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Paneth cells and Crohn's disease. The cause of Crohn's disease is not known, although many researchers believe that illness results when intestinal bacteria, which are harmless in most people, cause inflammation. Indeed, antibiotics are often used to treat a flare-up of Crohn's disease in patients. Crohn's disease occurs more commonly in families and it is clear that an individual's genetic make-up can make them more liable to develop this illness. Indeed, researchers have recently found that individuals with alterations (or 'mutations') in the N0D2 gene are more liable to develop Crohn's disease. The reasons why individuals with alterations in the N0D2 gene develop intestinal inflammation are not known, but it is possible that these individuals are more liable to intestinal infection. Researchers have recently shown that the level of 'defensins', which are naturally occurring proteins that kill bacteria, are lower in patients with Crohn's disease, especially in those individuals with alterations in the N0D2 gene.
The 'defensin' proteins are made and secreted by specialised cells called Paneth cells. Paneth cells are found in intestine and play a critical role in protecting against intestinal infections. These cells also secrete other types of proteins (called 'antimicrobial' proteins) that break bacteria down into smaller fragments. One of these bacterial fragments (known as MDP) is thought to be detected by the N0D2 protein. We have shown that Paneth cells also prominently express the N0D2 protein, which suggest that these cells may play a role in the development of Crohn's disease. To support this theory, scientists have shown that 'defensin' proteins are decreased in laboratory mice that have alterations in the N0D2 gene, and these mice develop intestinal infection more easily than normal mice. We are therefore analysing the levels of 'defensins' in patients with Crohn's disease, and are investigating how altered N0D2 proteins affect the function of human paneth cells and predispose to Crohn's disease. Extract taken from The Insider CICRA Autumn 2005.
Cannabis-derived medication for IBD? NEW EVIDENCE suggests that patients with IBD could benefit from medication containing extracts from cannabis. The findings came from a study at Bath University, where researchers explored anecdotal evidence that cannabis appeared to relieve some of the symptoms of IBD. Looking at gut samples from healthy patients and people with IBD, the researchers examined two particular molecules (known as receptors) called CB1 and CB2, which are activated by the presence of molecules found in cannabis. They discovered that whilst CB1 is present in healthy people, the presence of CB2 increases in IBD patients as their disease progresses.
The researchers believe that the presence of CB2 receptor only in patients with active IBD may indicate that it is part of the body's natural mechanisms that attempt to restore the normal healthy state of the gut, and that this makes it an ideal candidate for the development of new cannabis-derived drugs to help treat IBD. They also found that the CB1 receptor helps to promote wound healing in the lining of the gut. Dr Karen Wright from the University's Department of Pharmacy and Pharmacology said: "The normal job of the CB1 and CB2 receptors is to help moderate diverse responses throughout the body, but their presence in the gut means that they could be useful targets for the development of cannabisderived drugs for controlling the progression of IBD." Dr Peter McIntyre, NACC Medical Advisor, commented: "The gastroenterology community welcomes new research of this calibre as the paper draws interesting conclusions which may be relevant to people with Ulcerative Colitis and Crohn's Disease. The authors raise a possible hypothesis about the roles of cannabinoid receptors in UC and Crohn's Disease which now needs to be followed through with extensive development work and clinical studies." Extract taken from NACCNEWS Autumn 2005.
Adalimumab may be useful treatment for active Crohn's Disease. Several trials have been looking into the drug adalimumab (marketed as Humira) as a treatment for patients with Crohn's Disease. Following an earlier trial to assess the value of adalimumab as an induction therapy, ie the ability of the drug to induce remission in patients with active disease, an extension of the same study into the drug's long-term efficacy and safety found that 78% of patients showed improvement in their Crohn's symptoms after 24 weeks of treatment with the drug. Adalimumab belongs to the class of drugs called human monoclonal antibodies. In this case adalimumab is said to be structurally identical to naturally occurring antibodies which work to fight off infection. Adalimumab works by binding to and blocking the action of TNFalpha. This is a naturally occurring molecule which causes inflammation and which may play an important part in causing Crohn's Disease. Infliximab (Remicade), which is also effective in treating Crohn's, is a similar drug, but is partly engineered from mouse genes and so may cause more side effects.
The adalimumab trial included 220 patients who had taken part in the original CLASSIC study and whose disease had not gone into remission at key stages of the second trial. The trial was 'open label' - so all patients knew they were receiving active drugs, and patients were observed over a period of six months. After 24 weeks 78% of patients saw an improvement to their disease, as measured against the Crohn's Disease Activity Index, or CDAI, while one in three experienced clinical remission (again, defined against the CDAI). Formal double blind phase III trials will be completed later this year, and once these are completed, the data can be presented to the Medicines Control Agency who will forward it to the Committee on Safety of Medicines for approval. Adalimumab has also been tested in patients with severe Crohn's Disease who had stopped responding to infliximab. These were small trials, involving 15 and 24 patients respectively. The results indicated that adalimumab may be effective, but that larger doses may be required than were given to the patients in the trial, and that this could prove expensive.
In summary, it appears that there may be a role for adalimumab in active Crohn's Disease, possibly in patients who develop antibodies to infliximab, as it is a more completely humanised antibody. However, it is likely to be a year or two before it is available for use in routine clinical practice, and due to its cost it is likely to be restricted to difficult cases. Extract taken from NACCNEWS Autumn 2005.
