Internal Medicine III
Clin. Division of Nephrology & Dialyis
Transplantation Biology, Innate Immunity, Immunosuppression
Our research is primarily devoted to understand immunological effector arms that can be manipulated in order benefit the host, e.g. to down-regulate immune responsiveness against alloantigens in organ transplantation. Furthermore, molecular mechanisms and targets of currently employed immunosuppressants are analyzed to gain more insights into the molecular drug action and also the basic regulation of the immune response. Another part of our research is focused on the potential link between arteriosclerosis and inflammation. In particular we study the potent immunomodulatory capacity of high-density lipoprotein hypothesizing that its atheroprotective and thereby life-enhancing potency is due to its anti-inflammatory action rather than being a simple cholesterol transport molecule. Finally, we have a prime interest in the diverse immunological mechanisms operative during host cell evasion also to take advantage from evolutionary driven strategies that can be mimicked for therapeutic purposes.
(1) Regulation of innate immunity by mTOR
Our laboratory is studying the regulation innate immune responses evoked by monocytes and peripheral dendritic cells by the mammalian target of rapamycin, a key molecule traditionally associated with translational control of eukaryotic cells, cell-cycle regulation and cell survival and currently therapeutically targeted by its naturally occurring inhibitor rapamycin or its dereivatives as immunosuppressant and anticancer drug. We recently identified mTOR as negative regulator of proinflammatory cytolkines as IL-12 and IL-23 but suppressor of the prototypical anti-inflammatory cytokine IL-10 in murine and human monocytes and peripheral myeloid dendritic cells. We have further identified that its regulatory role is exerted by the specific control of NF-kB activity, a pivotal proinflammatory transcription factor. Finally, in a relevant murine disease model employing Listeria monocytogenes we demonstrated that genetically-susceptible mice display an increased survival after mTOR inhibition by differentially regulating protective cytokine production. Ongoing studies in the laboratory aim to further elucidate the relative contribution of the mTOR subunits mTORC1 or Raptor versus mTORC2 or Rictor in dictating the final outcome of innate and adaptive immune responses including studies on optimized vaccination protocols or preventing virally-mediated immune escape.
(2) The role of HDL as immunomodulatory molecule
Several pivotal studies indicate that the quality rather than the quantity of HDL is decisive for its atheroprotective potency. Our studies could demonstrate that HDL exerts very potent effects on innate immune cells like monocytes/macrophages and dendritic cells by suppressing e.g. the production of various inflammatory cytokines. Interestingly, this potent immunomodulatory role is lost in high-risk populations such as end-stage renal disease patients exhibiting both a state of chronic inflammation and an excessively increased mortality rate. This study project aims to define the molecular pathways underlying this peculiar property of HDL envisioning a translational approach in patients with qualitatively inferior HDL and also identifying such high-risk patients with immunological methods.
Current basic molecular and cellular biology techniques, biochemical analysis of signal transduction pathways (western blooting, immunoprecipitation, EMSA), RNAi approaches, FACS, in vitro and in vivo immunological assays and cell culture and finally mouse molecular genetics tools (knockout mouse models).