Can IL-23 be a good target for ulcerative colitis?
Introduction
Ulcerative colitis (UC) is a chronic, relapsing-remitting, inflammatory bowel disease (IBD), that causes continuous mucosal inflammation of the colon, leading to organ damage and impaired quality of life [1]. In the last two decades, the introduction of biologic therapies have changed the natural history of UC, with a higher probability to achieve and maintain remission; nevertheless, there is still a considerable percentage of patients who do not respond to therapies [2].
Anti-tumor necrosis factor (TNF) drugs were the first class of biologics developed. They are currently available for intravenous (infliximab) or subcutaneous administration (certolizumab pegol, adalimumab and golimumab). However, about 30% of patients are primary non responders and another third of patients will become secondary non-responders, losing response over time [3].
The second class of biologics developed in UC in the last years is currently represented by vedolizumab. Unlike anti-TNFs, it acts blocking the integrin α4β7 on leukocyte cells, thus reducing lymphocyte trafficking to intestinal mucosa. Vedolizumab is effective for induction and maintenance therapy in UC [4], but about 50% of patients do not respond to treatment or will lose response over time [5].
Hence the continuing need to find new therapeutic strategies and novel drugs to control this chronic debilitating disease.
Pathogenesis of UC is still poorly understood, but it is thought that environmental factors, such as microbiota, may provoke an aberrant immune response in subjects with a genetic predisposition, leading to chronic inflammation and finally to organ damage [6]. The excessive immune response has therefore been the target of most treatments for IBD, aimed at both reducing lymphocyte migration to inflammatory sites than blocking specific inflammatory cytokines, strategic keys in the development of inflammatory cascade.
In response to microbial pathogens, antigen-stimulated dendritic cells and macrophages produce interleukin (IL)-12 and IL-23, which in turn promote release of further cytokines, such as interferon gamma (IFN-γ), IL-17, IL-6, IL-1 and TNF [7]. In particular, IL-23 induces the differentiation of naïve CD4+ T cells into T helper (Th) 17 cells, followed by activation of a cascade of pro-in-inflammatory cytokines, including IL-17 A, IL-17 F, IL-6 and TNF [8,9]. Increased levels of IL23 and Th17 cell cytokines have been found in intestinal mucosa, plasma, and serum of patients with IBD [[10], [11], [12]]. Variants in several genes encoding for IL23 and Th17 cell pathways have been associated with risk for IBD [13]. In particular, a variant of the IL23 receptor (IL23R) gene, that encodes an amino acid change from arginine to glutamine at position 381, has been observed to reduce the risk for IBD, due to a loss-of-function of IL23R, with decreased STAT3 signaling and Th17 cell responses upon exposure to IL23 [14]. IL23-blocking has been shown to reduce the severity of inflammation in experimental colitis [[15], [16], [17]]. Lastly, ustekinumab, a monoclonal antibody (mAb) to the p40 subunit of IL-12 and IL-23, has showed good efficacy and safety profile in patients with Crohn's disease (CD) [18].
Accordingly, IL-23 and IL-23/IL-17 axis may be a promising target in both CD and UC.
This review aims to discuss the available data on IL-23 and Th17 cell pathways in UC, in order to define the role of IL-23 as possible target for the treatment of UC.
Section snippets
IL-23 pathway
Intestinal wall, in particular the lamina propria layer, contains a complex population of immune cells that work constantly to maintain tolerance to luminal microbiota, but also to prevent entry of pathogens. In IBD, there is an infiltration and expansion of innate and adaptive inflammatory cells in intestinal wall. Activation and proliferation of neutrophils, macrophages, dendritic cells, natural killer (NK) T cells, innate lymphoid cells (ILCs), B and T lymphocytes lead to an increase of
Murine studies
Several studies observed that IL23 and Th17 cell pathway cytokines were increased in intestinal wall of mice with colitis [10,41] and that ubiquitous transgenic expression of IL23p19 in mice resulted in severe intestinal inflammation and in systemic inflammation [42].
In C3H/HeSnJ SCID mice with induced colitis, by transfer of cecal bacterial antigen–specific C3H/HeJBir CD4+ T-cell line, an mAb anti-IL-23p19, administered at the same time as or 4 weeks after, reduced intestinal inflammation by
Human studies
Liu et al., demonstrated an increasing of IL-23p19 expression, performed by immunohistochemistry and quantitative real time PCR, in inflamed mucosa of CD patients, but not in UC patients. The treatment with anti-TNF markedly reduced IL-23 expression and Th17 cell infiltration in the inflamed mucosa of CD patients [46].
Kobayashi et al., analysed mucosal samples obtained from surgical specimens of 12 controls, 17 UC and 22 CD. They found a significant IL-17 mRNA upregulation in UC, while IFN-γ
Summary
Aberrant immune response to microbiota, in subjects with a genetic predisposition, is thought may be the pathogenetic mechanism underlying UC [6].
In response to microbial pathogens, antigen-stimulated dendritic cells and macrophages produce IL-23, which in turn induces the differentiation of naïve CD4+ T cells into Th17 cells followed by activation of a cascade of pro-in-inflammatory cytokines, including IL-17, IL-17 F, IL-6 and TNF [8,9]. It has been observed that IL23 and Th17 cell pathway
Practice points
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UC is a chronic, relapsing-remitting, inflammatory disease of the colon, leading to organ damage and impair quality of life
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Biologic therapies have changed the natural history of UC, with a higher probability to achieve and maintain remission
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30% of patients are primary non responders to anti-TNFs and another third of patients will become secondary non-responders
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Up to 50% of patients do not respond or will lose response over time to vedolizumab
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New therapeutic strategies and new drugs are
Research agenda
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The pathogenesis of UC needs to be defined
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Increased levels of IL23 and Th17 cell cytokines have been found in intestinal mucosa, plasma, and serum of patients with IBD, both CD and UC
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Variants in several genes in the IL23 and Th17 cell pathways have been associated with risk for IBD, including UC
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IL23-blocking has been shown to reduce the severity of inflammation in experimental colitis
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Prospective controlled studies are necessary to assess the efficacy and safety of molecules targeting IL-23 and
Conflicts of interest
Mariangela Allocca received consulting fees from Nikkiso Europe and lecture fees from Janssen and Pfizer; Federica Furfaro received consulting fees from MSD and Abbvie and lecture fees from Janssen and Pfizer; Gionata Fiorino served as a consultant and a member of Advisory Boards for MSD, Takeda Pharmaceuticals and Janssen Pharmaceuticals and received lecture fees from Janssen and Pfizer; Daniela Gilardi received consultancy fees from Nikkiso Europe and Sofar, and lecture fees from Janssen and
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