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Medizinische Hochschule Hannover | Carl-Neuberg-Str.1 | 30625 Hannover | Tel.:(+49) 0511-532-0

Research Program

The main topic of Dr. Markus Gräler’s lab is the function of lipids and their receptors in immunity. Recently we and others identified the sphingolipid receptor designated S1P1 as a critical player for egress of thymocytes from the thymus and for exit of B- and T-lymphocytes from secondary lymphoid organs (SLOs) such as lymph nodes and Peyer’s Patches. S1P1 is member of the G protein-coupled receptor family. It is expressed on the cell surface and transduces signals from the extracellular matrix into the cells. Sphingosine 1-phosphate (S1P) specifically binds to the receptor and initiates the signalling cascade. This process is blocked by the immunosuppressive agent FTY720 that down-regulates S1P1 expression on the cell surface and internalizes the receptor. We postulate a model in which the S1P1 receptor and blood-borne sphingosine 1-phosphate maintain circulation and systemic distribution of lymphocytes in primary and secondary lymphoid organs, and in peripheral tissues. In order to test this hypothesis, we are working on S1P1 transgenic mice that constitutively express the receptor on T-lymphocytes. We also work on conditional S1P1 knockout mice that allow us to selectively prevent receptor expression in certain cells at different stages. The investigation of S1P1 signal transduction pathways in lymphocytes provide clues about the requirements of sphingosine 1-phosphate signalling events. We recently established a high-performance liquid chromatography-based method to identify and to quantify different sphingolipids and their analogues in various biological samples. Our main goal is to regulate immune surveillance via sphingosine 1-phosphate and its receptor S1P1, which would be the basis for novel therapeutic and diagnostic tools to treat and cure immune and autoimmune diseases, and to prevent graft rejections after organ transplantations.

 

                   

 

Model for S1P/S1P1 regulation of lymphocyte circulation. S1P in blood or lymph stimulates the S1P1-R on mature single-positive thymocytes (A) and on naive patrolling lymphocytes (B). Stimulation of S1P1 consequently induces their exit from the thymus and SLOs respectively, which is blocked by FTY720-induced internalization of S1P1. The S1P/S1P1 axis may also trap lymphocytes in blood circulation by overruling chemokine signalling (C). FTY720 abrogates the S1P/S1P1-induced inhibition of local chemokine signalling through S1P1-R internalization and thereby accelerates lymphocyte homing. Activation of lymphocytes induces rapid down-regulation of the S1P1-R transcript (D). Down-regulation of S1P1 renders activated lymphocytes unresponsive to S1P and prevents their exit from SLOs. This retention period in SLOs could be important to ensure their accurate proliferation and differentiation. Supposedly the S1P1-R is up-regulated again on differentiated lymphocytes that exit from SLOs and enter sites of inflammation.

 

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