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Omvoh ™ (mirikizumab-mrkz) injection
300 mg/15 mL, 100 mg/mL
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What is the pathophysiology of inflammatory bowel disease?
Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, is a chronic, relapsing inflammatory disorder of the gastrointestinal tract.
Introduction to the Pathophysiology of Inflammatory Bowel Disease
The etiology of inflammatory bowel disease (IBD) is complex and not fully understood. The information presented here is based on interpretation of the current literature and presents the currently accepted theory of the pathogenesis of IBD.
The important role of interleukin-23 (IL-23) in the pathophysiology of IBD and the relevance of targeting IL-23 have been established via genetic studies, functional assessment in murine models, and studies using patient cells.1
This information focuses on the IL-23 axis only and does not preclude involvement of other immune factors within the pathophysiology of IBD.
Presentation of antigens from commensal microbiota and food antigens leads to activation of various T cells, including regulatory T cells. Regulatory T cells control and restrict any potential gut inflammatory responses via the release of anti-inflammatory cytokines.2,4
Development of Inflammatory Bowel Disease
Although the immune response to commensal microbiota is usually self-limiting, in patients with UC or CD, environmental factors and genetic susceptibility can combine with overactivation of the immune response to cause impaired barrier function of the intestinal wall.2,4,5
Inflammatory Mediators and Role of Interleukin-23
Dendritic cells, macrophages, and innate lymphoid cells amongst others in the intestinal lamina propria release a range of inflammatory mediators to propagate this inflammatory response. These can include
Binding of IL-23 to its receptor on macrophages promotes secretion of additional proinflammatory cytokines, including TNF-alpha and interleukin-1 beta (IL-1β).7-9
Interleukin-23 also contributes to the differentiation, expansion, and stabilization of Th17 and other interleukin-17 (IL-17)-producing cells, and in synergy with IL-1β, increases IL-17 secretion from effector T cells.2,3
Interleukin-17 is involved in the recruitment of neutrophils from nearby capillaries into the mucosa, where they degranulate and release toxic molecules, thus amplifying the inflammatory activity.10,11
Interleukin-23 Inhibition in Inflammatory Bowel Disease
Interleukin-23 is a heterodimeric cytokine made up of a p19 and a p40 subunit, and this provides different options for inhibition.13-15
Inhibition of the p40 subunit also inhibits interleukin-12 (IL-12) signaling because the p40 subunit is shared with IL-12.13-15
Nonclinical data support that specific inhibition of the p19 subunit of IL-23, therefore sparing the IL-12 pathway, preserves the perceived protective role of IL-12 in immune responses during infections and in antitumor immunity.4,15,16
The potential roles of IL-12 in the immune response during infections and in antitumor immunity are supported by genetic studies, assessment in murine models of IL-12 deficiency, and studies using human cells.4,15,16
Lilly is currently investigating IL-23 as a potential target for immune diseases, including UC and CD.
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Data on file, Eli Lilly and Company and/or one of its subsidiaries.
2Abraham C, Cho JH. IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2009;60(1):97-110. https://doi.org/10.1146/annurev.med.60.051407.123757
3Walsh KP, Mills KHG. Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol. 2013;34(11):521-530. https://doi.org/10.1016/j.it.2013.07.006
4Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-342. https://doi.org/10.1038/nri3661
5Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet. 2017;389(10080):1756-1770. https://doi.org/10.1016/S0140-6736(16)32126-2
6Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. Lancet. 2017;389(10080):1741-1755. https://doi.org/10.1016/S0140-6736(16)31711-1
7Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744-748. https://doi.org/10.1038/nature01355
8Duvallet E, Semerano L, Assier E, et al. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. 2011;43(7):503-511. https://doi.org/10.3109/07853890.2011.577093
9Eken A, Oukka M. Interleukin 23 in IBD pathogenesis. In: Huber S, ed. New Insights Into Inflammatory Bowel Disease. 2016. https://doi.org/10.5772/64882
10Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 2012;5(4):354-366. https://doi.org/10.1038/mi.2012.24
11Griffin GK, Newton G, Tarrio ML, et al. IL-17 and TNF-α sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol. 2012;188(12):6287-6299. https://doi.org/10.4049/jimmunol.1200385
12Rieder F, Brenmoehl J, Leeb S, et al. Wound healing and fibrosis in intestinal disease. Gut. 2007;56(1):130-139. https://doi.org/10.1136/gut.2006.090456
13Ma C, Panaccione R, Khanna R, et al. IL12/23 or selective IL23 inhibition for the management of moderate-to-severe Crohn's disease? Best Pract Res Clin Gastroenterol. 2019;38-39:101604. https://doi.org/10.1016/j.bpg.2019.02.006
14Teng MWL, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21(7):719-729. https://doi.org/10.1038/nm.3895
15Hamza T, Barnett JB, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci. 2010;11(3):789-806. https://doi.org/10.3390/ijms11030789
16Tugues S, Burkhard SH, Ohs I, et al. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22(2):237-246. https://doi.org/10.1038/cdd.2014.134
17Interleukin-23 and the pathophysiology of inflammatory bowel disease. Accessed October 12, 2023. https://www.lillymedical.com/en-us/answers/video-what-is-the-pathophysiology-of-inflammatory-bowel-disease-156474?hcpToken=A12DSa08bhrd123gg8
Date of Last Review: October 12, 2023