Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses

Imamura, Emiko; Taguchi, K; Sasaki-Iwaoka, Haruna; Kubo, Satoshi; Furukawa, Shigetada; Morokata, Tatsuaki

doi:10.1016/j.ejphar.2018.01.045

Cited by 16 publications

(6 citation statements)

References 24 publications

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“…IL-23 amplifies the Th17 cell response and restrains the regulatory T cell response, favoring gut inflammation and implicating the IL-23/IL-17 axis in autoimmune inflammation [53][54][55][56]. The efficacy of targeting IL-12p40 in mouse colitis models and treatment of monoclonal antibodies (ustekinumab and briakinumab) targeting p40 in IBD patients suggest that blocking IL-23 signaling is a promising therapeutic approach for IBD [38,[57][58][59].…”

Section: Cytokine-mediated Regulationmentioning

confidence: 99%

Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease

Chien

Hsu

et al. 2020

IJMS

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Inflammatory bowel disease (IBD) is a chronic disorder manifested as Crohn’s disease (CD) and ulcerative colitis (UC) characterized by intestinal inflammation and involves a dysregulated immune response against commensal microbiota through the activation of CD4 T helper cells. T helper cell differentiation to effector or regulatory phenotypes is controlled by cytokine networks and transcriptional regulators. Distinct polarized T helper cells are able to alter their phenotypes to adapt to diverse and fluctuating physiological environments. T helper cells exhibit intrinsic instability and flexibility to express cytokines of other lineages or transdifferentiate from one T helper cell type to another in response to various perturbations from physiological cytokine milieu as a means of promoting local immunity in response to injury or ensure tissue homeostasis. Furthermore, functional plasticity and diversity of T helper cells are associated with pathogenicity and are critical for immune homeostasis and prevention of autoimmunity. In this review, we provide deeper insights into the combinatorial extrinsic and intrinsic signals that control plasticity and transdifferentiation of T helper cells and also highlight the potential of exploiting the genetic reprogramming plasticity of T helper cells in the treatment of IBD.

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Section: Cytokine-mediated Regulationmentioning

confidence: 99%

Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease

Chien

Hsu

et al. 2020

IJMS

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“…This suggests the driving role for IL 23 in comparison with IL 12 in colitis. 41 Further studies showed similar results: Kullberg and his team investigated Helicobacter hepaticus-triggered T celldependent colitis in mice deficient for p40, p19 or p35 and concluded also, that IL 23 is the main force in driving inflammation. 42 While p19-deficiency ameliorated colitis in IL 10 −/mice, Yen et al could not observe a difference in p35 knock out mice regarding colitis.…”

Section: Interleukin 12 and Interleukin 23 In Experimental Colitis Momentioning

confidence: 81%

<p>All are Equal, Some are More Equal: Targeting IL 12 and 23 in IBD – A Clinical Perspective</p>

Jefremow¹

2020

ITT

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Chronic inflammatory diseases like inflammatory bowel diseases (IBD) or psoriasis represents a worldwide health burden. Researchers provided great achievements in understanding the origin of these diseases leading to improved therapeutic options. The discovery of cytokines like tumor necrosis factor-α or transforming growth factor-β are examples for these efforts. Interleukin 12 (IL 12) and interleukin 23 (IL 23) represent different important cytokines in this regard. They both belong to the interleukin 12 family and are related by sharing the subunit p40. Ustekinumab is an antibody that blocks p40 and thereby interleukins 12 and 23. Trials showed promising results in treating IBD patients with this drug. Consequently, new questions arose about the distinct features of IL 12 and 23. This review focuses on these interleukins regarding their functions in the healthy and inflamed gut and provides an overview about the results from in vitro and in vivo studies as well as clinical trials.

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“…The exact contribution of IL12 in IBD pathogenesis is up to debate. Preclinical studies seemingly suggest that the main driver of intestinal inflammation is represented by IL23, as various animal studies report that the inhibition of p19, rather than p35, can effectively prevent or block experimental colitis; 41 – 43 nevertheless, it has been observed that IL12 is responsible for wasting disease and serum cytokine production in colitic mice, thus suggesting that this cytokine might be implicated in (some of) the systemic manifestations associated with intestinal inflammation. 44 Furthermore, a recent work revealed that IL12 stimulates a subpopulation of pathogenic IL8 + T cells that co-express either IL17 or IFNγ and that are specific to UC.…”

Section: Introductionmentioning

confidence: 99%

Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab

Pugliese

Privitera

Fiorani

et al. 2022

Therap Adv Gastroenterol

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As our comprehension of the pathogenic mechanisms of inflammatory bowel disease (IBD) increases, the therapeutic armamentarium for its treatment can expand, and novel target therapies join the treatment pipeline. Interleukin (IL)-12 and IL23 are two key cytokines responsible for promoting and perpetuating bowel inflammation in IBD. Ustekinumab is a monoclonal antibody directed against the shared p40 subunit of both cytokines, and it was recently approved for the treatment of ulcerative colitis (UC). In the pivotal phase III UNIFI trial, ustekinumab showed a superiority over placebo in both clinical and endoscopic outcomes; furthermore, it was characterized by a favorable safety profile, with a similar rate of adverse events as compared with placebo. Recent evidence from real-life experiences have started accumulating, generally confirming the effectiveness and safety figures emerged from the registration studies. However, most of these observational studies enrolled multirefractory patients; moreover, comparative data with other target therapies are lacking, leaving physicians without clear indications about the appropriate positioning of ustekinumab in the therapeutic pipeline for UC. This review examines the basis of targeting IL12-23 in UC therapy and summarizes the data from both clinical trials and real-life studies, to highlight the main evidence already available and the research gaps that need to be filled for the optimal usage of ustekinumab in UC.

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Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses

Cited by 16 publications

References 24 publications

Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease

Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease

<p>All are Equal, Some are More Equal: Targeting IL 12 and 23 in IBD – A Clinical Perspective</p>

Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab

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