Transcriptional in vivo targeting of dendritic cells (DC) using the human CD83 promoter

Immune Modulation

Head of Department:
Prof. Dr. rer. nat. Alexander Steinkasserer (PhD)

Transcriptional in vivo targeting of dendritic cells (DC) using the human CD83 promoter

Project manager: Dr. I. Knippertz

Focus of the research group is the transcriptional targeting of DC and Treg for the treatment of cancer, chronic viral infections, and autoimmune diseases. Regarding this transcriptional targeting strategy, the human DCand maturation specific CD83 promoter has been successfully characterized in the past. The membrane-bound CD83 molecule is a 45 kDa glycoprotein expressed on the surface of mature, immunogenic DC. Since CD83 is not expressed on immature, tolerogenic DC, its regulatory DNA region, the CD83 promoter, is of high interest in the context of DC-mediated in vivo vaccination strategies directly in patients. For this purpose, therapeutic adenoviruses and nanoparticles are currently generated encoding different immune-modulatory and therapeutic transgenes under the control of the cell type- and stadium specific CD83 promoter. The potency of these therapeutic vectors will then be determined in vivo in humanized tumor mouse models.

Recent data from our Division demonstrated CD83 not only to be expressed by mature DC, but also by activated Treg. Interestingly, transcriptional regulation is different in DC and Treg. Therefore, another aim of our group is the characterization of the CD83 promoter in activated Treg, e.g. by ChiP-Seq for the development of new transcriptional targeting strategies for the treatment of autoimmune diseases.

The third emphasis of our group is to study the mechanisms by which different Aryl hydrocarbon receptor (AhR)-agonists modulate DC-specific CD83 expression on transcriptional level, thereby modulating the immune response in physiology and pathophysiology. Bioinformatic analyses revealed two transcription factor binding sites for AhR within the human CD83 promoter region which have been proven experimentally afterwards. The incubation of DC with different AhR-agonists in vitro led to a specific downregulation of CD83, accompanied with an altered cytokine secretion profile and T cell stimulatory capacity. The underlying molecular mechanisms are currently under investigation.

Publications

 
Contact
Dr. rer. nat. Ilka Knippertz
phone: +49 9131 85-36335
fax: +49 9131 85-36417
e-mail: ilka.knippertz@uk-erlangen.de
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