RESUMO
Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to OPC responses, but here we demonstrate that the combined actions of both cytokines are essential for resistance to OPC. Mice lacking IL-17RA and IL-22RA1 exhibited high fungal loads in esophagus- and intestinal tract, severe weight loss, and symptoms of colitis. Ultimately, mice succumbed to infection. Dual loss of IL-17RA and IL-22RA impaired expression of small proline rich proteins (SPRRs), a class of antimicrobial effectors not previously linked to fungal immunity. Sprr2a1 exhibited direct candidacidal activity in vitro, and Sprr1-3a-/- mice were susceptible to OPC. Thus, cooperative actions of Type 17 cytokines mediate oral mucosal anti-Candida defenses and reveal a role for SPRRs.
Assuntos
Candidíase Bucal , Interleucina-17 , Interleucina 22 , Interleucinas , Camundongos Knockout , Animais , Camundongos , Candida albicans/imunologia , Candidíase Bucal/imunologia , Candidíase Bucal/microbiologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Interleucina/imunologia , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismoAssuntos
Dermatite Atópica , Modelos Animais de Doenças , Progressão da Doença , Receptores de Interleucina-17 , Dermatite Atópica/imunologia , Dermatite Atópica/tratamento farmacológico , Animais , Camundongos , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , HumanosRESUMO
BACKGROUND: Brodalumab is a monoclonal antibody and IL-17 RA inhibitor that is approved for the treatment of moderate-to-severe psoriasis. The present study aims to estimate the drug survival (DS), effectiveness, and safety of brodalumab over a period of 156 weeks. METHODS: The primary objectives were: (i) to determine the treatment response rate at Weeks 16, 28, 52, 78, 104, and 156 as defined by PASI100, PASI90, and an absolute PASI ≤ 3 and (ii) long-term DS. Secondary objectives included the evaluation of possible predictive factors associated with the achievement of response outcomes, and possible predictive factors associated with lower DS. RESULTS: The treatment response was rapid, with 80.3% of patients achieving PASI ≤ 3, 66% PASI90, and 54.3% the complete clearance of disease at Week 16. The response improved at Week 28, when a plateau was achieved with mild loss of response at later time points, in particular for PASI100 and PASI90 in 55.2 and 65.5% of patients, respectively, at Week 156. After 156 weeks of treatment, 66.22% of patients were still on therapy, and the previous use of IL-17 inhibitors appeared to be associated with an increased risk of treatment discontinuation (HR: 2.51, CI: 1.06-5.98, P = 0.037), and achievement of PASI ≤ 3 until Week 16 with less risk (HR: 0.27 CI: 0.14-0.51, P < 0.001). Bio-naïve status was favorably associated with treatment response, while high BMI negatively affected the achievement of outcomes. CONCLUSION: Our study confirms the good effectiveness and favorable safety profile of brodalumab in a real-world setting for up to 3 years of treatment.
Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Índice de Gravidade de Doença , Humanos , Psoríase/tratamento farmacológico , Psoríase/imunologia , Masculino , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Fatores de Tempo , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , IdosoRESUMO
IL-17 is a cytokine produced by innate and acquired immunity cells that have an action against fungi and bacteria. However, its action in helminth infections is unclear, including in Toxocara canis infection. Toxocariasis is a neglected zoonosis representing a significant public health problem with an estimated seroprevalence of 19% worldwide. In the present study, we describe the immunopathological action of IL-17RA in acute T. canis infection. C57BL/6j (WT) and IL-17RA receptor knockout (IL-17RA-/-) mice were infected with 1000 T. canis eggs. Mice were evaluated 3 days post-infection for parasite load and white blood cell count. Lung tissue was harvested for histopathology and cytokine expression. In addition, we performed multiparametric flow cytometry in the BAL and peripheral blood, evaluating phenotypic and functional changes in myeloid and lymphoid populations. We showed that IL-17RA is essential to control larvae load in the lung; however, IL-17RA contributed to pulmonary inflammation, inducing inflammatory nodular aggregates formation and presented higher pulmonary IL-6 levels. The absence of IL-17RA was associated with a higher frequency of neutrophils as a source of IL-4 in BAL, while in the presence of IL-17RA, mice display a higher frequency of alveolar macrophages expressing the same cytokine. Taken together, this study indicates that neutrophils may be an important source of IL-4 in the lungs during T. canis infection. Furthermore, IL-17/IL-17RA axis is important to control parasite load, however, its presence triggers lung inflammation that can lead to tissue damage.
Assuntos
Pneumonia , Receptores de Interleucina-17 , Toxocara canis , Toxocaríase , Animais , Citocinas/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/parasitologia , Receptores de Interleucina-17/imunologia , Toxocara canis/imunologia , Toxocaríase/imunologia , Toxocaríase/parasitologiaRESUMO
Dry eye disease (DED) features the inflammatory response of the ocular surface. Pro-inflammatory T helper 17 (Th17) cells are important for the pathogenesis of DED. In the present study a mouse DED model was used to discover two Th17 subsets in draining lymph nodes and conjunctivae based on the expression of IL-17 receptor E (IL-17RE) and CCR10: IL-17RElowCCR10- Th17 and IL-17REhighCCR10+ Th17. IL-17REhighCCR10+ Th17 expressed more retinoic acid-related orphan receptor gamma t but fewer T-box-expressed-in-T-cells than IL-17RElowCCR10- Th17. In addition, the former expressed higher IL-17A, IL-21, and IL-22 but fewer IFN-γ than the latter. Further analysis showed that IL-17REhighCCR10+ Th17 did not express IFN-γ in vivo, whereas IL-17RElowCCR10- Th17 contained IFN-γ-expressing Th17/Th1 cells. Moreover, IL-17REhighCCR10+ Th17 possessed more phosphorylated p38 mitogen-activated protein kinase (MAPK) and Jnk than IL-17RElowCCR10- Th17, suggesting higher activation of MAPK signaling in IL-17REhighCCR10+ Th17. In vitro treatment with IL-17C effectively maintained IL-17A expression in Th17 cells through p38 MAPK rather than Jnk MAPK. Furthermore, the adoptive transfer of the two Th17 subpopulations indicated their equivalent pathogenicity in DED. Interestingly, IL-17REhighCCR10+ Th17 cells were able to phenotypically polarize to IL-17RElowCCR10- Th17 cells in vivo. In conclusion, the current study revealed novel Th17 subsets with differential phenotypes, functions, and signaling status in DED, thus deepening the understanding of Th17 pathogenicity, and exhibited Th17 heterogeneity in DED.
Assuntos
Síndromes do Olho Seco/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Receptores CCR10/imunologia , Receptores de Interleucina-17/imunologia , Células Th17/imunologia , Animais , Modelos Animais de Doenças , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Transgênicos , Receptores CCR10/genética , Receptores de Interleucina-17/genética , Células Th17/patologiaRESUMO
The IL-23/IL-17 axis plays causative roles in the development and progression of systemic lupus erythematosus (SLE). However, it remains unclear if the IL-17RA+ and IL-23R+ T helper (Th) cells populations are associated with the serum IL-17 and IL-23 levels, or with the immunological parameters and disease activities in SLE patients. Herein, we examined the proportion of IL-17RA+ and IL-23R+ Th cells and serum levels of IL-17 and IL-23 in established SLE patients (n = 50) compared with healthy controls (n = 50). The associations of these interleukins and their receptors with immunological parameters [anti-nuclear antibody (ANA), anti-dsDNA antibody, and C-reactive protein (CRP)] and SLE disease activity (SLEDAI-2K scores) in SLE patients were assessed. CD3+CD4+ Th cells of SLE patients demonstrated significantly elevated IL-17RA+ (p = 1.12 x 10-4) or IL-23R+ (p = 1.98 x 10-29) populations compared with the healthy controls. Serum IL-17 levels were significantly lower in SLE patients compared with the healthy controls (p = 8.32 x 10-5), while no significant difference was observed for the IL-23 serum levels between both groups. IL-23R+ Th cells population was significantly associated with higher SLEDAI-2K scores (p = 0.017). In multivariate analysis, the proportion of IL-23R+ Th cells remained significantly associated with higher SLEDAI-2K scores independent of prednisolone intake (p = 0.027). No associations were observed between the interleukin parameters (i.e., IL-17, IL-23, IL-17RA+ Th cells, and IL-23R+ Th cells) with ANA, anti-dsDNA, and CRP status, suggesting that the IL-17/IL-23 axis acts independently of these immunological parameters. In conclusion, our results support that therapeutic inhibition of the IL-23/IL-17 axis receptors on Th cells, particularly IL-23R, is potentially relevant in SLE patients.
Assuntos
Interleucina-17/imunologia , Interleucina-23/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Interleucina-17/imunologia , Receptores de Interleucina/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Anticorpos Antinucleares/sangue , Proteína C-Reativa/análise , Feminino , Humanos , Interleucina-17/sangue , Interleucina-23/sangue , Lúpus Eritematoso Sistêmico/sangue , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
Tissue-resident memory (TRM) cells are thought to play a role in lung mucosal immunity to pathogens, but strategies to elicit TRM by mucosal vaccines have not yet been fully realized. Here, we formulated a vaccine composed of outer membrane protein (Omp) X from Klebsiella pneumoniae and LTA1 adjuvant that was administered by the intrapulmonary route. This vaccine elicited both TH1 and TH17 cells that shared transcriptional features with cells elicited by heat-killed K. pneumoniae. Antibody responses were required to prevent bacterial dissemination but dispensable for lung-specific immunity. In contrast, lung immunity required CD4+ T cells, STAT3 expression, and IL-17R signaling in fibroblasts. Lung-specific CD4+ T cells from OmpX+LTA1immunized mice were observed homing to the lung and could mediate protection against infection in an adoptive transfer model. Vaccine-elicited TH17 cells showed reduced plasticity and were resistant to the immunosuppressant FK506 compared with TH1 cells, and TH17 cells conferred protection under conditions of transplant immunosuppression. These data demonstrate a promising vaccine strategy that elicits lung TRM cells and promotes serotype-independent immunity to K. pneumoniae.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Klebsiella pneumoniae/imunologia , Pulmão/imunologia , Receptores de Interleucina-17/imunologia , Vacinas/imunologia , Animais , Fibroblastos/imunologia , Imunidade nas Mucosas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologiaRESUMO
The interleukin-17 (IL-17) family consists of proinflammatory cytokines conserved during evolution. A comparative genomics approach was applied to examine IL-17 throughout evolution from poriferans to higher vertebrates. Cnidaria was highlighted as the most ancient diverged phylum, and several evolutionary patterns were revealed. Large expansions of the IL-17 repertoire were observed in marine molluscs and echinoderm species. We further studied this expansion in filter-fed Mytilus galloprovincialis, which is a bivalve with a highly effective innate immune system supported by a variable pangenome. We recovered 379 unique IL-17 sequences and 96 receptors from individual genomes that were classified into 23 and 6 isoforms after phylogenetic analyses. Mussel IL-17 isoforms were conserved among individuals and shared between closely related Mytilidae species. Certain isoforms were specifically implicated in the response to a waterborne infection with Vibrio splendidus in mussel gills. The involvement of IL-17 in mucosal immune responses could be conserved in higher vertebrates from these ancestral lineages.
Assuntos
Evolução Molecular , Imunidade nas Mucosas , Interleucina-17/imunologia , Mytilus/imunologia , Receptores de Interleucina-17/imunologia , Animais , Interações Hospedeiro-Patógeno , Interleucina-17/genética , Interleucina-17/metabolismo , Mytilus/genética , Mytilus/metabolismo , Filogenia , Isoformas de Proteínas , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Transdução de Sinais , Especificidade da Espécie , Vibrio/imunologia , Vibrio/patogenicidade , Vibrioses/imunologia , Vibrioses/metabolismo , Vibrioses/microbiologiaRESUMO
BACKGROUND: IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity [ST2]) is a differentially expressed gene in pathogenic TH2 cells, but its role in T-cell effector function has not been elucidated. OBJECTIVE: We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4+ T cells would confer susceptibility to the effects of IL-33. METHODS: PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor-dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4+ T cells by flow cytometry. Allergen-specific CD4+ T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay. RESULTS: ST2 expression on peripheral allergen-specific CD4+ T cells was confined to subjects with allergy and restricted to TH2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of TH2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive TH2A cells. Allergen-induced ST2 expression on peripheral CD4+ T cells can be used to track allergen-reactive TH2A cells from donors with allergy. CONCLUSION: ST2 expression on circulating CD4+ T cells represents a transient phenotype associated with TH2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic TH2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.
Assuntos
Hipersensibilidade/imunologia , Interleucina-33/imunologia , Células Th2/imunologia , Células Epiteliais/imunologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Receptores de Interleucina-17/imunologia , Transdução de SinaisRESUMO
Interleukin-17 receptor D (IL17RD or IL-17RD) also known as Sef (similar expression to fibroblast growth factor), is a single pass transmembrane protein that is reported to regulate several signaling pathways . IL17RD was initially described as a feedback inhibitor of fibroblast growth factor (FGF) signaling during zebrafish and frog development. It was subsequently determined to regulate other receptor tyrosine kinase signaling cascades as well as several proinflammatory signaling pathways including Interleukin-17A (IL17A), Toll-like receptors (TLR) and Interleukin-1α (IL1α) in several vertebrate species including humans. This review will provide an overview of IL17RD regulation of signaling pathways and functions with emphasis on regulation of development and pathobiological conditions. We will also discuss gaps in our knowledge about IL17RD function to provide insight into opportunities for future investigation. Video Abstract.
Assuntos
Receptores de Interleucina-17/imunologia , Animais , Humanos , Receptores de Interleucina-17/química , Transdução de SinaisRESUMO
Type 17 cytokines have been strongly implicated in mucosal immunity, in part by regulating the production of antimicrobial peptides. Using a mouse model of Citrobacter rodentium infection, which causes colitis, we found that intestinal IL-17RA and IL-17RC were partially required for control of infection in the colon and IL-17 regulates the production of luminal hydrogen peroxide as well as expression of Tnsf13 Reduced Tnfsf13 expression was associated with a profound defect in generating C. rodentium-specific IgA+ Ab-secreting cells. Taken together, intestinal IL-17R signaling plays key roles in controlling invading pathogens, in part by regulating luminal hydrogen peroxide as well as regulating the generation of pathogen-specific IgA+ Ab-secreting cells.
Assuntos
Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Imunoglobulina A Secretora/imunologia , Mucosa Intestinal/imunologia , Oxirredutases/imunologia , Receptores de Interleucina-17/imunologia , Transdução de Sinais/imunologia , Animais , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/genética , Humanos , Peróxido de Hidrogênio/imunologia , Imunoglobulina A Secretora/genética , Camundongos , Camundongos Knockout , Oxirredutases/genética , Receptores de Interleucina-17/genética , Transdução de Sinais/genéticaRESUMO
Candida auris is an emerging multi-drug-resistant human fungal pathogen. C. auris skin colonization results in environmental shedding, which underlies hospital transmissions, and predisposes patients to subsequent infections. We developed a murine skin topical exposure model for C. auris to dissect risk factors for colonization and to test interventions that might protect patients. We demonstrate that C. auris establishes long-term residence within the skin tissue compartment, which would elude clinical surveillance. The four clades of C. auris, with geographically distinct origins, differ in their abilities to colonize murine skin, mirroring epidemiologic findings. The IL-17 receptor signaling and specific arms of immunity protect mice from long-term C. auris skin colonization. We further determine that commonly used chlorhexidine antiseptic serves as a protective and decolonizing agent against C. auris. This translational model facilitates an integrated approach to develop strategies to combat the unfolding global outbreaks of C. auris and other skin-associated microbial pathogens.
Assuntos
Candida/imunologia , Candidíase/transmissão , Pele/imunologia , Pele/microbiologia , Tropismo Viral , Animais , Anti-Infecciosos Locais/farmacologia , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase/prevenção & controle , Clorexidina/farmacologia , Modelos Animais de Doenças , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-17/imunologia , Fatores de Risco , Pele/patologia , Células Th17/imunologiaRESUMO
Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α (TNF-α) /interleukin (IL) -23/IL-17 axis, epidermal hyperproliferation, and dysregulated differentiation. Psoriasis is occasionally associated with autoimmune liver diseases such as autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), caused by autoimmunity against hepatocyte- or cholangiocyte-specific autoantigens, respectively. Overlap syndrome is a condition in which patients have features of both AIH and PBC. It has been reported that AIH, PBC, or the overlap syndrome can be triggered by certain drug therapies. A 65-year-old Japanese man developed increased serum levels of aspartate and alanine aminotransferases, and positive anti-nuclear and anti-mitochondrial M2 antibodies, along with neutropenia, at 4 weeks of treatment with an anti-IL-17 receptor A antibody brodalumab for generalized pustular psoriasis. Histological evaluation of the liver revealed interface hepatitis and non-suppurative destructive cholangitis, which is compatible with the overlap syndrome of AIH and PBC. This is the first case of AIH/PBC overlap syndrome during treatment with brodalumab for generalized pustular psoriasis. The relationship between brodalumab and AIH/PBC overlap syndrome should be further elucidated. The risk of autoimmune liver diseases in patients with psoriasis treated with brodalumab should be carefully considered.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Hepatite Autoimune/etiologia , Cirrose Hepática Biliar/etiologia , Psoríase/complicações , Psoríase/tratamento farmacológico , Doença Aguda , Idoso , Alanina Transaminase/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Ácido Aspártico/sangue , Autoanticorpos/sangue , Fármacos Dermatológicos/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Humanos , Interleucina-17/imunologia , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/imunologia , Masculino , Neutropenia , Psoríase/imunologia , Receptores de Interleucina-17/imunologia , Síndrome , Resultado do TratamentoRESUMO
Interleukin-17 (IL-17) is a cytokine family that includes 6 members, IL-17A through IL-17F, most of them are reported to have pro-inflammatory role. Through binding to their receptors (IL-17Rs), IL-17 activates the intracellular signalling pathways to play an important role in autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). Ischaemic stroke is a complex pathophysiological process mainly caused by regional cerebral ischaemia. Inflammatory factors contribute to the physiological process of stroke that leads to poor prognosis. IL-17 plays a crucial role in promoting inflammatory response and inducing secondary injury in post-stroke. Though immune cells and inflammatory factors have been reported to be involved in the damage of stroke, the functions of IL-17 in this process need to be elucidated. This review focuses on the pathological modulation and the mechanism of IL-17 family in ischaemic stroke and seeking to provide new insights for future therapies.
Assuntos
Interleucina-17/imunologia , AVC Isquêmico/imunologia , Animais , Doenças Autoimunes/imunologia , Isquemia Encefálica/imunologia , Humanos , Receptores de Interleucina-17/imunologia , Transdução de Sinais/imunologiaRESUMO
Pancreatic cancer is the fourth leading cause of death worldwide due to its poorest prognoses with a 7% 5-year survival rate. Eighty percent of pancreatic cancer patients relapse after chemotherapy and develop early metastasis and drug resistance. Resistance to nucleoside analog gemcitabine frequently used in first-line therapy is an urgent issue in pancreatic cancer treatment. Expression of mucin (MUC) glycoproteins has been shown to enhance chemoresistance via increased cell stemness. Here we show interlukine-17 receptor B (IL-17RB) expression is positively correlated with MUC1 and MUC4 expression in pancreatic cancer cells and tumor tissue. Moreover, IL-17RB transcriptionally up-regulates expression of MUC1 and MUC4 to enhance cancer stem-like properties and resistance to gemcitabine. These results suggest IL-17RB can be a potential target for pancreatic cancer therapy. Indeed, treatment with IL-17RB-neutralizing antibody has a synergistic effect in combination with gemcitabine for killing pancreatic cancer cells. Altogether, these findings provide feasible applications for IL-17RB-targeting therapy in pancreatic cancer treatment.
Assuntos
Anticorpos Bloqueadores/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Células-Tronco Neoplásicas/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Receptores de Interleucina-17/metabolismo , Desoxicitidina/uso terapêutico , Regulação para Baixo , Resistência a Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Terapia de Alvo Molecular , Mucinas/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Células Tumorais Cultivadas , GencitabinaRESUMO
BACKGROUND AND AIMS: The interleukin-17 (IL-17) pathway would play an important role in the pathogenesis of atherosclerosis and coronary-artery disease (CAD). The IL-17 inflammatory mediators are expressed by Th17 cells, a group of CD4 + leukocytes that infiltrate the vascular milieu and are pivotal in the origin, progression, stability and rupture of the atherosclerotic lesion. Cigarette smoke compounds stimulated the expression of IL-17 and IL-17-receptors. In atherogenic mice models the deficiency of IL-17RA resulted in a reduction of the atherosclerotic lesion size and leukocyte infiltrate. We hypothesised that common the IL-17RA transcript might be differential expressed in the leukocytes from CAD patients and healthy individuals. METHODS: The relative amount of the IL-17RA to ACTB transcript was determined in total leukocytes of 55 patients and 50 controls, all smokers. We genotyped the IL-17RA rs48195554 promoter polymorphisms in 390 healthy controls and 450 early-onset CAD patients. RESULTS: Patients showed significantly higher mean IL-17RA normalised transcript value than controls (p < 0.001). For the IL-17RA rs48195554 promoter polymorphisms, IL-17RA G-carriers showed higher transcript values. However, allele and genotype frequencies did not differ between patients and controls and we thus excluded a significant association with CAD. CONCLUSIONS: The higher levels of the IL-17RA transcript among CAD-patients was in agreement with a role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis.
Assuntos
Alelos , Doença da Artéria Coronariana , Frequência do Gene , Polimorfismo Genético , Receptores de Interleucina-17 , Transcrição Gênica/imunologia , Idade de Início , Idoso , Animais , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologiaAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Monitoramento de Medicamentos/estatística & dados numéricos , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Artralgia/induzido quimicamente , Artralgia/epidemiologia , Artralgia/imunologia , Depressão/induzido quimicamente , Depressão/epidemiologia , Depressão/imunologia , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Diarreia/imunologia , Meia-Vida , Humanos , Farmacovigilância , Psoríase/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Complete lesion clearance is important to patients with psoriasis. OBJECTIVE: To conduct a network meta-analysis of randomized controlled trials of biologic agents available for psoriasis in Japan, using mixed-treatment comparisons. METHODS: MEDLINE and EMBASE were searched to identify randomized clinical trials (placebo-controlled or head-to-head) of infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, risankizumab or guselkumab in adult patients with moderate-to-severe plaque psoriasis published in English between 01 January 2000 and 31 August 2019. We assessed the proportion of patients who achieved a 100 %, 90 % and 75 % reduction in their Psoriasis Area and Severity Index (PASI) score (PASI100, PASI90 and PASI75) at 10, 12 or 16 weeks after starting biologic treatment, using contrast-based network meta-analysis methods and risk difference (RD). Probabilities of rank and surface under the cumulative ranking (SUCRA) were also estimated. RESULTS: Data were pooled from 41 trials in 19,248 patients. All biologics were significantly more effective than placebo for PASI100, PASI90 and PASI75. The RD for PASI100 for brodalumab vs ixekizumab was 0.05 (95 % Confidence intervals [CI] -0.02, 0.11), brodalumab vs risankizumab was 0.04 (95 %CI -0.03, 0.11), and risankizumab vs ixekizumab was -0.01 (95 %CI -0.08, 0.06). The SUCRA for PASI100 and PASI90 achievement was 96.8 % and 86.8 %, respectively, for brodalumab, 82.6 % and 90.3 %, respectively for risankizumab, and 78.3 %, 80.9 %, respectively, for ixekizumab. CONCLUSION: Of the biologics assessed, brodalumab, ixekizumab and risankizumab were the greatest rates of PASI90 and PASI100 achievement, and a higher probability of being most effective in the induction phase, compared with the other biologics.
Assuntos
Produtos Biológicos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/farmacologia , Fármacos Dermatológicos/farmacologia , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Subunidade p19 da Interleucina-23/metabolismo , Japão , Metanálise em Rede , Psoríase/diagnóstico , Psoríase/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismo , Indução de Remissão/métodos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Brodalumab, an interleukin-17 receptor A inhibitor, demonstrated rapid and robust efficacy with a favorable safety profile in patients with moderate to severe plaque psoriasis. Here, we present data from a multicenter, open-label extension study in patients with plaque psoriasis with/without psoriatic arthritis who completed 64 weeks of treatment with brodalumab (140 or 210 mg, every 2 weeks [Q2W]). Patients were enrolled to evaluate the long-term safety and efficacy of a modified dose of brodalumab. Eligible patients were switched to a reduced dose of brodalumab (140 mg every 4 weeks on day 1) in the extension study; the dose and dosing interval were modified sequentially at the physician's discretion (minimum 140 mg every 8 weeks and maximum 210 mg Q2W) until drug approval, after which all patients were switched to 210 mg Q2W for postmarketing surveillance. Of the 129 patients enrolled, 107 (82.9%) completed the 108-week or more extension study. All patients had psoriasis that was well controlled with brodalumab treatment on day 1. Improvement in psoriasis-related symptoms, evaluated with the Psoriasis Area and Severity Index, Psoriasis Scalp Severity Index, Dermatology Life Quality Index, Nail Psoriasis Severity Index, and American College of Rheumatology 20, 50 and 70, was maintained during the 108-week extension study. Brodalumab treatment was well tolerated throughout, and no new safety signals were identified. The most commonly reported treatment-related adverse event was nasopharyngitis, followed by influenza and oral candidiasis. No cases of serious candida infection or Crohn's disease were observed in this study. Serious treatment-related adverse events, such as appendicitis, brain abscess, bacterial meningitis, colon cancer, immunoglobulin A nephropathy and tubulointerstitial nephritis, were reported in one patient each. No anti-brodalumab-binding antibodies or brodalumab-neutralizing antibodies were detected in any patient throughout the extension study. Overall, the long-term efficacy and safety of brodalumab were demonstrated over 108 weeks.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase Bucal/epidemiologia , Influenza Humana/epidemiologia , Nasofaringite/epidemiologia , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Candidíase Bucal/induzido quimicamente , Candidíase Bucal/imunologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Influenza Humana/induzido quimicamente , Influenza Humana/imunologia , Japão , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , Nasofaringite/imunologia , Psoríase/diagnóstico , Psoríase/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The National Psoriasis Foundation has emphasized the importance of achieving skin clearance targets throughout the course of treatment. However, patients with psoriasis often stop and restart treatment for reasons such as psychological distress, dissatisfaction with treatment, inconvenience, cost, or comorbidities. Brodalumab is a fully human anti-interleukin-17 receptor A monoclonal antibody efficacious for the treatment of moderate-to-severe plaque psoriasis. This review discusses the efficacy and safety of brodalumab and other biologic therapies in patients with psoriasis who stop and restart treatment. These clinically relevant and important findings can help inform real-world treatment decisions. J Drugs Dermatol. 2020;19(4):384-387. doi:10.36849/JDD.2020.5026.