The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges

Abstract

Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.

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“…Treatment with ustekinumab was successful for controlling her recurrent CD lesions and led to the subsequent discontinuation of anakinra. This may be due to the fact that ustekinumab, a monocloncal antibody against IL-12p40, which blocks signaling pathways of IL-12 and IL-23, can successfully block IL-1β-mediated Th17 cell activation as well as TNF-α-induced Th1 activation [ 21 , 22 ].…”

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“…Moreover, most of the signaling pathways are also involved in immune and inflammatory responses, which are closely related to UC. For example, IL-17, which is secreted by T17 cells, acts as a key mediator in the pathogenesis of intestinal inflammation [ 36 ]. Furthermore, IL-17 can be promoted by IL-23 to increase, thus forming the IL-23/17 axis to amplify the inflammatory response [ 37 ].…”

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“…Both IL-12 and IL-23 are pro-inflammatory cytokines in the interleukin-6 [IL-6] family, which are produced by dendritic cells, monocytes, and macrophages in the intestinal mucosa. 6 , 7 IL-12 is involved in the pathogenesis of several autoimmune processes [including IBD] through its effects on both innate and adaptive immunity. Innate immunity is targeted through the activation of natural killer [NK] cells, NK T cells, and group 1 innate lymphoid cells (ILC1s, which in turn produce TNF and interferon γ [IFNγ]).…”

“…Indeed, the IL-23 receptor [IL23-R] is expressed on T cells, ILCs, intraepithelial lymphocytes, NK cells, intestinal epithelial cells, and granulocytes, highlighting IL-23’s expansive role in the pro-inflammatory response. 7 Most notable is its involvement in the T helper 17 [Th17] cell activation pathway in combination with transforming growth factor β [TGF-β] and cytokines IL-6, IL-1β, and IL-21, in turn increasing production of IL-17 and thus TNFα, IFNγ, granulocyte-macrophage colony-stimulating factor [GM-CSF], and other inflammatory chemokines through stimulation of endothelial cells and monocytes, as well as IL-21 and IL-22 [ Figure 1 ]. 5–10 Several studies have demonstrated that patients with IBD have increased intestinal, serum, and plasma levels of IL-23 and Th17 cytokines.…”

“…15 No data are yet available on the efficacy of risankizumab in UC; however, Phase II/III randomised, double-blind, placebo-controlled studies examining induction and maintenance therapy in patients with moderate to severe UC are under way. 7 , 13 Additionally, although there have not yet been trials comparing the efficacy of risankizumab with ustekinumab in IBD, data from Phase II and III clinical trials in patients with moderate-to-severe plaque psoriasis have demonstrated superior efficacy of risankizumab in this population, supporting the hypothesis that explicit targeting of IL-23 may be more effective than a combined blockade of IL-12 and IL-23. 22 , 23 …”