Lay Summary

Proposal No. IBD-0260R
Principal Investigator: Stella Knight, Ph.D. 
Applicant Organization: Imperial College of Science, Technology and Medicine (London, England)
Project Title: Modulation of inflammatory effects of leptin in inflammatory bowel disease
Period of Award:  April 1, 2009 – March 31, 2011

Patients who have Crohn’s disease have inflammation in their gut that underlies their symptoms. Although patients may lose weight overall, a surprising and early feature of the disease is the laying down of fat around the gut itself. This increased fat within the intestinal region is accompanied by changes in the nature of the fat. There are increases in the proportion of saturated fats, evidence of increased numbers of cells of the immune system in the fat and increases of growth factors that are produced mainly within the fat. One of these growth factors, called leptin, is important in controlling appetite. However, it is now apparent that this growth factor also has effects on different cell types and these effects include promoting the growth of cells of the immune system.

The inflammation in the gut in Crohn’s disease is thought to be due to the development of an immune response directed at gut bacteria. There is change in the balance of different types of bacteria in the gut which involves the loss of bacteria that we know can inhibit inflammation, and increases in other bacteria which may be promoting intestinal inflammation. The major cells involved in the inflammatory reaction are T lymphocytes which are increased in the gut in Crohn’s disease. However, the activities of T lymphocytes are orchestrated through another type of cell known as an antigen presenting cell; these cells are called dendritic cells. There are only small numbers of dendritic cells present in the wall of the intestine but they spread out long veiled extensions so that they are able to sample the complete environment in that region. They even have veiled extensions that pass between the lining cells of the gut into the intestinal tract itself where they can sample materials passing through the gut. These cells, which constantly sample the environment, are able to recognise harmful bacteria or “friendly” bacteria and take appropriate action. They will either stimulate T cells to respond to the bacteria through inflammatory activity, or alternatively they can promote tolerance of the useful bacteria within the gut. There is now evidence that these dendritic cells have multiple surface ‘receptors’ which bind the growth factor leptin that is produced in excess in Crohn’s disease. One form of the leptin binding surface receptor penetrates deep into the cell and is involved in the immunological activation. Other forms of receptor are more superficial and binding of leptin preferentially to these forms may prevent activation of the cells or cause different effects. In studies, particularly in mice, leptin has been shown to cause inflammatory activity by promoting the maturation of dendritic antigen presenting cells and the up-regulation of their capacity to recognise bacteria and to travel to the lymph nodes where T cells will be stimulated.