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60 Executive Briefing TNF, IL-1, IL-6, IL-8, IL-12 and IL-18) by other cell types such as macrophages, endothelial cells and monocytes. xvii The role of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been well-established as being central to mediating IBD, but more recent data have implicated the IL-23/Th17 axis as also being a pivotal player. xviii In fact, a genetic variant of the IL-23R has been found to be significantly associated with CD. Additionally, other types of mediators are known to play a role, such as the Janus kinases (JAKs), which play a central role in innate and adaptive immunity and are utilized by nearly all cytokines as a common signaling pathway, and NKG2D, a critical mediator of communication between intraepithelial cells and innate and adaptive immune cells. As the players and pathways involved in IBD pathogenesis are elucidated, new treatment strategies are being developed targeting different points within the disease. xvii Janssen is committed to exploring treatments targeting the mucosal barrier and interface. We recognize that every part of the body is different, and no two diseases or their patient populations are alike (e.g., CD and UC, despite similar/ overlapping symptoms). As an example, ileocecal CD can be viewed as a separate disease with a distinct genetic- and non- genetic pathophysiology, which translates into distinct clinical burden with high unmet medical need. xix Our development strategy recognizes important differences within each disease and aims to find specific differentiated treatments for different phenotypic classifications. In addition to insight regarding common pathways and mechanisms of inflammation, each disease requires special considerations and a specific, thorough, deep disease understanding. In terms of the GI tract, we are committed to investigating the role of various players involved in barrier maintenance and repair in each disease state (rather than assuming a role for one disease based on that in another). Janssen is actively exploring such roles in diseases such as UC, CD, and Celiac disease. Recognizing the burden of distinct patient populations and differences in clinical outcome and pathophysiology enables us to develop differentiated therapies. At Janssen, we're working to deliver transformational and accessible therapies and regimens to patients with gastrointestinal disease and know that we can't go it alone. We continue to seek bright and passionate minds to help us in our vision in restoring the immune balance for the millions of people living with immune-mediated diseases. n i. Fields, H. (2015). The Gut: Where Bacteria and Immune System Meet. Johns Hopkins Medicine. https://www.hopkinsmedicine.org/research/ advancements-in-research/fundamentals/in-depth/the-gut-where- bacteria-and-immune-system-meet. ii. Fakhoury, M., Negrulj, R., Mooranian, A., & Al-Salami, H. (2014). Inflammatory bowel disease: clinical aspects and treatments. Journal of inflammation research, 7, 113–120. Pg. 114. https://doi.org/10.2147/JIR.S65979 iii. Wehkamp, J., Götz, M., Herrlinger, K., Steurer, W., & Stange, E. F. (2016). Inflammatory Bowel Disease. Deutsches Arzteblatt international, 113(5), 72–82. pg. 74. https://doi.org/10.3238/arztebl.2016.0072 iv. Groschwitz, K. R., & Hogan, S. P. (2009). Intestinal barrier function: molecular regulation and disease pathogenesis. The Journal of allergy and clinical immunology, 124(1), 3–22. pg. 12. https://doi.org/10.1016/j.jaci.2009.05.038 v. Groschwitz, K. R., & Hogan, S. P. (2009). Intestinal barrier function: molecular regulation and disease pathogenesis. The Journal of allergy and clinical immunology, 124(1), 3–22. pg. 12. https://doi.org/10.1016/j.jaci.2009.05.038 vi. Schreiner, P., Neurath, M. F., Ng, S. C., El-Omar, E. M., Sharara, A. I., Kobayashi, T., Hisamatsu, T., Hibi, T., & Rogler, G. (2019). Mechanism- Based Treatment Strategies for IBD: Cytokines, Cell Adhesion Molecules, JAK Inhibitors, Gut Flora, and More. Inflammatory intestinal diseases, 4(3), 79–96. pg. 88. https://doi.org/10.1159/000500721 vii. Lin, L., & Zhang, J. (2017). Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC immunology, 18(1), 2. https://doi.org/10.1186/s12865-016-0187-3, pg 2. viii. Lin, L., & Zhang, J. (2017). Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC immunology, 18(1), 2. https://doi.org/10.1186/s12865-016-0187-3, pg 10.