Expert opinion on interleukin-12/23 and interleukin-23 antagonists as potential      therapeutic options for the treatment of inflammatory bowel disease

Wong, Uni; Cross, Raymond K.

doi:10.1080/13543784.2019.1597053

Cited by 32 publications

(30 citation statements)

References 37 publications

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“…Another consideration is the possible contribution of Th17/Th1 cells, a pathogenic population of RORC2 + TBET + cells that cosecrete IL-17A and IFN-γ; these cells have been linked to various autoimmune conditions as well as IBD [21,22]. Overall, these notions have fuelled the development of more global approaches to inhibit Th17 cells, such as targeting IL-23 [23,24] or Th17-relevant transcription factors such as RORC2 [25,26].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

et al. 2020

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Inflammatory bowel diseases (IBD) are chronic conditions that result from uncontrolled intestinal inflammation. Pathogenic Th17 cells, characterized by production of IL‐17A in the absence of IL‐10, are thought to contribute to this inflammation, but in humans, antibody‐mediated blockade of IL‐17A is an ineffective IBD therapy whereas IL‐23 blockade is effective. Here, we investigated the effects of pharmacological inhibition of RORC2, the Th17 cell lineage‐defining transcription factor, on in vivo‐differentiated human Th17 cells and Th17‐like Tregs (Th17‐Tregs). BMS‐336, a small molecule RORC2 inverse agonist, inhibited expression of RORC2‐regulated genes in peripheral Th17 cells (CD4+CD25–CD127+CXCR3–CCR4+CCR6+) in a dose–dependent manner, with similar inhibitory effects on laminar propria mononuclear cells from IBD and non‐IBD subjects. Exposure of peripheral Th17‐Tregs (CD4+CD25hiCD127loCXCR3–CCR4+CCR6+) to BMS‐336 also inhibited IL‐17A production and prevented inflammatory cytokine‐induced destabilization, as evidenced by preserved FOXP3 expression and epigenetic status of the Treg‐specific demethylation region. In parallel, RORC2 inhibition increased the production of IL‐10 in Th17‐Tregs, resulting in enhanced suppression of inflammatory cytokines from myeloid cells. Thus, via its ability to simultaneously inhibit Th17 cells and enhance the stability and function of Th17‐Tregs, pharmacological inhibition of RORC2 is a promising approach to suppress inflammation and promote immune regulation in IBD.

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Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

et al. 2020

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“…Ustekinumab appears to have a swift and lasting effect with potential for mucosal healing and systemic anti-inflammatory response with no known immunogenicity [8][9][10][11], in contrast to TNFα blockers. Ustekinumab may be preferred over anti-TNF therapy in older patients with increased risk for infections and malignancy, as concurrent immunosuppression may not be required due to its low immunogenicity [12]. In addition, after the firstintravenous injection, it is followed by subcutaneous self-administration.…”

Section: Discussionmentioning

confidence: 99%

Rapid Induction and Maintenance of Remission in Refractory Ulcerative Colitis with Ustekinumab

Chen

2019

Diseases

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Ulcerative colitis is a chronic debilitating disease characterized by relapsing in intestinal inflammation and ulcers with no available cure. This is a clinical case report of a 52-year-old female patient with 30 years history of left-sided chronic ulcerative colitis controlled with standard of care (mesalamine and azathioprine) which subsequently relapsed and developed into active refractory ulcerative colitis. The patient became unresponsive to her medications including different forms of mesalamines and did not respond favorably to any of the other current therapies. Numerous attempts to stabilize her condition with immunosuppressants, steroids, probiotics, antibiotics, mesalamines, and various biologic agents failed to improve her clinical symptoms, and the patient was being considered for colectomy. As the last resort, modified therapy was prescribed with ustekinumab, a non-selective, anti-IL12/23 p40 monoclonal antibody. This medication has not been yet approved for use in ulcerative colitis patients. In this clinical case we report the efficacy of ustekinumab to rapidly induce and maintain remission of the severe chronic ulcerative colitis in the patient. To the best of our knowledge, this is the first report of utilizing ustakinamub therapy for rapid induction in an active refractory ulcerative colitis patient resulting in complete remission for over one year.

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“…[250][251][252] There also appears to be a common link emerging between PDE4I and IL-23. Several diseases report efficacy of both apremilast and IL-12/23 blockers, such as psoriasis, Behcet's disease, IBD, and hidradenitis suppurativa [253][254][255][256] Of note, both apremilast and IL-12/IL-23 blockers failed to show efficacy in both RA and AS, suggesting apremilast mode of action may mediated through IL-23 downregulation. The potential benefit of apremilast on enthesitis in PsA patients has also been evaluated with improvements in enthesitis scores.…”

Section: Evidence Of Pathogenic Role Of Il-23 In Enthesitis From CLmentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Expert opinion on interleukin-12/23 and interleukin-23 antagonists as potential therapeutic options for the treatment of inflammatory bowel disease

Cited by 32 publications

References 37 publications

Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

Rapid Induction and Maintenance of Remission in Refractory Ulcerative Colitis with Ustekinumab

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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