IL-12 protects from psoriasiform skin inflammation

Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.

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“…2b). IL-12 did not impact CCR6 expression, consistent with a reported absence of IL-12R expression by γδT17 cells29 (Supplementary Fig. 2b).…”

Section: Resultssupporting

confidence: 88%

IL-17-producing γδ T cells switch migratory patterns between resting and activated states

et al. 2017

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“…on day 8 and 13 after immunization and compared the effect with an anti-mouse IL-17 mAb (clone 17F3) (25)(26)(27). Remarkably, injection of our anti-CCR6 mAb at 5 mg/kg significantly reduced disease severity, in comparison with an isotype control ( Figure 3A).…”

Section: Anti-ccr6 Treatment Prevents and Inhibits Clinical Progressimentioning

confidence: 99%

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice

Robert¹,

Ang²,

Sun³

et al. 2017

JCI Insight

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“…[22][23][24][25][26] However, another anti-IL-12/23p40 agent, briakinumab, showed signs of a possible increased risk of major cardiovascular adverse events (MACE), infections and malignancies in clinical trials, 27,28 and development was stopped before approval. Additionally, there is evidence that blockade of IL-12 may be counterproductive in treating patients with psoriasis: mice lacking IL-12 signalling components develop worse psoriasis than wild-type animals 29 and IL-12 exhibits protective roles against malignancies 30 and infections. 31,32 However, clinical studies of IL-12/23 inhibitors have not detected signals for these safety events.…”

Section: Introductionmentioning

confidence: 99%

Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Crowley

Warren

Cather³

2019

Acad Dermatol Venereol

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Psoriasis is a chronic disease that requires long‐term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)‐23. This article reviews published data on the safety of these IL‐23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo‐ and active‐controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk–benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL‐23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL‐23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long‐term extension studies and patient registries will further establish the safety profile of IL‐23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.

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IL-12 protects from psoriasiform skin inflammation

Cited by 169 publications

References 71 publications

IL-17-producing γδ T cells switch migratory patterns between resting and activated states

IL-17-producing γδ T cells switch migratory patterns between resting and activated states

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice

Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

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