Surgery /Transplantation Medicine (Andrassy/Renz)

Department / Institute
Department of General, Visceral, and Transplantation Surgery
Subject area
Surgery /Transplantation Medicine
Project title
Role of the sympathetic nervous system in the rejection process after solid organ transplantation
Name of supervisor
Prof. Dr. J. Andrassy / PD Dr. med. Bernhard Renz
Number of open positions
Language requirements
Proficiency in English
Academic requirements
Master's Degree
Project time plan
Full Doctoral Study-Model: 36 or 48 months

Project description

Adrenergic modulation of the immune system is a well-known and widely investigated research area. In the field of transplantation, however, the effect of adrenergic signaling on the immune system in the setting of solid organ transplantation is insufficiently investigated. So far it is known that β2-adrenergic receptor signaling impairs Th1-cell differentiation and function in a cAMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4+ Foxp3+ Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance and are known to express β2-adrenergic receptors. Recent data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through β-adrenergic mediated signaling. In our preliminary experiments, in which we transplanted a segment of the thoracic aorta of C57BL/6 (H-2b) mice into MHC class II-mismatched B6.C-H-2bm12 (H-2bm12) recipient mice, a significant decrease in neointima formation as measured by intima/media ratio (0.7 ± 0.1 vs. 1.9 ± 0.1, p< 0.001) was seen in mice which received continuously a synthetic catecholamine (Isoproterenol) administered via an osmotic pump for 4 weeks. In order to further investigate the effect of adrenergic signaling on chronic allograft vasculopathy, hearts of B6.C-H-2bm12 (H-2bm12) mice will be transplanted into MHC class II-mismatched C57BL/6 (H-2b) recipients. Hearts will be monitored by daily palpation. When heart pulsation cannot be monitored anymore, hearts will be classified as rejected and mice will be sacrificed. The allografts as well as serum samples will be harvested. Further analyses will focus on infiltrating immune cells (CD4/CD8 positive) with a detailed characterization of subpopulations. We will define the surface adrenergic receptor profile of these cells and in an in vitro approach investigate adrenergic signaling pathways by using agonist and antagonist of adrenergic receptors. In particular we want to investigate the effect of adrenergic signaling on CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells and reveal the downstream effects caused by adrenergic signaling. In addition, serum cytokine levels (e.g. IL-2, IL-6, TNF-alpha and IFN-γ) will be measured. Depending on the results the in vivo experiments will be designed in order to clarify the role of adrenergic signaling in a chronic model of solid organ transplantation.

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