |
| Last Modified: | 16 Dec 2020 14:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/32971 |
Actions (login required)
 |
View Item |
