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OBJECTIVES: We have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner. METHODS: We used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19-/- mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively. RESULTS: We present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P. CONCLUSIONS: The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.
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Artrite Experimental , Camundongos Endogâmicos C57BL , Camundongos Knockout , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Camundongos , Interleucina-23/metabolismo , Interleucina-23/imunologia , Subunidade p19 da Interleucina-23/imunologia , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/genética , Dor/etiologia , Zimosan , Masculino , Inflamação/imunologia , Inflamação/metabolismoRESUMO
Risankizumab is a humanized monoclonal antibody that inhibits the p19 subunit of IL-23 cytokine. Recently it has been approved for the treatment of patients with moderate-to-severe Crohn's disease (CD). We conducted a scoping review to summarize the available data on risankizumab and to define its positioning in the treatment algorithm of CD. Pubmed, Embase and Scopus databases were searched up to Oct 31, 2023 to identify studies reporting efficacy and safety data of risankizumab in patients with CD. Risankizumab is an effective and safe drug for the management of patients with moderate-to-severe CD. It could be used as first-line therapy in biologic-naive patients and in patients who have previously failed other biological therapies.
When we eat the food is processed and absorbed by the gastrointestinal tract. Sometimes, in some people, the gastrointestinal tract gets inflamed, causing problems like tummy ache and diarrhea: this condition is called Crohn's disease. To help turn off this inflammation and make people with Crohn's disease feel better, there's a new treatment called risankizumab. Risankizumab binds to the proteins in the body that cause inflammation and blocks their effects. This helps to reduce gastrointestinal inflammation and relieve its symptoms. Scientific studies have shown that is effective, safe, and it starts working quickly. Patients using this treatment do not have to go to the hospital every time. After three times in the outpatient's clinic, they can continue the treatment comfortably at home using a small device that sticks to the body and administers the medicine.
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Algoritmos , Doença de Crohn , Humanos , Doença de Crohn/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Índice de Gravidade de Doença , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Resultado do TratamentoRESUMO
OBJECTIVE: To assess long-term efficacy and safety of guselkumab, an interleukin-23 p19 subunit (IL-23p19) inhibitor, in patients with active psoriatic arthritis (PsA) from the phase III DISCOVER-2 trial. METHODS: In the DISCOVER-2 trial, patients with active PsA (≥5 swollen joints and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite prior nonbiologic therapy were randomized to receive the following: guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks; or placebo with crossover to guselkumab 100 mg every 4 weeks, beginning at week 24. Efficacy assessments included American College of Rheumatology ≥20%/50%/70% improvement criteria (ACR20/50/70), Investigator's Global Assessment (IGA) of psoriasis score of 0 (indicating complete skin clearance), resolution of enthesitis (Leeds Enthesitis Index) and dactylitis (Dactylitis Severity Score), and changes in the Sharp/van der Heijde modified radiographic scores for PsA. Clinical data (imputed as no response/no change from baseline if missing) and observed radiographic data were summarized through week 100; safety assessments continued through week 112. RESULTS: Of the 739 randomized and treated patients, 652 (88%) completed treatment through week 100. Across groups of guselkumab-treated patients (including those in the placebo-guselkumab crossover group), the following findings at week 100 indicated that amelioration of arthritis signs/symptoms and extraarticular manifestations was durable through 2 years: ACR20 response (68-76%), ACR50 response (48-56%), ACR70 response (30-36%), IGA score of 0 (55-67%), enthesitis resolution (62-70%), and dactylitis resolution (72-83%). Mean changes in the Sharp/van der Heijde modified score for PsA from weeks 52 to week 100 (range 0.13-0.75) indicated that the low rates of radiographic progression observed among guselkumab-treated patients at earlier time points extended through week 100. Through week 112, 8% (5.8 per 100 patient-years) and 3% (1.9 per 100 patient-years) of the 731 guselkumab-treated patients had a serious adverse event or serious infection, respectively; 1 death occurred (road traffic accident). CONCLUSION: In biologic-naive PsA patients, guselkumab provided durable improvements in multiple disease domains with no unexpected safety findings through 2 years.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Subunidade p19 da Interleucina-23/imunologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1ß pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.
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Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Interleucina-1beta/genética , Neoplasias Pulmonares/tratamento farmacológico , Oxidiazóis/farmacologia , Pirimidinas/farmacologia , Sinteninas/genética , Animais , Antineoplásicos/síntese química , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quimiocina CCL11/genética , Quimiocina CCL11/imunologia , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Oxidiazóis/síntese química , Pirimidinas/síntese química , Transdução de Sinais , Sinteninas/antagonistas & inibidores , Sinteninas/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Among various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4+ T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4+ T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19/CD5L. This p19/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells. Both CD4+ T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF+CD4+ T cells. During the course of EAE, the serum level of p19/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.
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Proteínas Reguladoras de Apoptose/genética , Antígenos CD5/genética , Encefalomielite Autoimune Experimental/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Subunidade p19 da Interleucina-23/genética , Receptores Depuradores/genética , Animais , Células Apresentadoras de Antígenos/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD5/imunologia , Antígenos CD5/ultraestrutura , Dimerização , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Subunidade p19 da Interleucina-23/imunologia , Subunidade p19 da Interleucina-23/ultraestrutura , Camundongos , Receptores Depuradores/imunologia , Células Th1/imunologia , Células Th17/imunologiaRESUMO
OBJECTIVE: ZAP-70W163C BALB/c (SKG) mice develop reactive arthritis (ReA) following infection with Chlamydia muridarum. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells infected with C muridarum drive arthritis. METHODS: SKG, Il17a-deficient SKG, and BALB/c female mice were infected with C muridarum or C muridarum luciferase in the genitals. C muridarum dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-tumor necrosis factor (anti-TNF) and anti-interleukin-23p19 (anti-IL-23p19) were administered after infection or arthritis onset. Gene expression of Hspa5, Tgtp1, Il23a, Il17a, Il12b, and Tnf was compared in SKG mice and BALB/c mice. RESULTS: One week following infection with C muridarum, macrophages and neutrophils were observed to have infiltrated the uteri of mice and were also shown to have carried C muridarum DNA to the spleen. C muridarum load was higher in SKG mice than in BALB/c mice. Macrophage depletion was shown to reduce C muridarum load and prevent development of arthritis. Compared with BALB/c mice, expression of Il23a and Il17a was increased in the uterine and splenic neutrophils of SKG mice. The presence of anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was overexpressed in the joints of SKG mice within 1 week postinfection, and persisted beyond the first week. TNF inhibition during infection or at arthritis onset suppressed the development of arthritis. Levels of endoplasmic reticulum stress were constitutively increased in the joints of SKG mice but were induced, in conjunction with immunity-related GTPase, by C muridarum infection in the uterus. CONCLUSION: C muridarum load is higher in SKG mice than in BALB/c mice. Whereas proinflammatory IL-23 produced by neutrophils contributes to the initiation of C muridarum-mediated ReA, macrophage depletion reduces C muridarum dissemination to other tissues, tissue burden, and the development of arthritis. TNF inhibition was also shown to suppress arthritis development. Our data suggest that enhanced bacterial dissemination in macrophages of SKG mice drives the TNF production needed for persistent arthritis.
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Artrite Reativa/imunologia , Infecções por Chlamydia/imunologia , Subunidade p19 da Interleucina-23/imunologia , Interleucina-23/imunologia , Macrófagos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Artrite Experimental/genética , Artrite Reativa/genética , Chlamydia muridarum , Chaperona BiP do Retículo Endoplasmático , Feminino , Perfilação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Subunidade p19 da Interleucina-23/genética , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/imunologia , Fator de Necrose Tumoral alfa/genética , Proteína-Tirosina Quinase ZAP-70/genéticaRESUMO
Introduction: Risankizumab is a fully human monoclonal antibody that selectively targets interleukin (IL)-23A, interfering with the IL-23/17 axis that plays a crucial role in keratinocyte proliferation. In 2019, risankizumab was approved globally for the treatment of moderate-to-severe psoriasis.Areas covered: The safety profile of risankizumab for the treatment of psoriasis is assessed in this review. A literature search was performed on 18 October 2019, and additional data from pooled safety analyses were evaluated.Expert opinion: Drugs blocking the IL-23 pathway are the most recently approved treatment for psoriasis, and risankizumab seems to be the most effective one among the three IL-23 blockers approved. Risankizumab was generally well tolerated in the clinical trials and was found to be relatively safe. The safety profile of risankizumab is generally similar in clinical trials compared to adalimumab and ustekinumab. In a subset of patients with latent tuberculosis, no active tuberculosis developed after risankizumab treatment for 55 weeks without tuberculosis prophylaxis. The combination of safety, efficacy and less frequent injection (every 12 weeks) make risankizumab an attractive new choice for individuals with moderate-to-severe psoriasis. However, the long-term impact of anti-drug antibodies (24%) observed in pivotal studies as well as safety concerns in those with viral infections, hepatitis, malignancies and those in endemic tuberculosis areas, await further studies.
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Anticorpos Monoclonais/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Esquema de Medicação , Humanos , Subunidade p19 da Interleucina-23/imunologia , Tuberculose Latente/complicações , Psoríase/patologia , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Psoriasis is a chronic, inflammatory skin disorder resulting from a complex interplay between immune and skin cells via release of soluble mediators. While a lot is known about the molecular mechanisms behind psoriasis pathogenesis, there is still a need for preclinical research models that accuratelyreplicate the disease. OBJECTIVE: This study aimed to develop and characterize ex vivo culture of psoriasis skin as a model for pharmacological testing, where the immunological events of psoriasis can be followed. METHODS: Full thickness punch biopsies of lesional psoriasis skin were cultured in submerged conditions up to 144â¯h followingin situ T cell stimulation with rhIL-23 and anti-CD3 and anti-CD28 antibodies. The T cell mediated skin inflammation was assessed by gene and protein l analysis for a panel of inflammatory mediators. Tissue integrity and morphology were evaluated by histological analysis. RESULTS: T cell stimulation resulted in functional and psoriasis specificin situ activation of T cells. The expression levels of most of the proinflammatory mediators related to both immune and skin cells were comparable to these in freshly isolated tissue at 48 and 96â¯h of culture. Tissue integrity and morphology were sustained up to 96â¯h. Treatment with a corticosteroid reduced the expression of several pro-inflammatory cytokines and chemokines, whereas anti-IL-17A antibody treatment reduced the expression of the IL-17A downstream markers IL-8 and DEFB4. CONCLUSION: By preserving keyimmunopathological mechanisms of psoriasis, ex vivo culture of psoriasis skin can be used for the investigation of inflammatory processes of psoriasis and for preclinical drug discovery research.
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Fármacos Dermatológicos/farmacologia , Psoríase/tratamento farmacológico , Pele/patologia , Técnicas de Cultura de Tecidos , Biópsia , Meios de Cultura/metabolismo , Citocinas/metabolismo , Fármacos Dermatológicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Subunidade p19 da Interleucina-23/imunologia , Subunidade p19 da Interleucina-23/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Psoríase/imunologia , Psoríase/patologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
BACKGROUND: Long-term maintenance treatment is required for patients with psoriasis. OBJECTIVES: To evaluate the efficacy and safety of guselkumab in patients with moderate to severe psoriasis through 3 years of treatment. METHODS: In 2 ongoing, phase 3 trials of guselkumab (VOYAGE 1 and VOYAGE 2), the proportions of patients achieving at least 90% and 100% improvement in the Psoriasis Area and Severity Index (PASI 90 and PASI 100, respectively) and Investigator's Global Assessment (IGA) scores of 0/1 and 0 were summarized for the guselkumab group (including placebo-to-guselkumab crossover). Patients who met treatment failure rules were considered nonresponders. Safety outcomes (rates/100 patient-years [PY]) were evaluated based on data pooled across studies through week 156. RESULTS: Three-year response rates for the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively, were 82.8% and 77.2% for PASI 90, 50.8% and 48.8% for PASI 100, 82.1% and 83.0% for IGA score of 0/1, and 53.1% and 52.9% for IGA score of 0. Safety event rates across studies occurred through week 156 as follows: serious adverse events, 5.68/100 PY; serious infections, 1.15/100 PY; nonmelanoma skin cancers, 0.28/100 PY; malignancies other than nonmelanoma skin cancer, 0.47/100 PY; and major adverse cardiovascular events, 0.28/100 PY. Week 156 and week 100 rates were consistent. LIMITATIONS: There was no comparator arm beyond 1 year. CONCLUSIONS: Guselkumab shows durable efficacy and a consistent safety profile in patients with moderate to severe psoriasis treated for up to 3 years.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
We investigated the effects of resolvin E (RvE) 1, RvE2, and RvE3 on IL-4- and IL-33-stimulated bone marrow-derived dendritic cells (BMDCs) from house dust mite (HDM)-sensitized mice. We also investigated the role of RvE3 in a murine model of HDM-induced airway inflammation. In vitro, BMDCs from HDM-sensitized mice were stimulated with IL-4 and IL-33 and then treated with RvE1, RvE2, RvE3, or vehicle. RvE1, RvE2, and RvE3 suppressed IL-23 release from BMDCs. In vivo, RvE3 administrated to HDM-sensitized and challenged mice in the resolution phase promoted a decline in total numbers of inflammatory cells and eosinophils, reduced levels of IL-23 and IL-17 in lavage fluid, and suppressed IL-23 and IL-17A mRNA expression in lung and peribronchial lymph nodes. RvE3 also reduced resistance in the lungs of HDM-sensitized mice. A NanoBiT ß-arrestin recruitment assay using human embryonic kidney 293 cells revealed that pretreatment with RvE3 suppressed the leukotriene B4 (LTB4)-induced ß-arrestin 2 binding to LTB4 receptor 1 (BLT1R), indicating that RvE3 antagonistically interacts with BLT1R. Collectively, these findings indicate that RvE3 facilitates the resolution of allergic airway inflammation, partly by regulating BLT1R activity and selective cytokine release by dendritic cells. Our results accordingly identify RvE3 as a potential therapeutic target for the management of asthma.-Sato, M., Aoki-Saito, H., Fukuda, H., Ikeda, H., Koga, Y., Yatomi, M., Tsurumaki, H., Maeno, T., Saito, T., Nakakura, T., Mori, T., Yanagawa, M., Abe, M., Sako, Y., Dobashi, K., Ishizuka, T., Yamada, M., Shuto, S., Hisada, T. Resolvin E3 attenuates allergic airway inflammation via the interleukin-23-interleukin-17A pathway.
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Asma/imunologia , Ácidos Graxos Insaturados/imunologia , Interleucina-17/imunologia , Subunidade p19 da Interleucina-23/imunologia , Transdução de Sinais/imunologia , Animais , Asma/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Leucotrieno B4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/imunologia , Receptores do Leucotrieno B4/imunologia , beta-Arrestina 2/imunologiaRESUMO
The effect and safety of monoclonal antibodies (mAbs) targeting the interleukin-23 (IL-23) p19 subunit for treatment of psoriasis has not previously been systematically evaluated. To perform a systematic review and meta-analysis of randomized clinical trials (RCTs) (including Phase I-III trials) to evaluate the efficacy and safety of these mAbs for treatment of psoriasis. The databases of PubMed, Baidu Scholar, and Cochrane Library of Clinical Trials were searched from inception of the databases to January 1st, 2018. A systematic review and meta-analysis was conducted using Review Manager Software version 5.3 (RevMan 5.3). Nine RCTs with a total of 2,478 subjects met our inclusion criteria. A significant increase in PASI 75 (RR: 11.65; 95% CI: 9.01-15.06), PASI 90 (RR: 21.74; 95% CI: 14.28-33.10), PASI 100 (RR: 31.56; 95% CI: 14.66-67.96), PGA 0/1 (OR: 23.21; 95% CI: 14.61-36.89), and DLQI 0/1 (RR: 10.29; 95% CI: 7.52-14.09) was identified for anti-IL-23p19 mAb vs. placebo, and PASI 75 (RR: 1.25; 95% CI: 1.18-1.32), PASI 90 (OR: 2.56; 95% CI: 2.13-3.09), PASI 100 (OR: 2.38, 95% CI: 1.89-2.99), and DLQI 0/1 (RR: 1.33; 95% CI: 1.20-1.47) vs. tumour necrosis factor (TNF) antagonists for the treatment of psoriasis. Furthermore, there was no significant difference in adverse events between placebo and TNF antagonists. Anti-IL-23p19 mAbs are effective with acceptable safety as therapy for psoriasis, and may be superior to TNF antagonists. More RCTs with a larger sample size are required to verify the current findings.
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Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Subunidade p19 da Interleucina-23/imunologia , Terapia de Alvo Molecular/métodos , Psoríase/tratamento farmacológico , Feminino , Humanos , Masculino , Segurança do Paciente , Psoríase/imunologia , Psoríase/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Vibrio cholerae infection provides long-lasting protective immunity, while oral, inactivated cholera vaccines (OCV) result in more-limited protection. To identify characteristics of the innate immune response that may distinguish natural V. cholerae infection from OCV, we stimulated differentiated, macrophage-like THP-1 cells with live versus heat-inactivated V. cholerae with and without endogenous or exogenous cholera holotoxin (CT). Interleukin 23A gene (IL23A) expression was higher in cells exposed to live V. cholerae than in cells exposed to inactivated organisms (mean change, 38-fold; 95% confidence interval [95% CI], 4.0 to 42; P < 0.01). IL-23 secretion was also higher in cells exposed to live V. cholerae than in cells exposed to inactivated V. cholerae (mean change, 5.6-fold; 95% CI, 4.4 to 11; P < 0.001). This increase in IL-23 secretion was more marked than for other key innate immune cytokines (e.g., IL-1ß and IL-6) and dependent on exposure to the combination of both live V. cholerae and CT. While IL-23 secretion was reduced following stimulation with either heat-inactivated wild-type V. cholerae or a live isogenic ctxAB mutant of V. cholerae, the addition of exogenous CT restored IL-23 secretion in combination with the live isogenic ctxAB mutant V. cholerae, but not when it was paired with stimulation by heat-inactivated V. cholerae The posttranslational regulation of IL-23 under these conditions was dependent on the activity of the cysteine protease cathepsin B. In humans, IL-23 promotes the differentiation of Th17 cells to T follicular helper cells, which maintain and support long-term memory B cell generation after infection. Based on these findings, the stimulation of IL-23 production may be a determinant of protective immunity following V. cholerae infection.IMPORTANCE An episode of cholera provides better protection against reinfection than oral cholera vaccines, and the reasons for this are still under study. To better understand this, we compared the immune responses of human cells exposed to live Vibrio cholerae with those of cells exposed to heat-killed V. cholerae (similar to the contents of oral cholera vaccines). We also compared the effects of active cholera toxin and the inactive cholera toxin B subunit (which is included in some cholera vaccines). One key immune signaling molecule, IL-23, was uniquely produced in response to the combination of live bacteria and active cholera holotoxin. Stimulation with V. cholerae that did not produce the active toxin or was killed did not produce an IL-23 response. The stimulation of IL-23 production by cholera toxin-producing V. cholerae may be important in conferring long-term immunity after cholera.
Assuntos
Antígenos de Bactérias/imunologia , Imunidade Inata , Subunidade p19 da Interleucina-23/genética , Monócitos/imunologia , Processamento Pós-Transcricional do RNA/imunologia , Vibrio cholerae/imunologia , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/química , Toxina da Cólera/imunologia , Vacinas contra Cólera/imunologia , Citocinas/imunologia , Regulação da Expressão Gênica/imunologia , Temperatura Alta , Humanos , Subunidade p19 da Interleucina-23/imunologia , Monócitos/microbiologia , Células THP-1 , Vacinas de Produtos Inativados/imunologia , Vacinas Vivas não Atenuadas/imunologia , Vibrio cholerae/patogenicidadeRESUMO
Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1ß and IL-23. We also report a role for transforming growth factor-ß in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.
Assuntos
Interleucina-17/imunologia , Linfócitos/imunologia , Psoríase/patologia , Pele/patologia , Células Cultivadas , Humanos , Interleucina-1beta/imunologia , Subunidade p19 da Interleucina-23/imunologia , Interleucina-4/imunologia , Linfócitos/citologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Psoríase/imunologia , Receptores CCR10/metabolismo , Pele/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Pathogenic lymphocytes initiate the development of chronic inflammatory diseases. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (encoded by Csf2) is a key communicator between pathogenic lymphocytes and tissue-invading inflammatory phagocytes. However, the molecular properties of GM-CSF-producing cells and the mode of Csf2 regulation in vivo remain unclear. To systematically study and manipulate GM-CSF+ cells and their progeny in vivo, we generated a fate-map and reporter of GM-CSF expression mouse strain (FROG). We mapped the phenotypic and functional profile of auto-aggressive T helper (Th) cells during neuroinflammation and identified the signature and pathogenic memory of a discrete encephalitogenic Th subset. These cells required interleukin-23 receptor (IL-23R) and IL-1R but not IL-6R signaling for their maintenance and pathogenicity. Specific ablation of this subset interrupted the inflammatory cascade, despite the unperturbed tissue accumulation of other Th subsets (e.g., Th1 and Th17), highlighting that GM-CSF expression not only marks pathogenic Th cells, but that this subset mediates immunopathology and tissue destruction.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-1beta/imunologia , Subunidade p19 da Interleucina-23/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Inflamação/genética , Inflamação/patologia , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR6/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Human neutrophils contribute to the regulation of inflammation via the generation of a range of cytokines that affect all elements of the immune system. Here, we investigated their ability to express some of the members of the IL-12 family after incubation with TLR8 agonists. Highly pure human neutrophils were thus incubated for up to 48 h with or without R848, or other TLR8 agonists, to then measure the expression levels of transcripts and proteins for IL-12 family member subunits by RNA-seq, reverse transcription quantitative PCR, and ELISA. We show a TLR8-mediated inducible expression of IL-12B and IL-23A, but not IL-12A, mRNA, which occurs via chromatin remodeling (as assessed by ChIP-seq), and subsequent production of IL-23 and IL-12B, but no IL-12, proteins. Induction of IL-23 requires endogenous TNF-α, as both mRNA and protein levels were blocked in TLR8-activated neutrophils via a TNF-α-neutralizing Ab. We also show that supernatants from TLR8-activated neutrophils, but not autologous monocytes, induce the differentiation of Th17 cells from naïve T cells in an IL-23-dependent fashion. This study unequivocally demonstrates that highly pure human neutrophils express and produce IL-23, further supporting the key roles played by these cells in the important IL-17/IL-23 network and Th17 responses.
Assuntos
Subunidade p40 da Interleucina-12/imunologia , Subunidade p19 da Interleucina-23/imunologia , Ativação de Neutrófilo , Neutrófilos/imunologia , Receptor 8 Toll-Like/imunologia , Humanos , Monócitos/citologia , Monócitos/imunologia , Neutrófilos/citologia , Células Th17/imunologia , Receptor 8 Toll-Like/agonistas , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Long-term evaluation is required to confirm the safety profile of newer biologic agents. OBJECTIVES: To report on pooled safety data from the ongoing VOYAGE 1 (NCT02207231) and VOYAGE 2 (NCT02207244) trials through 100 weeks of follow-up. METHODS: Patients were randomized to either guselkumab 100 mg at weeks 0 and 4 and every 8 weeks thereafter; placebo at weeks 0, 4, 12 followed by guselkumab 100 mg at weeks 16 and 20 and every 8 weeks thereafter; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every 2 weeks thereafter. Patients who received adalimumab crossed over to guselkumab at week 52 (VOYAGE 1) and at/after week 28 based on clinical response (VOYAGE 2). Open-label extensions, in which all patients received guselkumab, started at week 52 (VOYAGE 1) and week 76 (VOYAGE 2). Rates of adverse events (AEs) per 100 patient-years (PYs) are presented through 100 weeks of follow-up. RESULTS: Through week 52, observed rates for guselkumab- and adalimumab-treated patients, respectively, were 262·45 per 100 PYs and 328·28 per 100 PYs for AEs, 6·20 per 100 PYs and 7·77 per 100 PYs for serious AEs (SAEs), 1·22 per 100 PYs and 1·79 per 100 PYs for serious infections (SIs), 0·28 per 100 PYs and 0·40 per 100 PYs for malignancies other than nonmelanoma skin cancers (NMSCs), 0·56 per 100 PYs and 0·40 per 100 PYs for NMSCs, and 0·47 per 100 PYs and 0·40 per 100 PYs for major adverse cardiovascular events (MACEs). Rates among patients treated with guselkumab through week 52 and week 100, respectively, were 262·45 per 100 PYs and 210·41 per 100 PYs for AEs, 6·20 and 6·29 per 100 PYs, for SAEs, 1·22 per 100 PYs and 1·06 per 100 PYs for SIs, 0·28 per 100 PYs and 0·38 per 100 PYs for malignancies, 0·56 per 100 PYs and 0·39 per 100 PYs for NMSCs, and 0·47 per 100 PYs and 0·38 per 100 PYs for MACEs. Among patients treated with adalimumab, rates of AEs, SAEs, SIs, malignancies, NMSCs, and MACEs showed some variability before and after crossover to guselkumab, although no new safety signals were noted after crossover. CONCLUSIONS: The safety profile for guselkumab remains favourable through 100 weeks of treatment in patients with moderate-to-severe psoriasis.
Assuntos
Adalimumab/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Psoríase/tratamento farmacológico , Adulto , Doenças Cardiovasculares/induzido quimicamente , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Health-related quality of life (HRQoL) may be markedly impaired in patients with moderate-to-severe psoriasis. OBJECTIVES: Our objectives were to compare improvements in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) scores between patients receiving guselkumab compared with placebo or adalimumab and to correlate these improvements with skin clearance. METHODS: Pooled phase III VOYAGE 1 and VOYAGE 2 data were evaluated through week 24. At baseline, patients were randomized to guselkumab 100 mg, placebo, or adalimumab 40 mg. At week 16, patients receiving placebo switched to guselkumab. Assessment measures included DLQI percent change from baseline, DLQI 0/1, DLQI minimal clinically important difference (MCID), individual domain scores, PSSD symptoms and signs score = 0, DLQI association with PSSD, Investigator's Global Assessment (IGA), and Psoriasis Area and Severity Index (PASI). RESULTS: Significantly greater improvements from baseline DLQI were observed with guselkumab versus placebo (weeks 8 and 16) and versus adalimumab (week 24; p < 0.001). The proportion of patients achieving DLQI 0/1 ("no impact") at week 24 was higher with guselkumab than with adalimumab (58.9 vs. 40.2%; p < 0.001), and more patients attained a ≥ 4-point reduction in DLQI (MCID) at this timepoint (p < 0.001). Changes in individual DLQI domains were significantly greater for patients receiving guselkumab than for those receiving adalimumab, and among patients with individual baseline domain scores = 3 or 6 (severest impact), more guselkumab recipients than those receiving adalimumab achieved a score = 0 across all domains at week 24. DLQI 0/1 scores were associated with a PSSD symptom or sign score = 0 (no impact) and greater improvement of PASI and IGA (week 24). CONCLUSIONS: Pooled VOYAGE 1/VOYAGE 2 data demonstrated that guselkumab was superior to adalimumab in improving HRQoL, which was associated with greater skin clearance. CLINICAL TRIAL REGISTRATION: NCT02207231 and NCT02207244.
Assuntos
Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Psoríase/tratamento farmacológico , Adalimumab/farmacologia , Adulto , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Fármacos Dermatológicos/farmacologia , Esquema de Medicação , Feminino , Humanos , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/imunologia , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND AND AIMS: Mucosal gene expression have not been fully enlightened in inflammatory bowel disease (IBD). Aim of this study was to define IL23A, IL17A, IL17F and TLR9 expression in different IBD phenotypes. METHODS: Evaluation of mRNA levels was performed in paired non-inflamed and inflamed mucosal biopsies of newly diagnosed 50 Crohn's disease (CD) and 54 ulcerative colitis (UC) patients by quantitative real-time PCR analysis. RESULTS: IL17A and IL17F expression levels were significantly increased in inflamed IBD mucosa. Inflamed CD ileal and UC mucosa showed increased IL23A, while only inflamed CD ileal samples showed increased TLR9 mRNA level. Correlation between analysed mRNAs levels and endoscopic and clinical disease activity were found in UC, but only with clinical activity in CD. CONCLUSION: Both CD and UC presented expression of Th17-associated genes. Nevertheless, expression profiles between different disease forms varies which should be taken into account for future research and therapeutics strategies.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Interleucina-17/genética , Subunidade p19 da Interleucina-23/genética , Receptor Toll-Like 9/genética , Adulto , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/imunologia , Colo/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Estudos Transversais , Feminino , Perfilação da Expressão Gênica , Humanos , Íleo/imunologia , Íleo/metabolismo , Interleucina-17/imunologia , Subunidade p19 da Interleucina-23/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Sérvia , Transdução de Sinais , Receptor Toll-Like 9/imunologiaRESUMO
Interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (ILC3) maintains gut homeostasis but can also promote inflammatory bowel disease (IBD). The regulation of ILC3-dependent colitis remains to be elucidated. Here we show that Foxp3+ regulatory T cells (Treg cells) prevented ILC3-mediated colitis in an IL-10-independent manner. Treg cells inhibited IL-23 and IL-1ß production from intestinal-resident CX3CR1+ macrophages but not CD103+ dendritic cells. Moreover, Treg cells restrained ILC3 production of IL-22 through suppression of CX3CR1+ macrophage production of IL-23 and IL-1ß. This suppression was contact dependent and was mediated by latent activation gene-3 (LAG-3)-an immune checkpoint receptor-expressed on Treg cells. Engagement of LAG-3 on MHC class II drove profound immunosuppression of CX3CR1+ tissue-resident macrophages. Our study reveals that the health of the intestinal mucosa is maintained by an axis driven by Treg cells communication with resident macrophages that withhold inflammatory stimuli required for ILC3 function.
Assuntos
Antígenos CD/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Colite/imunologia , Colite/patologia , Subunidade p19 da Interleucina-23/imunologia , Mucosa Intestinal/patologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/transplante , Proteína do Gene 3 de Ativação de Linfócitos , Interleucina 22RESUMO
BACKGROUND AND AIMS: We aimed to investigate the underlying mechanism of action of risankizumab, a monoclonal antibody targeting the IL-23 p19 subunit, previously reported to induce clinical and endoscopic remission in a randomised phase II study in patients with active Crohn's disease. METHODS: Ileum and colon biopsies obtained at screening and Week 12 from a subgroup of patients [n = 106] in the risankizumab phase II study were analysed by transcriptome-wide RNA-Seq profiling. Univariate associations were assessed using linear modelling. RESULTS: By Week 12, risankizumab significantly decreased [p < 0.005] the expression of 1880 and 765 genes in the colon [false-discovery rate = 0.02] and ileum [false-discovery rate = 0.05], respectively. These genes were associated with the IL-23/IL-17 axis, Th1 pathway, innate immunity, and tissue turnover. Colonic transcriptomic profiles following risankizumab treatment reflected the transcriptomic changes observed in patients achieving endoscopic response and remission at Week 12 and were significantly different from placebo [p < 0.005]. The colonic transcriptomic profile, significantly modulated by risankizumab at Week 12, was indicative of suppression of pathways associated with epithelial biology. Furthermore, pathways associated with Crohn's disease modulated by risankizumab treatment included second messenger-mediated signalling, immune response, lymphocyte and leucocyte activation, lymphocyte differentiation and cell-cell adhesion. CONCLUSIONS: Endoscopic remission and response observed with risankizumab in patients with active Crohn's disease was associated with significant transcriptomic changes in the colon, compared with placebo. Differentiated expression of genes associated with the IL-23/IL-17 axis was observed in the colon and ileum 12 weeks after risankizumab treatment.