Translational IBD research at Gut Research

The Department of Gastroenterology and Hepatology of the Academic Medical Center in Amsterdam is an expert and referral centre for IBD and has a longstanding tradition of excellent patient care combined with both clinical and fundamental research activities. Since several years now its fundamental IBD-research is bundled in the Tytgat Institute. The close collaboration between the Tytgat Institute and the Gastroenterology department is an important strength of our approach. See also IBD-AMC. We have various relevant models for colitis in our lab including acute and chronic innate driven colitis models, and acute and chronic Tcells driven colitis models. See for details on the models of choice for your compound efficacy testing this link.

In the Netherlands, but also internationally, the AMC fulfils a leading role in state-of the art treatment options for IBD. In the past the AMC IBD unit introduced the concept to treat patients with Crohn’s disease with antibodies against tumor necrosis factor (anti-TNF), a breakthrough in the therapy of this disabling disease. Over the years, other novel insights in the pathogenesis and genetics of IBD have been introduced, including the importance of IL-10 as potential treatment. The latter has led to the generation of genetically manipulated lactobacillae producing IL-10 (tested in patients with Crohn´s disease). At present the clinical IBD group is headed by Prof G. D’Haens who plays a crucial and coordinating role in phase I and II clinical trials evaluating the therapeutic potential of new biologicals. His internationally acclaimed expertise ensures timely ‘bench to bedside’ translation of results obtained in the Tytgat Institute.

In vitro and in vivo

At the Tytgat Institute state of the art in vitro assays and in vivo models (used on a routine basis) allow us to investigate the role of pathways relevant to the development of IBD. In a large number of publications we not only used conventional mouse models like DSS- and TNBS-colitis but also the CD45RB T cell transfer model that most closely reflects human IBD. These models were used to establish basic mechanisms in IBD as well as pharmacological and dietary intervention strategies.

Since we have broad access to patient tissues and isolated cells we also validate our experimental data by immunological phenotyping and activation of mucosal lymphocytes, dendritic cells and macrophages. Data obtained in these in vitro investigations can be correlated with clinical phenotype and (epi)genetic profile of patients suffering from this chronic condition.

These models are optimized for testing of pharmaca, biological, or nutritional interventions to relieve the severity of colitis. An in vivo mouse endoscope has been recently set up to be able to perform life imaging of the colitic lesions, and the recovery due to experimental treatment.

Human resection material can be processed in MLII environments. All ethical approval is in place for the use of human material in test setting in our lab.

This research can lead to major paradigm shift in common medication for inflammatory bowel disease

Nerve stimulation in the treatment of inflammatory bowel disease

The autonomic nervous system has a significant regulatory impact on immune responses. Pioneering studies on electrical or pharmacological stimulation of autonomic nervous system have shown to hold promise in ameliorating chronic inflammatory disease conditions such as RA and IBD. However, underlying cellular mechanisms and neural networks to be targeted are not well understood. Hence there is a need for a more targeted peripheral approach.

In the context of IBD, selective (para)sympathetic resection of the respective two branches of the colon allow us to identify their role in the immune response regulation and progression in colitis-models. We have so far collected data in which the GI related nerves are essential controllers of the severity and progression of colitis. These data are in line with the in vitro potential of adrenergic neurotransmitter receptors to dampen dendritic cell and macrophage maturation. Therefore the implantation of cut-off electrodes will allow the recording and the stimulation of those nerves providing a specific nerve ‘’treatment code’’ to regulate the disease severity/progression of IBD. This research will impact our understanding of the mechanism of neuronal regulation of intestinal inflammation and can lead to major paradigm shift in common medication for IBD.

IBD

GSK alliance

The bioelectronics study is a joined project with the Research and Development Department of GlaxoSmithKline (GSK) in the United Kingdom.

Some of our team members joined the GSK Bioelectronics meeting in New York City on December 16th & 17th in 2013. Two videos of that meeting can be watched here.

For more information about GSK, click on this link.