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For medical media only The role of IL-12/IL-23 in Crohn’s disease What is Crohn’s disease? Crohn’s disease is a chronic inflammatory condition affecting the gastrointestinal (GI) tract, most often occurring in the end of the small intestine (ileum) or the beginning of the large intestine (colon), but may involve any part from the mouth to the anus. 1,2 In Europe 250,000 people are living with Crohn’s disease, with around 18,000 new cases diagnosed each year.3 Though anyone can be affected by Crohn’s disease at any age, it most often impacts those between the ages of 15 to 35 in both men and women.3 Crohn’s disease belongs to a group of conditions known as Inflammatory Bowel Diseases (IBD) and is marked by an abnormal response from the body’s immune system to food, bacteria and other materials in the intestine that are mistaken for foreign substances. 2 How is the immune system involved in Crohn’s disease? The intestines are home to a complex mucosal immune system which is thought to interact with bacteria (microbiota) that live in the gut in order to maintain homeostatic balance. If the balance of the intestinal immune system is disrupted, it can make the normally harmonious bacteria in the gut induce a response from the body’s own immune system. 4,5 The immune system’s initial first line response, known as the innate immune system, will be activated; however, these short-term inflammatory processes may not be enough to deal with the invasion and the adaptive immune response will then become activated. This may result in acute intestinal inflammation which can usually be resolved by the suppression of these pro-inflammatory immune responses and anti-inflammatory mechanisms.6 However, in Crohn’s disease, the inflammation caused by the immune response may not be resolved by these means and can, in turn, induce an uncontrolled activation of the mucosal immune system leading to chronic intestinal inflammation. This inflammation can cause further complications such as tissue destruction and ongoing disease activity.6 What are IL-12 and IL-23 and how are they involved in Crohn’s disease? Specific immune cells that form part of the immune response respond to certain bacteria from the gut by producing signaling molecules known as cytokines that can promote chronic inflammation of the GI tract and cause the symptoms of Crohn’s disease. 6 These signalling molecules, among others, include interleukins (IL) -6, -10, -12, -23 and tumour necrosis factor.6 IL-12 and IL-23 are small proteins that regulate the adaptive immune response and are seen at increased levels in active Crohn’s disease.7 They are involved in the mucosal immune response that responds to inflammation and the further activation and recruitment of immune cells that contribute to uncontrolled chronic intestinal inflammation.6,8,9 Why are IL-12 and IL-23 inhibitors potential treatments for Crohn’s disease? IL-12 and IL-23 have been shown to have a fundamental role in controlling mucosal inflammation and have therefore been identified as a relevant and realistic therapeutic approach to target autoimmune driven diseases.10 Moreover, both IL-12 and IL-23 share a common component known as the p40 subunit. There is evidence to show that therapies which target the p40 subunit and inhibit parts of the inflammatory cascade, an approach that has proved successful for psoriasis and psoriatic arthritis, are also credible therapeutic agents for Crohn’s disease and are currently being assessed in clinical trials.10,11,12 March 2016 PHEM/IMM/0216/0003 For medical media only References 1 www.ccfa.org/what-are-crohns-and-colitis/what-is-crohns-disease/. http://www.cdc.gov/ibd/what-is-ibd.htm. 3 http://www.efpia.eu/diseases/78/59/Inflammatory-Bowel-Disease. 4 Duchmann R et al. Clin Exp Immunol 1995;102:448–455. 5 Mow WS et al. Gastroenterology 2004;126:414–424. 6 Neurath MF et al. Nat Rev Immunol 2014;14:329-342. 7 Sartor RB. Nat Clin Pract Gastroenterol Hepatol 2006;3:390–407. 8 Melmed GY et al. Nat Rev Gastroenterol Hepatol 2010;7:110–117. 9 Tato CM et al. Nature 2006;441:166–168. 10 Toussirot E. Inflamm Allergy Drug Targets 2012;11(2):159–68. 11 Sandborn W, et al. AIBD 2015:Abstract O-0001. 12 Feagan B, et al. UEGW 2015:Abstract UEG15-LB-5668. 2 March 2016 PHEM/IMM/0216/0003