Immunopathogenesis of inflammatory bowel disease

A/Prof Michael Grimm

Inflammatory bowel diseases (IBD) are relatively common chronic inflammatory conditions that affect predominantly working-age people, and they manifest as abdominal pain, diarrhea and bleeding. Their cause is unknown but it involves an interaction between genetic predispositions, bacteria within the gut and a number of environmental factors, which combine to generate a chronically activated immune system that attacks the intestinal lining. Although some potent new therapies are being introduced, there remains a pressing need for novel, targeted treatments.

We have been exploring the immune mechanisms by which the chronic relapsing and remitting nature of intestinal inflammation is perpetuated. Over several years we have examined the mechanisms by which damaging white cells exit the blood and move into the intestine, particularly focusing on a group of peptides known as chemokines, and their receptors, and proteins produced by both nerves and immune cells, known as neuropeptides. More recently we have turned our attention to a long-postulated but only recently confirmed type of cell know as the regulatory T cell, which is known to inhibit immune and inflammatory responses, proposing that a relative deficiency in number or activity of this cell might be a contributor to the chronic inflammation of IBD. In addition we have begun to explore the immune mechanisms behind a strongly confirmed epidemiological observation, that appendicitis and appendicectomy protect against the later development of IBD, and lessen its severity if it does occur.


These studies have yielded the first described model of appendicitis in the mouse. This appendicitis model is associated with acute inflammation, oedema and occasionally (as in humans) in abscess formation and peritonitis. The cellular constituents of the appendix are significantly altered by appendicitis, with marked increases in the numbers of several types of lymphocytes, including regulatory T cells. These changes are only observed when appendicitis is induced in young mice. These cells are capable of migrating from the inflamed appendix, through the circulation and back to the bowel. As has been observed in human epidemiological studies, appendicitis and appendicectomy, if they are performed in young mice, protect against the development of TNBS colitis. This protection is associated with markedly increased numbers of regulatory T cells in the bowel. These cells have a potent capacity to produce the immunoregulatory cytokine, IL-10. Indeed, if we block the activity of IL-10 in this model, protection against TNBS colitis is lost completely. These studies show the critical immune effects of this cell type, and the mechanism by which these cells protect against bowel inflammation.

Future studies will go on to explore the activities in the bowel that might normally lead to inflammation that are being inhibited by these potent regulatory T cells. We will also begin exploration of similar effects in human subjects, using tissues removed during various types of appendicectomy and bowel surgery.