Homing in on the mechanisms and treatment of inflammation in IBD

July 31, 2015 By: Philip J. Smith

Homing in on the mechanisms and treatment of inflammation in IBD

α4β7 integrin has recently emerged as a new target for therapy in patients with inflammatory bowel disease (IBD), via the monoclonal antibody vedolizumab. The therapeutic benefit of α4β7 integrin blockade using vedolizimab has been successfully shown for both Crohn’s disease and ulcerative colitis.1,2

The process by which T cells enter the gut mucosa is tightly controlled by a specific homing process involving regulatory molecules on the T-cell surface and their ligands on intestinal endothelial cells. The blockade of T-effector cells (Teff cells) has been demonstrated to be effective in IBD; however, little is known about the mechanisms that control the homing of regulatory T cells (Treg) to the inflamed bowel, although recent research has demonstrated that the G-protein-coupled homing receptor, GPR15, controls the homing of Treg cells to the colon in mice.

In a new study in Gut, Fischer et al.3 studied the in vivo homing of Teff and Treg cells to the inflamed gut via α4β7 integrin and GPR15. The authors looked at expression of homing receptors on T cells from both peripheral blood and inflamed mucosa. They also used a ‘humanised’ mouse model in dextran sodium sulfate (DSS) treated mice to study the migration pattern and homing of Teff and Treg cells to inflamed gut.

Expression of α4β7 integrin and GPR15 on human Treg cells was upregulated in ulcerative colitis, as opposed to Crohn’s disease and controls, and regulated by inflammatory cytokines. In addition, the in vivo homing of Treg cells from patients with ulcerative colitis to the inflamed colon in humanised mice was demonstrated to be augmented when compared with the homing of Treg cells from controls.  Using vedolizumab to block adhesion molecule function did not alter the homing of Treg cells from controls, but showed that α4β7 integrin rather than GPR15 is crucial for controlling homing of Treg cells of patients with ulcerative colitis to the inflamed colon in vivo. By contrast, both molecules were shown to be involved in Teff  cell homing in ulcerative colitis. Finally, the authors demonstrated that vedolizumab therapy results in the accumulation of Treg cells in the peripheral blood of patients with ulcerative colitis.

This is an interesting study because it clearly identifies GPR15 as another potential therapeutic target for the blockade of Teff cell homing in IBD. However, possibly more significantly, via the use of the humanised mouse model, this study offers researchers another method to evaluate the use of anti-adhesion therapies and human T-cell homing in vivo in IBD. 

References 

1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710.

2. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369: 711–721.

3. Fischer A, Zundler A, Atraya R, et al. Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut Epub ahead of print 24 July 2015. doi:10.1136/gutjnl-2015-310022.

About the author

Dr Philip J. Smith is a gastroenterology specialist registrar in London, United Kingdom. He has a specialist interest in Inflammatory Bowel Diseases (IBD), both as a patient with Crohn's disease and as a Medical Research Council Clinical Research Fellow currently writing up his thesis in the field of IBD! Dr Smith has written and co-authored a number of peer-reviewed clinical and scientific papers and a number of published books; he is co-author of the BMJ Best Practice series on Crohn's disease. He is the immediate past chair of the BSG Trainees Section, and was awarded the prestigious BSG President's Medal in 2014. He has developed a number of national and international educational courses related to gastroenterology training, IBD and Nutrition and is an associate editor of a number of peer-reviewed journals.

 

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