William Winston Agace

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Primary fields of research

Barrier Immunology

The scientific focus of the Barrier Immunology Group is to understand the cellular and molecular mechanisms regulating immune responses at our barrier surfaces, primarily the intestine. Broadly, we are interested in determining how different cell populations and niches within barrier tissues interact to support local immune homeostasis, the environmental and tissue derived factors that regulate barrier immune function and how alterations in this cross-talk contribute to the initiation and maintenance of barrier and systemic inflammation.

 

The intestinal mucosa represents the largest surface area of the body that is exposed to the outside environment and is continually exposed to foreign material derived from our diet and the trillions of microorganisms residing within the intestinal lumen.

The maintenance of intestinal homeostasis is dependent upon the immune system’s ability to remain tolerant to such material, while retaining the ability to mount appropriate immune responses to the many viral, parasitic, and bacterial pathogens that utilize the intestine as a primary site of entry into the host. A breakdown in such mechanisms is thought to contribute to the development and maintenance of inflammatory bowel disease (IBD; Crohn’s disease and ulcerative colitis).

While biologics such as TNF-a inhibitors have improved the treatment of IBD, many patients do not respond to such treatment, develop intolerable adverse events or lose the therapeutic effect over time. There is thus an urgent and unmet need for new directions and approaches to disease management and treatment.

Center for Intestinal Immune Regulation (CIIR)

Funding: NNF-Challenge grant

The overall aim of CIIR is to investigate the mechanisms by which intestinal fibroblasts regulate intestinal immune function in health and disease. CIIR is focused on testing two major hypotheses; (1) that intestinal fibroblasts play a key role in intestinal immune cell development, maintenance and function and that such processes are essential for maintaining intestinal immune homeostasis and (2) that alterations in intestinal fibroblast-immune cell crosstalk can contribute to the initiation and maintenance of IBD.

To test these hypotheses, CIIR brings together 4 collaborating groups (Agace (Copenhagen University), Prof. Flemming Bengtsen (Hvidovre Hospital), Ass. Prof. Lars Rønn Olsen (Technical University of Denmark) and Prof. Kathy McCoy (University of Calgary)) with expertise in gastroenterology, mucosal immunology and bioinformatics where we combine the analysis of human intestinal tissues using in-house developed isolation protocols in combination with single cell (transcriptional and proteomic) analysis and in vitro modelling with more mechanistic studies using state-of-the-art transgenic animal models (see Figure below).
The long-term goals of CIIR are to identify novel treatment modalities for IBD as well as biomarkers of disease severity and treatment response.

An Atlas of intestinal immune niches in health and Crohn’s disease

Funding: The Leona M. and Harry B. Helmsley Charitable Trust, Gut Cell Atlas Consortium

As part of the Gut Cell Atlas (GCA) consortium and together with Prof. Eugene Butcher (Stanford University), we are generating a single cell transcriptional and proteomics atlas of immune niches of the human ileum and proximal colon in health and in Crohn’s disease, including human GALT (Gut associate lymphoid tissues; Peyer’s patches, mucosal and submucosal isolated lymphoid follicles), intestinal draining mesenteric lymph nodes and GALT-free intestinal lamina propria. Bioinformatic analysis of generated data sets as well as in vitro culturing techniques are focused on assessing antigen presenting cell diversity as well as adaptive immune cell priming and trafficking within intestinal inductive and effector sites in health and in Crohn’s disease.

Immune crosstalk along Gut-Skin axis

Funding: LEO Foundation Skin Immunology Research Center (SIC)

IBD is often associated with extra-intestinal co-morbidities. For example, approximately 1 in 10 patients with IBD display skin associated comorbidities including psoriasis, psoriatic arthritis, atopic dermatitis, pyoderma gangrenosum, and erythema nodosum. Despite this the underlying immunological processes linking intestinal and skin inflammation in these patients remains poorly understood. The aim of this project is, together with collaborators within SIC, to perform deep immunological profiling of affected skin and intestinal tissues from these patients to determine whether one can identify commonalities in inflammatory pathways and cell types across inflamed tissues.