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Abstract Rationale IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment. Objectives To determine efficacy and safety of brodalumab, a human anti–IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids. Methods Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation. Measurements and Main Results Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction. Conclusions Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).

Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (T H 17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of T H 17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IκBζ via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a , encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating T H 17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival. Fibroblastic reticular cells support lymph-node function and adaptive immunity. McGeachy and colleagues show that the cytokine IL-17 is needed to trigger metabolic changes required for the proliferation and survival of these cells in reactive lymph nodes.

In two trials in patients with moderate-to-severe plaque psoriasis, the anti–interleukin-17A monoclonal antibody secukinumab was more effective than placebo and etanercept. Infectious complications occurred more often with secukinumab than with placebo. Psoriasis is a chronic, immune-mediated inflammatory skin disease that is associated with substantial impairment of physical and psychological quality of life. 1 , 2 Our understanding of the pathogenesis of psoriasis was advanced by the discovery of the class of type 17 helper T (Th17) cells, which regulates innate and adaptive immunity. The proinflammatory cytokine interleukin-17A is the primary effector of Th17 cells, but it is also produced by other cell types in psoriatic lesions, including γδ T cells, neutrophils, and possibly mast cells. 3 – 7 Interleukin-17A stimulates keratinocytes to secrete chemokines and other proinflammatory mediators that recruit additional inflammatory cells, including neutrophils, . . .

ObjectiveInterleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone.MethodsPreclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated.ResultsIL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals.ConclusionsThese data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions.Trial registration numberNCT02141763; Results.

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases 1 . The compositions and structures of functional IL-17 family ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses 2 . Here we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25–IL-17RB–IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two ‘wing-like’ IL-17RA co-receptors through a ‘tip-to-tip’ geometry that is the key receptor–receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor. Cryo-electron microscopy structures of IL-25–IL-17RB–IL-17RA and IL-17A–IL-17RC–IL-17RA complexes show a tip-to-tip architecture, which is a key organizing principle of the IL-17 receptor family.

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. The mechanisms through which gut microbiota affect extramucosal tumors are poorly understood. Here the authors show that the gut microbiota promotes multiple myeloma by inducing differentiation and migration of Th17 cells in the bone marrow resulting also in increased recruitment of pro-tumorigenic eosinophils.

In this 12-week phase 2 trial, a humanized anti–interleukin-17 monoclonal antibody was effective for chronic plaque psoriasis. Larger studies of longer duration are necessary to assess the safety and efficacy of long-term treatment. Psoriasis vulgaris (plaque psoriasis) is a chronic, frequently painful, and often debilitating skin disorder. The estimated prevalence of diagnosed psoriasis in the United States is 3%, with approximately 17% of these patients having moderate-to-severe plaque psoriasis. 1 Psoriasis is characterized by inflammation and keratinocyte hyperproliferation 2 thought to be the pathological consequence of a T-cell–mediated immune response to an as-yet unidentified autoantigen. Studies have shown that a subgroup of CD4+ T cells, type 17 helper T (Th17) cells, may play a specific pathological role in psoriasis. 3 Type 17 helper T cells secrete a number of proinflammatory cytokines, including interleukin-17A, a member of . . .

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. Design In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

In this 12-week, phase 2 trial, an anti–interleukin-17–receptor antibody was effective in treating moderate-to-severe psoriasis. Adverse events included neutropenia. Larger trials of longer duration are needed to assess the risk of infections. Psoriasis is a chronic T-cell–mediated autoimmune disease 1 that affects 2 to 3% of the U.S. population 2 , 3 and 0.6 to 6.5% of the European population. 4 Emerging data identify a subset of helper T cells, Th17, that preferentially produce interleukin-17 and play a major role in orchestrating inflammation in psoriasis. 5 – 7 Levels of interleukin-17 are elevated in the lesional skin and blood of patients with psoriasis 5 , 8 – 10 and correlate with disease severity. 11 The interleukin-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE). 12 The interleukin 17A, 17F, and 17A/F heterodimer ligands share . . .

Background/Aims: Interleukin (IL)-17A, a proinflammatory cytokine, has been implicated in several autoimmune diseases. However, it is unclear whether IL-17A is involved in diabetic retinopathy (DR), one of the most serious complications of autoimmune diabetes. This study aimed to demonstrate that IL-17A exacerbates DR by affecting retinal Müller cell function. Methods: High glucose (HG)-treated rat Müller cell line (rMC-1) was exposed to IL-17A, anti-IL-17A-neutralizing monoclonal antibody (mAb) or/and anti-IL-17 receptor (R)A-neutralizing mAb for 24 h. For in vivo study, DR was induced by intraperitoneal injections of streptozotocin (STZ). DR model mice were treated with anti-IL-17A mAb or anti-IL-17RA mAb in the vitreous cavity. Mice that were prepared for retinal angiography were sacrificed two weeks after intravitreal injection, while the rest were sacrificed two days after intravitreal injection. Results: IL-17A production and IL-17RA expression were increased in both HG-treated rMC-1 and DR retina. HG induced rMC-1 activation and dysfunction, as determined by the increased GFAP, VEGF and glutamate levels as well as the downregulated GS and EAAT1 expression. IL-17A exacerbated the HG-induced rMC-1 functional disorders, whereas either anti-IL-17A mAb or anti-IL-17RA mAb alleviated the HG-induced rMC-1 disorders. Intravitreal injections with anti-IL-17A mAb or anti-IL-17RA mAb in DR model mice reduced Müller cell dysfunction, vascular leukostasis, vascular leakage, tight junction protein downregulation and ganglion cell apoptosis in the retina. Conclusions: IL-17A aggravates DR-like pathology at least partly by impairing retinal Müller cell function. Blocking IL-17A is a potential therapeutic strategy for DR.