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About ILREMU

Background: Th2 characterized chronic inflammatory diseases

Ulcerative colitis, atopic dermatitis and asthma are chronic diseases in which relapses are followed by periods of remission. In severe cases they are treated with immunosuppressive drugs that may induce severe side effects such as opportunistic infections, osteoporosis and diabetes. This is hard to accept for patients who are usually young and in full swing of their professional and private lives. A better understanding of the mechanisms underlying relapses might ultimately lead to custom-tailored therapies. Development of therapeutics targeting specifically the development of pathological manifestation might improve current therapies.

The Inflammatory Milieu of Th2 Characterized Chronic Inflammatory Diseases

Th2 characterized inflammatory diseases are highly dynamic processes initiated by epithelial cell damage resulting in remodeling of the tissue architecture to prevent further harm caused by a dysfunctional epithelial barrier.  This process is a temporal and spatial response that requires communications between immobile cells such as fibroblasts, epithelial, endothelial, and muscle cells, and the highly mobile cells of the innate and adaptive immunity.

Figure 1: The route from Th2 response to pathological manifestations 

Figure 1: The route from Th2 response to pathological manifestations

 

It is further characterized by a high cellular plasticity which enables the cells to adapt to a specific inflammatory milieu. In the beginning, this milieu is shaped by cytokines released from epithelial cells which stimulate Th2-, innate lymphoid and invariant NKT cells to secrete Th2 cytokines and to activate dendritic cells which results in the further differentiation of Th2 cells.
This milieu promotes wound healing processes which are beneficial in parasitic infections or toxin exposure but account for increasingly dysfunctional vital organs such as the colon in ulcerative colitis and the lung in the case of asthma. A better understanding of the dynamics underlying relapses and remissions might ultimately lead to improved therapeutics for chronic inflammatory diseases adapted to individual needs and to different phases of the inflammation.

ILREMU Projects

A - Characterization of the inflammatory milieu

 

Figure 2: Schematic depiction of the approach. In snapshot and longitudinal studies cellular and molecular profiles of patients will be generated and analysed with cluster analysis.
Figure 2: Schematic depiction of the approach. In snapshot and longitudinal studies cellular and molecular profiles of patients will be generated and analysed with cluster analysis.

B - Development of specific IL-13R antagonists

Inhibition of pathological manifestation by IL-4 mutation and derivatisation.  ... 

Figure 3: Inhibition of pathological manifestation by IL-4 mutation and derivatisation. In collaboration with Prof. Dr. Thomas Mueller, University of Würzburg, an IL-4 / IL-13 receptor antagonist will be developed. This antagonist will be designed to suppress the pathological manifestations of the diseases without interfering with T-cell responses which are important to mount immune responses against general infections.

C - Improved animal models: HuCID Mouse Models

C - Improved animal models: HuCID Mouse Models

Figure 4: The HuCID Mouse technology platform has been developed in collaboration with Prof. Dr. Eckhard Wolf, Gene Center Munich. The platform is based on NOD / Scid mice engrafted with human peripheral blood mononuclear cells (PBMCs) isolated from patients suffering from chronic inflammatory diseases. Engrafted mice reflect pathophysiological mechanisms of the genetically heterogeneous patient population.  Selection and in vitro analysis of PBMCs prior to engraftment allows for stratification of patients already at this early point of development. Studies in this model create value and reduce risks of later clinical trials.