Mirikizumab

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Mirikizumab: Interleukin-23 and the Pathophysiology of Inflammatory Bowel Disease

Inflammatory bowel disease including UC and CD, is a chronic, relapsing inflammatory disorder of the gastrointestinal tract.

Detailed Information

In the healthy gut, antigen-presenting cells, such as macrophages and dendritic cells continually process intraluminal, antigens and present to T lymphocytes.1

The Development of Inflammatory Bowel Disease

Inflammatory bowel disease including UC and CD, is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. 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 over activation of the immune response to cause impaired barrier function of the intestinal wall.1,2

Cells such as dendritic cells, macrophages, and innate lymphoid cells in the intestinal lamina propria release a plethora of inflammatory mediators to propagate this inflammatory response. These can include

  • IL -4, -9, and -13

  • TNF-alpha, and

  • interferon-γ.1,2

Interleukin-23 released from activated dendritic cells and macrophages, plays a critical role in the amplification of the inflammatory response by

  • binding to its receptors on macrophages promoting the secretion of additional pro-inflammatory cytokines such as TNF-alpha and IL-1β

  • contributing to the differentiation, expansion, and stabilization of TH17 cells, and

  • in synergy with IL-1β, increasing IL-17 secretion from effector T cells.3,4

Interleukin-17 is involved in the recruitment of neutrophils from nearby capillaries into the mucosa to amplify the inflammatory activity by

  • degranulation, and

  • release of toxic molecules.5,6

In UC, large numbers of activated neutrophils in the lamina propria can cross the epithelium to form a crypt abscess. The exacerbated inflammatory response leads to

  • epithelial breakdown

  • depleted goblet cells, and

  • an impaired mucus layer in UC, or

  • intestinal wall fibrosis in CD.2,5

The etiology of IBD is complex and is not fully understood. The information presented here is based on interpretation of the current literature and presents the currently accepted theory of pathogenesis of IBD. The information focuses on the IL-23 axis only and does not preclude involvement of other immune factors within the pathophysiology of IBD.7

Eli Lilly and Company is currently investigating IL-23 as a potential target for immune diseases, including UC and CD.

A video with a more detailed description of the mechanism of disease of IBD can be accessed at: https://www.kaltura.com/tiny/x712w.8

References

1. Abraham C, Cho JH. IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2009;60:97-110. https://doi.org/10.1146/annurev.med.60.051407.123757

2. Ungaro 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

3. Cua 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://dx.doi.org/10.1038/nature01355

4. Duvallet E, Semerano L, Assier E, et al. Interleukin-23: A key cytokine in inflammatory diseases. Ann Med. 2011;43(7):503-511. https://dx.doi.org/10.3109/07853890.2011.577093

5. Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 2012;5(4):354-366. https://dx.doi.org/10.1038/mi.2012.24

6. Gabriel GK, Newton G, Tarrio ML, et al. IL-17 and TNFα sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol. 2012;188(12):6287-6299. https://dx.doi.org/10.4049/jimmunol.1200385

7. Eken 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

8. Interleukin-23 and the Pathophysiology of Inflammatory Bowel Disease. https://www.kaltura.com/tiny/x7i2w. Accessed June 18, 2019.

Glossary

CD = Crohn’s Disease 

IBD = inflammatory bowel disease

IL-1β = Interleukin-1 beta

IL-17 = Interleukin-17

IL-23 = Interleukin-23

TH17 = T helper 17 cells

TNF = tumor necrosis factor

TNF-alpha = tumor necrosis factor alpha

UC = ulcerative colitis

Date of Last Review: May 03, 2019

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