Mahima Swamy lab in the MRCPPU, have identified a new potential drug target for coeliac disease that could relieve inflammation and unlock alternative treatment options.
Her lab has investigated how the cytokine IL-15 leads to activation of intestinal immune cells, and discovered the PIM kinases as potential new drug targets for Coeliac disease.
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.
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.
Mahima's team obtained high-resolution proteomics of IL-15 activated intestinal T cells, using the world-class facilities at the MRC PPU. These studies revealed that IL-15 directly regulates the cytotoxic activity, proliferation, protein synthesis, metabolism, and immunomodulatory molecules expression of intestinal T cells. Inflammatory IL-15 also drove the expression of the PIM1 and PIM2 kinases in intestinal T cells. Using animal models, they have shown that without PIM kinases, IEL do not proliferate, grow or increase their cytotoxic machinery. They were further able to show that PIM kinases are overexpressed in intestinal tissue from Coeliac disease patients.
Olivia James, first author on the paper and postgraduate researcher 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 intestinal 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, and we identified the PIM kinases as being key to IEL responses to IL-15.
"Importantly, we have shown that coeliac disease patients express high levels of PIM kinases.
“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."
Mahima said, “While we are still exploring the mechanisms of action PIM kinases in IEL, this research opens up new avenues of research investigation whether drugs targeting PIM kinases can be used to treat inflammatory bowel diseases, particularly coeliac disease. PIM kinase inhibitors are in phase I/II clinical trials for treatment of certain types of cancers, and in the future could 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.