University of Dundee

Researchers discover coeliac disease drug target

13 Jul 2021

At least 1 in 100 people in the UK are estimated to have the gluten-driven autoimmune disorder, coeliac disease. The only treatment for coeliac disease is a life-long gluten-free diet, and there is an unmet clinical need for alternative treatment options.

A lab team led by Dr Mahima Swamy in the School of Life Sciences has investigated how IL-15 leads to activation of intestinal immune cells and identified PIM Kinases as potential targets to reduce inflammatory responses.

Their findings open new avenues of research to investigate whether drugs targeting PIM kinases can be used to treat inflammatory bowel diseases, particularly coeliac disease.

One of the hallmarks of coeliac disease is the overexpression of IL-15 in the gut. IL-15 acts as a communicator between the lining of the gut and intestinal immune cells, and when the lining of the gut is distressed or damaged more IL-15 is released, causing the immune cells to kill the damaged cells.

In coeliac disease and other inflammatory bowel diseases, IL-15 is overproduced, leading to extensive damage of the gut wall.

The studies have revealed that IL-15 not only triggers cytotoxic activity in intestinal immune cells, but that it also directly regulates their proliferation, protein synthesis, metabolism, and immunomodulatory molecules expression.

Dr Mahima Swamy, Wellcome Trust and Royal Society Sir Henry Dale Fellow and Programme Leader in the MRC Protein Phosphorylation and Ubiquitylation Unit, in the School of Life Sciences said, “In patients with coeliac disease both the levels of IL-15 and the numbers of IEL, a type of T-cell, are increased in the small intestine, leading to T cell-mediated damage of the intestinal lining.

“We wanted to understand how high levels of IL-15 might trigger the IEL to damage the intestinal tissue.

“We have shown that coeliac disease patients express high levels of PIM kinases, and using animal models, we have shown that without PIM kinases, IEL do not proliferate, grow or increase their cytotoxic machinery.

“These are exciting results as uncovering the mechanisms by which IL-15 leads to T cell-mediated damage in the small intestine is instrumental in treating coeliac disease.

“While we are still exploring the mechanisms of PIM kinases in IEL, we are really excited about the possibilities. PIM kinase inhibitors are in phase I clinical trials for treatment of certain types of cancer,  so in the future these drugs could potentially be used to treat coeliac disease patients by limiting IEL numbers and subsequent damage to the small intestine.

The research was funded by the Wellcome Trust and has been published in Nature Communications.

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