This joint research center in Erlangen and Berlin is thought to expand our insights into the crosstalk between the gut barrier and mucosal immune cells in the pathophysiology of IBD with the ultimate aim of developing novel therapeutic strategies.
The scientific program of the TRR 241 has been structured into three project areas:
- Project area A is denoted Immune Regulation of Intestinal Barrier Functions and comprises projects whose main focus is on studying the effects exerted by acute and chronic inflammation on epithelial cells, especially on their homeostasis, differentiation and barrier-forming functions.
- Project area B is denoted Epithelium as Modifier of Mucosal Immunity and Inflammation. It comprises projects that focus on the impact of barrier dysfunction and antigen translocation on the mucosal immune system.
- Project area C is denoted Diagnostics and Therapeutic Intervention of IBD and its projects aim to develop and clinically evaluate innovative therapeutic and diagnostic approaches.
Collectively, it is expected that our research will allow unique insights into the immune-epithelial crosstalk in IBD that can be translated into new concepts on IBD pathophysiology and therapy.
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Chronic intestinal inflammation is characterized by increased expression of pro-inflammatory cytokines, such as interferons, TNF-a, IL-6 and IL-1β (Khor et al., Nature 2011; Neurath et al., Nature Rev Immunol 2014; Becker et al., Immunity 2004). While their role in inducing and shaping immune responses is well defined, their role on tissue resident cells such as IECs is far less known. In fact, cytokines such as TNF-a, IL-22 and IL‑33 have recently emerged as key players in the context of gut inflammation as well as in the regulation of epithelial cell function (Neufert et al., J Clin Invest 2013; Wittkopf et al., J Gastroenterol 2014; Günther et al., Nature 2011; Nenci et al., Nature 2007). It is therefore becoming increasingly clear that inflammatory cytokines direct intestinal inflammation not only by activation of immune cells but also by direct effects on IECs thereby regulating homeostasis and intestinal barrier functions. In support of this view, IECs express a wide array of receptors for pro- and anti-inflammatory cytokines. The unifying aim of projects within project area A is to better understand the nature and consequences of signaling from immune and stromal cells to the intestinal epithelium.
Dysregulation of the crosstalk between IECs and the immune system is of central importance in the pathogenesis of IBD. While cytokines derived from activated immune cells affect IEC function and homeostasis, IEC stress and barrier dysfunction in turn lead to bacterial translocation and immune activation (Lopez-Posadas et al., J Clin Invest 2016; Takahashi et al., Nature 2014; Zeissig et al., Gut 2004). On a more subtle level, epithelial cells release immunogenic molecules that can shape the mucosal immune system and anti-microbial effectors that shape the luminal microbiota both in the steady state and during inflammation. The fact that mice devoid of intestinal microbiota have defects in the maturation of the immune system completes the triangle of microbiota-epithelial-immune interaction. The unifying aim of project area B is to reveal how intestinal epithelial cells and the associated barrier function affect and shape mucosal immune reactions and inflammation in IBD.
A major success of research-driven drug development, which has doubtlessly improved the clinical therapy of IBD, has been the development of biological therapies as well as upcoming small molecules, which selectively inhibit crucial pathways of the inflammatory process. However, potential side effects, such as infections and onset of cancer, have been described and up to half of the antibody treated patients fail to show clinical response to the treatment. This has raised an urgency to identify novel therapeutic targets and to identify biomarkers that predict therapeutic efficacy for biological therapy. The identification of novel pathways will not only pave the way ahead in the identification of novel therapeutic and diagnostic approaches, but will also lead us into an era of personalized medicine where prognostic classification of patients into “responders” and “non-responders” to a given therapeutic alternative can be achieved to avoid adverse outcomes. Such an approach would avoid exposure of non-responders to an inefficient targeted therapy and hence prevent potential side effects. Moreover, similar to the general concepts of pathophysiology, therapy and diagnostics of IBD, new therapeutic strategies have mainly been centered on the excessive activation of the immune system. However, with the emerging appreciation of the essential role of the epithelium and its interaction with the microbiota on one side and the immune system on the other side, our aim is to establish the therapeutic potential of interfering with the dysregulated immune-epithelial crosstalk and to develop novel diagnostic and therapeutic strategies. It is the unifying aim of project area C to develop and clinically evaluate such innovative therapeutic and diagnostic approaches.