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CCFC Sponsors National Symposium on Find the Cure The Journal, Spring 1998 by Dr. K. J. McHugh B.Sc. Ph.D. Recently, at the Canadian Digestive Diseases Week Conference in Banff, a satellite symposium was held entitled "Toward a Cure for Inflammatory Bowel Disease". This symposium was jointly sponsored by The Canadian Gastroenterology Association (CAG) and the Crohn's and Colitis Foundation of Canada (CCFC). The symposium was organized by Dr. Mary Perdue of McMaster University and Dr. Phil Sherman, of the Hospital for Sick Children in Toronto who assembled an internationally recognized group of inflammatory bowel disease (IBD) researchers from top institutions in Canada. The first speaker was Dr. Ann Griffiths, director of the IBD program at the University of Toronto, discussing the Genetics of IBD. Dr. Griffiths discussed the importance of genetic susceptibility in IBD and what researchers can learn about IBD by studying genetics? Evidence for the role of genetics in IBD comes from clinical studies that show an increased prevalence of IBD within certain families and ethnic groups. The demonstration that the spouses of IBD sufferers are not at increased risk of IBD indicates that increased prevalence in families is not caused by a contagious agent. Studies of twins offer the strongest support for a genetic influence on the disease. The chances of one twin developing the disease if the other twin has IBD is much higher in identical/monozygotic twins (identical genetics) than fraternal/dizygotic twins (different genetics). But not all identical twins with an affected sibling will develop the disease, which suggests that some "trigger" is also required for the disease to manifest itself. This also indicates that the onset of IBD stems from a number of genes and not a single gene defect as one sees in diseases like cystic fibrosis. The human body has more than 150,000 genes which provide the blueprint for manufacturing specific proteins. Even small defects in a gene can alter the proper production of that gene's intended protein, which in turn can lead to disease. Clearly, it is a daunting task to find which of the 150,000 genes contain the defect(s) that brings about the onset of IBD. Finding the gene(s) for any disease follows similar methodologies. First find which of our 23 chromosomes contains the abnormal gene(s). Then find the specific location of the gene(s) which displays the abnormality. The final step is to determine which protein that particular gene is coded for. Every gene "codes for" a specific protein, meaning it is responsible for activating the production of a specific protein. The easiest way to do this is to look for common genetic indicators or abnormalities in families with a high prevalence of the disease. This is done by comparing the genetic map of family members who suffer from IBD with those who are disease-free. Genetic sequences, or markers, that show up repeatedly in sufferers but are absent in non-affected family members are potential sites for the IBD gene. This approach is called genetic linkage and uses a technique called positional cloning. The technique consists of four steps:
These studies require a very large sample of families with multiple cases of IBD. Several preliminary studies using this technique have suggested some potential gene sites on certain chromosomes. However, confirmation of these results is needed before any conclusions can be drawn. Another option is to look for "candidate genes" or abnormalities in genes which control intestinal permeability, immune function or other mechanisms that may be involved in the onset or maintenance of IBD. This approach relies heavily on existing knowledge of how the disease develops and therefore results in a great deal of guesswork which is inefficient. Once the IBD gene(s) is identified among the candidate genes, it might be possible to develop diagnostic tests and early treatments to prevent or delay onset of the disease. Novel pharmacological agents could be developed based on what proteins the IBD gene(s) codes for. As mapping of the entire human genome continues, we narrow the search for the IBD gene and wait anxiously for what will be an important step in finding the cause and cure for IBD. The second speaker was Dr. Derek McKay from McMaster University, discussing the potential role of Microbes in IBD. There is a great deal of speculation that an as-yet-unidentified microbe is the triggering agent that leads to the onset of IBD in genetically-susceptible individuals. The role of microbes in IBD has been investigated for over 30 years. Microscopically, IBD looks like several animal diseases that are caused by microbes, including Jhones disease in cattle. Recently, several specially-bred (SCID, IL-4, IL-10 knockout) rats and mice have been shown to develop spontaneous colitis. It's been suggested that microbes play a role in the development of colitis because these animals do not develop the disease if they are kept in a germ (microbe) free environment. IL-10 knockout animals can be prevented from developing severe disease if they are treated with a certain type of bacteria (lactobacillus). This finding indicates that the balance of microbes in the gastrointestinal (GI) tract, rather than a specific microbe infection, may play a role in IBD. This finding, together with the fact that the GI tract (particularly the large bowel) is populated by hundreds of strains of bacteria, means that examining the role of microbes in IBD is a very difficult proposition. In humans, extensive efforts have failed to identify any causative microbial agent(s). This process is difficult because researchers must determine whether the changes in microbial agents are a cause or an effect of IBD. However, the recent discovery that the microbe H. Pylori was responsible for gastric ulcer disease has prompted researchers to persevere with investigations in this area. It is well-documented that microbes can change both GI tract physiology and the immune system in a direct way. E-coli infections can mimic most of the symptoms of IBD in humans. Other bacteria produce products (lipopolysacheride, toxins, peptidoglycans, superantigens) that activate the immune system, which indirectly influences GI function. The connection or link between microbes and IBD is also supported by studies that some IBD patients respond favourably to antibiotic (antimicrobial) treatment. Examinations with new biological techniques and markers are sure to provide clues about the role of specific microbes or their imbalance in the cause, maintenance or exacerbation of IBD. The third speaker was Dr. John Wallace from the University of Calgary who presented Mediators and Inhibitors of Mucosal Inflammation. Mediators and inhibitors of mucosal inflammation will probably not be a cure for IBD. However, they hold great promise as potential new therapies, particularly for people with advanced and complicated cases of IBD. It is important to remember that even if a cure were found it may only prevent new cases or be effective for newly-diagnosed cases. The mucosal inflammation of IBD is characterized by cells of the immune system attacking and destroying cells of the GI tract. This suggests a problem with the communication pathways that exists between the gut and the immune system. Thus, mediators of mucosal inflammation can be targeted at either the inflammatory cell or cells of the GI tract. In animal models of IBD, immune cells called neutrophils are critical to the inflammatory process. These cells must migrate from the blood stream into the tissue of the GI tract for inflammation to occur. This involves the neutrophil slowing down (rolling) and sticking inside a blood vessel, then forcing itself between cells (migration) into the GI epithelial tissue. If you treat animals that develop spontaneous colitis with molecules that prevent neutrophils from sticking inside the blood vessels, you can prevent the inflammation in their bowel. An example of this type of anti-adhesion molecule is "Nactins." While treatment with Nactins is effective if you treat the animal before it develops colitis, it does not seem to be effective in treating the existing inflammation. This makes it unlikely to be an effective IBD treatment because we can not predict who will develop IBD. If genetic markers for IBD can be identified as discussed previously, this type of treatment (pre-treatment) may prove useful in the future. Another possible use of inhibitors of mucosal inflammation is being studied in animal models. Rats given an enema of a chemical called TNBS develop inflammation in their bowel. The inflammation can be made to relapse once the bowel has healed. If inhibitors of a molecule called nitric oxide are given to TNBS treated animals, relapse of the inflammation can be prevented. Nitric oxide effects the function of neutrophils which are also important in human IBD. It is difficult to explain the anti-inflammatory mechanism of nitric oxide because it exists everywhere in the body and can be pro-inflammatory under certain conditions. Compounds that block inflammation at the level of immune or gastrointestinal cells are mediators of mucosal inflammation, while compounds that block inflammation by altering mediators like nitric oxide are inhibitors of mucosal inflammation. Research in this area is sure to produce new and better targeted IBD therapies in the near future. Ideally, these therapies will target specific cells or molecules and have fewer negative side effects. Some of these therapies were discussed by the final speaker Dr. Bruce Yacyshyn from the University of Alberta who discussed Novel therapies for IBD, including monoclonal antibodies, cytokines, antisense therapy and biodrugs. As with the mediators and inhibitors of mucosal inflammation, these novel therapies are unlikely to be cures. However, since these therapies target very specific substances, they might provide clues about the development of IBD. All novel drug therapies are tested in animal models and then evaluated in humans for effectiveness and toxicity. The lack of appropriate animal models and a patient database for IBD have hampered the development of some new therapies. Immune cells called T-cells (cd4 cells) have been shown to be abnormally activated in IBD patients. A specific antibody (anti-cd4) is used to get rid of the T-cells. In a recent study, anti-cd4 treatment was shown to be effective in eliminating the excess T-cells in a small group of patients, but adverse effects (general suppression of the immune system) were reported in a large percentage of the patients. This general suppression of the immune system no doubt reflects the relative non-specificity of anti-cd4. Fewer adverse effects would be expected with more specific antibodies targeted toward individual molecules rather than targeted at a group of cells. An example of a more specific antibody is the anti-TNF a antibody. TNF a may play a key role in IBD as it can effect intestinal permeability (cause diarrhea) and is found in increased concentrations in the stools of IBD patients during a flare-up. The anti-TNF a antibody is called cA2 and it was shown to improve IBD symptoms in 61 per cent of Crohn's patients treated compared to only 17 per cent treated with a placebo. The 39 per cent of patients who did not respond initially to cA2 also did not respond to a re-treatment. These results suggest that there are two sub-populations of IBD patients, one in which TNF plays a more important, causative role in the disease. There were few side effects with this treatment but more work is needed and long term follow up to monitor adverse events are underway. The molecule interleukin-10 (IL-10) is released by immune cells to slow or inhibit the inflammatory process. IL-10 deficient mice develop colitis spontaneously (except in germ free conditions). Treatment of IBD patients with IL-10 has been shown to be effective in improving the symptoms of almost 80 per cent of subjects tested. However, most patients relapsed after the treatment ended. IL-10 remains in the body for a very short time, but may effect T-cell activity for an extended period. These studies continue. Other therapies in early stages of evaluation in IBD include:
The startling number of potentially useful novel therapies provided a positive note on which to end the symposium. Notably, at the end of the symposium, an informal poll was taken as to which of the four topics presented was the most important to finding the cure for IBD. Remarkably, all in attendance agreed that research in all four areas was equally important and that focusing research efforts in only one area would not be a useful approach. The consensus was that only by funding as many research projects in many diverse areas of IBD will the cure be found. Overall, the session was an excellent demonstration that Canada and Canadian researchers are at the forefront of IBD research world wide. Dr. McHugh's attendance at Canadian Digestive Diseases Week was supported by CCFC and Axcan Pharma. The Journal, the CCFC member publication covers the latest in IBD research and management. For more information on how to receive The Journal click here. |
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