Subproject A13

Significance of tumor necrosis factor and lymphotoxin signalling for mucosal immunity.

PhD / D. Sc. Sergei Nedospasow

Nedospasow Bild

Leader of the Subproject A13

Deutsches Rheuma-Forschungszentrum Berlin - Inflammation Biology

Postal address:

Charitéplatz 1

10117 Berlin

t: +49 30 28460 677

f: +49 30 28460 604

Our research aims at elucidating the distinct physiological functions of tumor necrosis factor (TNF) and lymphotoxin (LT) expressed by individual types of immunocytes and stromal cells in mucosal immunity and mucosal inflammation. We joined this consortium in 2006 and during the previous four-year period we discovered non-redundant functions of TNF, LTα and LTβ produced by lymphoid tissue-inducing cells (LTIC) in the genesis of mucosal lymphoid tissues. We have also uncovered an unexpected role of soluble LTα from the same cellular source in the control of IgA production in the gut – one of the first clearly distinct physiological functions of LTα different from LTβ and TNF.
In the next funding period we will extend our study to include innovative mouse models and additional disease models. In particular, we shall employ experimental colitis based on T cell transfer into RAG-/-animals [1] which is known to be TNF-dependent. We will determine the sources of pathogenic TNF, using a panel of cell type-restricted TNF knockout mice. Then we will address the consequences of cell type-specific overexpression of TNF (in particular, by T cells, LTIC and enterocytes) based on innovative transgenic system which we are generating. Intestinal inflammation and the effects of regulated TNF overexpression on the T cell compartment (Th17, Th1, regulatory T cells, as well as CD8+ T effector cells) will be assessed. This approach will be complementary to the one utilizing cell type specific TNF/LT gene deletions. Additionally, we are in the process of generating a novel TNF reporter mouse based on the far-red fluorescent protein Katushka [2] which should allow highlighting the spots of TNF production in the gut using multiphoton and fluorescent microscopy, as well as using FACS analysis. There is no useful TNF reporter mouse yet available for such analyses. Overall, the proposed study should provide mechanistic data allowing in depth exploration of TNF/LT physiology with particular focus on a possibility of TNF and LT blockade in gut inflammatory diseases.

Head of office

Birgit Röders

Birgit Roeders

Charité – Universitätsmedizin Berlin

CBF: Campus Benjamin Franklin

Charité Center Internal Medicine with Gastroenterology and Nephrology CC 13

Postal address:

Hindenburgdamm 30

12203 Berlin

t: +49 30 8445 2820

f: +49 30 8445 2820