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1.
Nihon Yakurigaku Zasshi ; 158(3): 282-289, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-37121713

RESUMO

Nemolizumab (Mitchga® syringes) is a biologic with a novel mechanism of action that was first approved in Japan in March 2022 for pruritus associated with atopic dermatitis (AD) only when existing treatments were insufficiently effective. Nemolizumab is a humanized antihuman interleukin-31 (IL-31) receptor A (IL-31RA) monoclonal antibody that targets the receptor for IL-31, the major pruritogen in AD. Nemolizumab inhibits IL-31 signaling and suppresses pruritus by competitively preventing IL-31 from binding to IL-31RA. In the phase III study, nemolizumab, 60 |mg, was administered subcutaneously once every 4 weeks, in combination with topical therapy, to patients aged 13 years or older who had AD and inadequately controlled moderate-to-severe pruritus. The efficacy of the treatment was verified by mean percentage change in the pruritus visual analogue scale score from baseline to 16 weeks. Skin symptoms and quality of life (QOL) were improved after 16 weeks. Furthermore, data for up to 68 weeks revealed continuous improvement and/or maintenance of itching, skin symptoms, and QOL. The most common adverse effects were worsening of AD, skin infection, and upper respiratory tract infection. Because skin symptoms may worsen during treatment with this product, patients must be monitored carefully and managed appropriately (e.g., by intensifying treatment with topical anti-inflammatory drugs or withdrawal of medication as needed). Nemolizumab effectively suppresses itching, the most distressing symptom of AD, and improves skin symptoms. It is also expected to help improve QOL, including sleep.This review describes the pharmacological properties of nemolizumab, pharmacokinetics, efficacy and safety in clinical trials in Japan.


Assuntos
Dermatite Atópica , Humanos , Dermatite Atópica/complicações , Dermatite Atópica/tratamento farmacológico , Qualidade de Vida , Prurido/etiologia , Prurido/induzido quimicamente , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Receptores de Interleucina/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego
2.
Biomed Pharmacother ; 159: 114225, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36621146

RESUMO

BACKGROUND: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AIM: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. METHODS: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. RESULTS: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). CONCLUSIONS: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.


Assuntos
Doença de Crohn , Humanos , Adulto , Infliximab/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Polimorfismo de Nucleotídeo Único/genética , Fármacos Gastrointestinais/uso terapêutico , Estudos Transversais , Resultado do Tratamento , Proteína ADAM17/genética , Receptores de Interleucina/genética , Receptores de Interleucina/uso terapêutico
3.
BMC Cancer ; 22(1): 707, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761256

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) is a molecular subtype of breast cancer, which is a major health burden of females worldwide. Thymoquinone (TQ), a natural compound, has been found to be effective against TNBC cells, and this study identified IL17RD as a novel target of TQ in TNBC cells. METHODS: We have performed chromatin immunoprecipitation Sequence (ChIP-Seq) by MBD1 (methyl-CpG binding domain protein 1) antibody to identify genome-wide methylated sites affected by TQ. ChIP-seq identified 136 genes, including the tumor suppressor IL17RD, as a novel target of TQ, which is epigenetically upregulated by TQ in TNBC cell lines BT-549 and MDA-MB-231. The IL17RD expression and survival outcomes were studied by Kaplan-Meier analysis. RESULTS: TQ treatment inhibited the growth, migration, and invasion of TNBC cells with or without IL17RD overexpression or knockdown, while the combination of IL17RD overexpression and TQ treatment were the most effective against TNBC cells. Moreover, higher expression of IL17RD is associated with longer survival in TNBC patients, indicating potential therapeutic roles of TQ and IL17RD against TNBC. CONCLUSIONS: Our data suggest that IL17RD might be epigenetically upregulated in TNBC cell lines by TQ, and this might be one of the mechanisms by which TQ exerts its anticancer and antimetastatic effects on TNBC cells.


Assuntos
Neoplasias de Mama Triplo Negativas , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Processos Neoplásicos , Receptores de Interleucina/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
4.
J Allergy Clin Immunol ; 143(5): 1878-1891, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30339851

RESUMO

BACKGROUND: Ras homolog gene family H (RhoH) is a membrane-bound adaptor protein involved in proximal T-cell receptor signaling. Therefore RhoH plays critical roles in the differentiation of T cells; however, the function of RhoH in the effecter phase of the T-cell response has not been fully characterized. OBJECTIVE: We sought to explore the role of RhoH in inflammatory immune responses and investigated the involvement of RhoH in the pathogenesis of psoriasis. METHODS: We analyzed effector T-cell and systemic inflammation in wild-type and RhoH-null mice. RhoH expression in T cells in human PBMCs was quantified by using RT-PCR. RESULTS: RhoH deficiency in mice induced TH17 polarization during effector T-cell differentiation, thereby inducing psoriasis-like chronic dermatitis. Ubiquitin protein ligase E3 component N-recognin 5 (Ubr5) and nuclear receptor subfamily 2 group F member 6 (Nr2f6) expression levels decreased in RhoH-deficient T cells, resulting in increased protein levels and DNA binding activity of retinoic acid-related orphan receptor γt. The consequential increase in IL-17 and IL-22 production induced T cells to differentiate into TH17 cells. Furthermore, IL-22 binding protein/Fc chimeric protein reduced psoriatic inflammation in RhoH-deficient mice. Expression of RhoH in T cells was lower in patients with psoriasis with very severe symptoms. CONCLUSION: Our results indicate that RhoH inhibits TH17 differentiation and thereby plays a role in the pathogenesis of psoriasis. Additionally, IL-22 binding protein has therapeutic potential for the treatment of psoriasis.


Assuntos
Dermatite/metabolismo , Interleucinas/metabolismo , Psoríase/metabolismo , Células Th17/imunologia , Fatores de Transcrição/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Doença Crônica , Dermatite/tratamento farmacológico , Dermatite/genética , Modelos Animais de Doenças , Humanos , Interleucinas/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Psoríase/tratamento farmacológico , Psoríase/genética , Receptores de Interleucina/uso terapêutico , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Proteínas rho de Ligação ao GTP/genética , Interleucina 22
5.
Cartilage ; 9(3): 293-303, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29986604

RESUMO

Objective Early intervention therapies targeting inflammation and cell death during the acute phase of cartilage injury have the potential to prevent posttraumatic osteoarthritis. The objective of this study was to investigate the effects of interleukin receptor antagonist protein (IRAP), hyaluronan (HA), dexamethasone (DEX), and mesenchymal stem cell (MSC) treatment on the expression of established genetic markers for matrix degradation, apoptosis, and inflammation in articular cartilage during the acute phase of injury. Design A custom impact device was used to create replicable injury ex vivo to intact porcine knee joint. One hour after impact, IRAP, HA, DEX, or MSCs was intra-articularly injected. At 8 hours postinjury, cartilage and meniscus samples were harvested for genetic expression analysis. Expression of miR-27b, miR-140, miR-125b, miR-16, miR-34a, miR-146a, miR-22, ADAMTS-4, ADAMTS-5, MMP-3, IL-1ß, and TNF-α was analyzed by real-time polymerase chain reaction. Results At 8 hours postinjury, expression of ADAMTS-4, ADAMTS-5, MMP-3, IL-1ß, and TNF-α in cartilage was significantly decreased in IRAP- and DEX-treated joints as compared to nontreated injured joints, whereas only IRAP upregulated expression of miR-140, miR-125b, miR-27b, miR-146a, and miR-22 in cartilage. HA and MSC treatments had no significant effects on catabolic and inflammatory gene expression in cartilage. However, HA treatment significantly upregulated expression of all miRNAs except miR-16. In addition, the treatments tested also exhibited significant influences on meniscus. Conclusions This study provides a valuable starting point for further research into potential targets for and efficacy of various early intervention strategies that may delay or prevent the progression of posttraumatic osteoarthritis after acute cartilage injury.


Assuntos
Anti-Inflamatórios/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Osteoartrite do Joelho/genética , Proteína ADAMTS4/efeitos dos fármacos , Proteína ADAMTS4/genética , Proteína ADAMTS5/efeitos dos fármacos , Proteína ADAMTS5/genética , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/lesões , Morte Celular/efeitos dos fármacos , Células Cultivadas/metabolismo , Condrócitos/efeitos dos fármacos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Expressão Gênica , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/uso terapêutico , Inflamação/metabolismo , Injeções Intra-Articulares/métodos , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/genética , Menisco/efeitos dos fármacos , Menisco/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , MicroRNAs/genética , Modelos Animais , Osteoartrite do Joelho/prevenção & controle , Receptores de Interleucina/antagonistas & inibidores , Receptores de Interleucina/uso terapêutico , Suínos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
6.
Int Immunopharmacol ; 46: 133-140, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28282577

RESUMO

Repeated airway inflammation and unremitting remodeling provoke irreversible pulmonary dysfunction and resistance to current drugs in patients with chronic bronchial asthma. Interleukin (IL)-13 and IL-25 play an important role in airway inflammation and remodeling in asthma. We aimed to investigate whether co-inhibiting IL-13 and IL-25 can effectively down-regulate allergen-induced airway inflammation and remodeling in mice. Mice with asthma induced by chronic exposure to ovalbumin (OVA) were given soluble IL-13 receptor α2 (sIL-13R) or soluble IL-25 receptor (sIL-25R) protein alone and in combination to neutralize the bioactivity of IL-13 and IL-25, and relevant airway inflammation and remodeling experiments were performed. We found that the co-blockade of IL-13 and IL-25 with sIL-13R and sIL-25R was more effective than either agent alone at decreasing inflammatory cell infiltration, airway hyperresponsiveness (AhR) and airway remodeling including mucus production, extracellular collagen deposition, smooth muscle cell hyperplasia and angiogenesis in mice exposed to OVA. These results suggest that the combined inhibition of IL-13 and IL-25 may provide a novel therapeutic strategy for asthma, especially for patients who are resistant to current treatments.


Assuntos
Asma/terapia , Imunoterapia/métodos , Interleucina-13/metabolismo , Interleucinas/metabolismo , Pulmão/efeitos dos fármacos , Receptores de Interleucina-13/uso terapêutico , Receptores de Interleucina/uso terapêutico , Remodelação das Vias Aéreas/efeitos dos fármacos , Alérgenos/imunologia , Animais , Asma/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Humanos , Imunoglobulina E/sangue , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia
7.
Reumatol. clín. (Barc.) ; 9(2): 106-112, mar.-abr. 2013. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-110342

RESUMO

La artritis reumatoide (AR) es una enfermedad sistémica e inflamatoria que afecta la membrana sinovial de las articulaciones, los tendones y algunos sitios extra-articulares. La prevalencia de la AR en Latinoamérica se encuentra entre 0.4–1.6%. El tratamiento precoz de la enfermedad se traduce en una reducción del costo para la sociedad. En vista de esto, se han establecido clínicas de AR temprana en varios países de la región. Se han identificado barreras para el tratamiento de la AR como lo son el retraso en la referencia al reumatólogo y limitaciones en el acceso al tratamiento. Varios países han desarrollado y adaptado guías para el tratamiento basadas en la evidencia y en sus propias realidades. La necesidad de tener registros detallados de las prescripciones de biológicos ha sido abordada con registros de biológicos lo que llevará a un mejor entendimiento de las enfermedades reumáticas y su tratamiento. Los biológicos disponibles en la actualidad son los inhibidores del factor de necrosis tumoral (TNF)-alpha (etanercept, infliximab y adalimumab), un agente depletor de células B (rituximab), un bloqueador del receptor de interleucina-6 (tocilizumab) y un bloqueador de la co-estimulación de células T (abatacept). En el futuro se incluirán los inhibidores de cinasas (tofacitinib y fostamatinib) e inhibidores del TNF-alpha alternativos (golimumab y certolizumab) y biosimilares (AU)


Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting the synovium of joints, tendons, and some extra-articular sites. RA prevalence in Latin America ranges from 0.4 to 1.6%. Early treatment of RA translates into a substantial reduction in the cost to society. In light of this, early disease clinics are being established in some countries. Barriers to RA management, such as delay in referral to rheumatologists and limited access to therapy, have been identified. Evidence-based treatment guidelines have been adapted by countries according to their own situations. The need for keeping accurate records of biologics prescribed has been addressed by biologic registries, thereby contributing toward a better understanding of rheumatic diseases and their treatment. Current biologics include the tumor necrosis factor (TNF)-alpha inhibitors (etanercept, infliximab, and adalimumab), B-cell depletion agent (rituximab), interleukin-6 receptor blocker (tocilizumab), and T-cell co-stimulatory blocker (abatacept). Future therapies include kinase inhibitors (tofacitinib and fostamatinib), alternative TNF-alpha inhibitors (golimumab and certolizumab), and biosimilars (AU)


Assuntos
Humanos , Masculino , Feminino , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/prevenção & controle , Diagnóstico Precoce , Interleucinas/uso terapêutico , Receptores de Interleucina/uso terapêutico , Fatores Socioeconômicos , América Latina/epidemiologia , Artrite Reumatoide/economia , Fator de Necrose Tumoral alfa/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , 24436
8.
Circ Heart Fail ; 5(3): 366-75, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22454393

RESUMO

BACKGROUND: IL-33 through its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models but, paradoxically, increases autoimmune disease. In this study, we examined the effect of IL-33 or ST2 administration on autoimmune heart disease. METHODS AND RESULTS: We used pressure-volume relationships and isoproterenol challenge to assess the effect of recombinant (r) IL-33 or rST2 (eg, soluble ST2) administration on the development of autoimmune coxsackievirus B3 myocarditis and dilated cardiomyopathy in male BALB/c mice. The rIL-33 treatment significantly increased acute perimyocarditis (P=0.006) and eosinophilia (P=1.3×10(-5)), impaired cardiac function (maximum ventricular power, P=0.0002), and increased ventricular dilation (end-diastolic volume, P=0.01). The rST2 treatment prevented eosinophilia and improved heart function compared with rIL-33 treatment (ejection fraction, P=0.009). Neither treatment altered viral replication. The rIL-33 treatment increased IL-4, IL-33, IL-1ß, and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not to IL-1ß or IL-6. CONCLUSIONS: We show for the first time to our knowledge that IL-33 induces eosinophilic pericarditis, whereas soluble ST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function through the IL-33 receptor.


Assuntos
Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/prevenção & controle , Eosinofilia/etiologia , Coração/fisiopatologia , Interleucinas/efeitos adversos , Pericardite/etiologia , Receptores de Interleucina/uso terapêutico , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/prevenção & controle , Doenças Autoimunes/virologia , Cardiomiopatia Dilatada/metabolismo , Infecções por Coxsackievirus/complicações , Modelos Animais de Doenças , Eosinofilia/prevenção & controle , Eosinofilia/virologia , Coração/efeitos dos fármacos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-1beta/deficiência , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-33 , Interleucina-6/deficiência , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Pericardite/prevenção & controle , Pericardite/virologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
9.
Clin Exp Immunol ; 164(2): 248-55, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21352201

RESUMO

Acute lung injury is characterized by a diffuse inflammatory parenchymal process, implicated in the context of significant morbidity and mortality. Previously, we have reported that soluble ST2 (sST2), a member of the Toll-interleukin (IL)-1 receptor (TIR) superfamily, represses proinflammatory cytokine production of macrophage exposed to lipopolysaccharide (LPS). In this study, we examined the possibility of modulating LPS-induced murine inflammatory pulmonary damage by recombinant adenovirus-mediated sST2-Fc (Ad-sST2-Fc) gene transfer. Single intranasal administration of Ad-sST2-Fc led to a profound decrease in LPS-induced bronchoalveolar lavage leucocyte exudation and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Histological examination revealed alveolitis with inflammatory cell infiltration and alveolar haemorrhage in the alveolar airspace was less severe in Ad-sST2-Fc-treated mice when compared with control groups. In addition, high levels of sST2-Fc in vivo reduced the transcription of tumour necrosis factor-α, IL-6 and Toll-like receptor-4 gene remarkably, and suppressed the nuclear translocation of nuclear factor-κB in lung tissues in response to LPS challenge. Taken together, these results suggested that administration of Ad-sST2-Fc gene transfer may have therapeutic potential for the immunomodulatory treatment of LPS-mediated inflammatory lung injury.


Assuntos
Lesão Pulmonar Aguda/terapia , Adenoviridae/genética , Terapia Genética , Vetores Genéticos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Receptores de Interleucina/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/patologia , Administração Intranasal , Animais , Anti-Inflamatórios/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Hemorragia/etiologia , Hemorragia/prevenção & controle , Fatores Imunológicos/genética , Fatores Imunológicos/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-6/biossíntese , Interleucina-6/genética , Leucócitos/imunologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/fisiologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/fisiologia , Proteínas Recombinantes de Fusão/uso terapêutico , Solubilidade , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/genética , Transgenes , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
10.
Trauma (Majadahonda) ; 20(4): 201-210, oct.-dic. 2009. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-84335

RESUMO

Objetivo: Valorar la repercusión y comportamiento de los niveles séricos de factores proinflamatorios con respecto a la aparición de complicaciones médico–quirúrgicas en pacientes politraumatizados. Material y métodos: se incluyeron 18 pacientes politraumatizados, 10 hombres y 8 mujeres, con 2 o más fracturas óseas y un ISS>16, con edad media de 42 años y cuyo mecanismo lesional más frecuente fue el accidente de tráfico (44%). El valor medio del ISS fue de 26,83 y de 33,72 para el NISS. Se recogieron datos demográficos, lesiones ocasionadas, intervenciones quirúrgicas realizadas, datos de evolución, complicaciones y secuelas. Se analizó en sangre, leucocitos, fibrinógeno, proteína C reactiva, TNFα, interleucina 1β, interleucina 6, proteína de choque térmico HSP70i y anticuerpos antiHSP70i. Resultados: Los valores de TNFα, tienen una curva ascendente, con un aumento de la pendiente a partir de las 48 horas del traumatismo. La IL-1‚ mostró el pico máximo en la primera medición inmediatamente después del traumatismo, para disminuir de manera progresiva. La IL-6 presentó cifras por encima de 500 pg/ml. Los niveles séricos elevados de HSP70i máximos en el momento inicial para disminuir en las siguientes 48 horas. Conclusiones: Las curvas de reacción de factores proinflamatorios establecidas servirán de base para futuros estudios que los afiancen como biomarcadores de politraumatismo (AU)


Objective: To evaluate the repercussion and behavior of the serum levels of proinflammatory factors in relation to the appearance of clinical-surgical complications in polytraumatized patients. Material and methods: The study comprised 18 polytraumatized patients, 10 males and 8 females, with two or more bone fractures and an injury severity score (ISS) >16, and with a mean age of 42 years, in which traffic accidents were the main cause of injury (44%). The mean ISS was 26.83, with a new injury severity score (NISS) of 33.72. Demographic data were collected, together with information on the injuries produced, the surgical interventions, outcome, complications and sequelae. Blood tests were performed to record leukocyte count, fibrinogen, C-reactive protein, TNF·, interleukin 1‚, interleukin 6, heat shock protein HSP70i and antiHSP70i antibodies. Results: The TNF· values showed an ascending tendency, with an increase in slope starting 48 hours after trauma. IL-1 in turn showed a maximum value on occasion of the first measurement immediately after injury, followed by a gradual decrease. IL-6 showed values above 500 pg/ml. Peak serum HSP70i elevation were recorded at first determination, followed by a decrease over the following 48 hours. Conclusions: The established proinflammatory factor response curves will serve as a basis for future studies to consolidate them as biomarkers applicable to polytraumatized patients (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Citocinas/uso terapêutico , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/uso terapêutico , Interleucinas/uso terapêutico , Receptores de Interleucina/uso terapêutico , Proteínas de Choque Térmico/administração & dosagem , Acidentes de Trânsito/tendências , /economia , Fixação Interna de Fraturas/tendências , Fixação Intramedular de Fraturas/tendências
11.
Gastroenterology ; 131(1): 130-41, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16831597

RESUMO

BACKGROUND & AIMS: The cytokines interleukin (IL)-4 and IL-13 have pleiotropic effects on a variety of cell types and impact both pathologic changes and tissue remodeling. The aim of this study was to clarify the roles of IL-13 receptor alpha2 (IL-13Ralpha2), which is the high-affinity decoy receptor for IL-13, in gastrointestinal tract epithelial cell turnover and repair. METHODS: We have compared the regenerative process following mucosal damage induced by whole-body 3-Gy X-ray irradiation of wild-type (WT) and IL-4 receptor alpha gene-deficient (IL-4R(-/-)) mice. Then we treated mice with IL-13Ralpha2 human immunoglobulin (Ig) chimeric protein. RESULTS: Up-regulation of mRNA levels for IL-13 in NK cells in the lamina propria was seen after irradiation of WT mice. Concomitant with vigorous epithelial cell division in the jejunum following irradiation, expression of the IL-13Ralpha2 dramatically increased in myofibroblasts and fibroblasts. In contrast, epithelial cell repair was delayed in IL-4R(-/-) mice, which did not show transient up-regulation of IL-13Ralpha2, although up-regulation of IL-13 was seen. Addition of IL-13 but not IL-4 to primary cultures of small intestine from both WT and IL-4R(-/-) mice induced epithelial cell damage. Treatment of IL-4R(-/-) mice with IL-13Ralpha2-Ig resulted in increased numbers of dividing epithelial cells and improved tissue repair after irradiation. Further, treatment with IL-13Ralpha2-Ig increased numbers of microcolonies of regenerating epithelial cells in the intestine of WT mice after severe damage induced by 12-Gy irradiation. CONCLUSIONS: The IL-13Ralpha2 is a major regulatory factor involved in the regeneration of epithelial cells in the gastrointestinal tract.


Assuntos
Células Epiteliais/fisiologia , Jejuno/efeitos da radiação , Lesões Experimentais por Radiação/tratamento farmacológico , Receptores de Interleucina/uso terapêutico , Regeneração/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13 , Jejuno/metabolismo , Jejuno/patologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , Lesões Experimentais por Radiação/patologia , Receptores de Interleucina-13 , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/metabolismo , Regulação para Cima
12.
World J Gastroenterol ; 12(2): 317-21, 2006 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-16482637

RESUMO

AIM: There is strong evidence that interleukin-11 (IL-11) is involved in the regulation of tumor progression, cellular growth and differentiation. Recently, interleukin-11 receptor (IL-11R) has been detected on some cancer cells. In this study, we investigated the expression of IL-11 and IL-11R in colorectal adenocarcinoma. METHODS: To elucidate the involvement of IL-11 and IL-11Ra in human intestinal adenocarcinomas, we examined 115 cases of surgically resected human colonic adenocarcinoma and 11 cases of adenoma by immunohistochemistry and Western blotting. RESULTS: Among 115 cases of adenocarcinoma, 100 cases (87.0%) showed positive staining in the cytoplasm of carcinoma cells for the IL-11, and 87 cases (75.6%) were positive for the IL-11Ra. Six cases (54.5%) and four cases (36.4%) of 11 adenomas were positive for IL-11 and IL-11Ra, respectively. The expression of IL-11Ra correlated with the histological differentiation (P = 0.033503), the depth of tumor invasion (P = 0.006395), Dukes'classification (P = 0.015648) and lymphatic invasion (P = 0.003865). However, the expression of IL-11Ra was not correlated with the venous invasion and the presence of lymph node metastasis. The expression of IL-11 was not correlated with any clinicopathological factors. In Western blot analysis, two human colorectal carcinoma cell lines and four tissues of surgically resected human carcinoma expressed both IL-11 and IL-11Ra proteins. CONCLUSION: IL-11 and IL-11Ra are highly expressed in human colorectal adenocarcinoma and the IL-11Ra expression is correlated with clinicopathological factors. These findings suggest that the expression of IL-11Ra is an important factor for the invasion of human colorectal adenocarcinoma.


Assuntos
Adenocarcinoma/química , Neoplasias Colorretais/química , Interleucina-11/análise , Receptores de Interleucina/análise , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Imuno-Histoquímica , Subunidade alfa de Receptor de Interleucina-11 , Receptores de Interleucina/uso terapêutico , Receptores de Interleucina-11
13.
Int Immunol ; 16(7): 1009-17, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15184346

RESUMO

IL-13 is a Th2 cytokine that plays crucial roles in the pathophysiology of allergy, asthma and helminth infection. The high affinity receptor for IL-13, IL-13Ralpha2, may act as a decoy receptor for IL-13. The anti-tumor effect of IL-13 and its soluble receptor IL-13Ralpha2 have been examined in different tumor systems. Previous studies have shown that IL-13 enhances anti-tumor responses in some model systems, whereas IL-13Ralpha2Fc prevents IL-13 mediated suppression of tumor immuno-surveillance in a different model system. In this study, we have used a cytokine (receptor) gene therapy approach and studied the immune responses mediated by IL-13 and IL-13Ralpha2Fc in poorly immunogenic B16F1 melanoma and immunogenic MethA fibrosarcoma tumor models. We find that IL-13 reduces the tumorigenicity of B16F1 melanoma and MethA fibrosarcoma cells in vivo, most likely through the recruitment of neutrophils and macrophages. IL-13 mediated anti-tumor responses do not lead to the generation of tumor-specific T cells. Neither IL-13Ralpha2Fc gene transduction nor in vivo treatment with soluble IL-13Ralpha2Fc has a statistically significant effect of tumor growth. IL-13Ralpha2 deficient host background does not alter tumor growth, suggesting that endogenous levels of IL-13 do not contribute to an anti-tumor response in these models. We conclude that IL-13, but not soluble IL-13Ralpha2, has anti-tumor activity in the models described here, possibly by enhancing innate anti-tumor immunity.


Assuntos
Fibrossarcoma/imunologia , Interleucina-13/imunologia , Melanoma/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Interleucina/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral/transplante , Fibrossarcoma/terapia , Terapia Genética , Subunidade alfa1 de Receptor de Interleucina-13 , Macrófagos/imunologia , Melanoma/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/imunologia , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/uso terapêutico , Receptores de Interleucina-13
14.
J Immunol ; 169(12): 7119-26, 2002 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-12471149

RESUMO

Tumor-directed therapeutic approaches require unique or overexpressed specific Ag or receptor as a target to achieve selective tumor killing. However, heterogeneous expression of these targets on tumor cells limits the efficacy of this form of therapy. In this study, we forced abundant expression of IL-13Ralpha2 chain by plasmid-mediated gene transfer in head and neck, as well as prostate tumors to provide a potential target. This was followed by successfully treating xenograft tumor-bearing nude mice with IL-13R-directed cytotoxin (IL13-PE38QQR). Although we did not observe an indirect cytotoxic bystander effect conveyed to nontransduced tumor cells in vitro, our approach in vivo led to a complete regression of established tumors transfected with IL-13Ralpha2 chain in most animals. We found that the tumor eradication was achieved in part by infiltration of macrophages and NK cells, assessed by immunohistochemistry. Moreover, head and neck tumors xenografted in macrophage-depleted nude mice were less sensitive to the antitumor effect of IL-13 cytotoxin. Because we did not observe vector-related toxicity in any vital organs, our novel combination strategy of gene transfer of IL-13Ralpha2 chain and receptor-directed cytotoxin therapy may be a useful approach for the treatment of localized cancer.


Assuntos
Antineoplásicos/uso terapêutico , Exotoxinas/uso terapêutico , Técnicas de Transferência de Genes , Neoplasias de Cabeça e Pescoço/terapia , Interleucina-13/uso terapêutico , Fagócitos/imunologia , Neoplasias da Próstata/terapia , Pseudomonas aeruginosa/imunologia , Receptores de Interleucina/genética , Animais , Antineoplásicos/imunologia , Antineoplásicos/toxicidade , Citotoxicidade Imunológica/genética , Modelos Animais de Doenças , Exotoxinas/genética , Exotoxinas/toxicidade , Vetores Genéticos/administração & dosagem , Vetores Genéticos/biossíntese , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Injeções Intralesionais , Interleucina-13/genética , Interleucina-13/toxicidade , Subunidade alfa1 de Receptor de Interleucina-13 , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fagócitos/patologia , Plasmídeos/administração & dosagem , Plasmídeos/biossíntese , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Pseudomonas aeruginosa/genética , Receptores de Interleucina/administração & dosagem , Receptores de Interleucina/biossíntese , Receptores de Interleucina/uso terapêutico , Receptores de Interleucina-13 , Transfecção , Células Tumorais Cultivadas
15.
Mol Cancer Ther ; 1(12): 999-1007, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12481422

RESUMO

Apoptosis is not only essential for homeostasis in normal cells but also in cancer cells, in which it is associated with cell death mechanisms caused by novel therapeutics. We have previously reported that interleukin-13 receptors (IL-13R) are constitutively overexpressed on a majority of human malignant glioma cell lines and primary cell cultures. In addition, we have reported that IL-13 cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin, is highly and specifically cytotoxic to these cells and can lead to pronounced antitumor activity in malignant glioma tumors in animal models. However, the molecular mechanisms of tumor cytotoxicity induced by IL-13 cytotoxin are poorly understood. In this study, we demonstrate that glioma tumors undergo apoptotic cell death on intratumoral administration of IL-13 cytotoxin. This conclusion was made based on (a) time-dependent induction of several proapoptotic molecules, such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from mitochondria to the cytosol on injection of IL-13 cytotoxin in U251 glioblastoma tumors established in immunodeficient animals. These indicators of two major pathways of apoptosis were detected in tumors even though IL-13 cytotoxin was no longer present in tumors. In addition, we found that inducible nitric oxide was expressed in tumors in a time-dependent manner with primary localization in infiltrating phagocytes after treatment with IL-13 cytotoxin. These studies demonstrate that IL-13 cytotoxin mediates apoptotic death of glioma cells, resulting in regression of established tumors. Our studies will help unravel the molecular pathways of cell death associated with tumor regression and provide additional insight and define apoptosis as possible surrogate marker of tumor response.


Assuntos
Citotoxinas/metabolismo , Glioma/patologia , Receptores de Interleucina/química , Receptores de Interleucina/uso terapêutico , Animais , Apoptose , Western Blotting , Caspase 3 , Caspases/metabolismo , Morte Celular , Grupo dos Citocromos c/metabolismo , Citosol/metabolismo , Precursores Enzimáticos/metabolismo , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Subunidade alfa1 de Receptor de Interleucina-13 , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/terapia , Óxido Nítrico/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Receptores de Interleucina-13 , Proteínas Recombinantes/metabolismo , Frações Subcelulares , Fatores de Tempo , Células Tumorais Cultivadas
16.
Transplantation ; 72(2): 348-50, 2001 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-11477368

RESUMO

BACKGROUND: Blocking the action of interleukin (IL) 17 with an IL-17 receptor (R):Fc fusion protein inhibits T-cell proliferative responses to alloantigens and prolongs vascularized heart graft survival. In this study, we examined whether IL-17 antagonism could suppress the development of chronic rejection. METHODS: A 0.6-cm section of C57BL10 (H2b) thoracic aorta was transplanted to recipient C3H (H2k) abdominal aorta. IL-17R:Fc or control human immunoglobulin G was administered i.p. (500 microg/day) from days 0 to 6 or from days 0 to 29. Mice were killed on days 7 or 30. Grafts were examined histologically and stained for alpha-smooth muscle actin (alpha-smA). Antidonor mixed leukocyte reaction, cytotoxic T cell, and alloantibody responses were quantified. RESULTS: On day 7, control grafts showed mononuclear cell (MNC) infiltration, pronounced endothelial damage, and apoptosis of intimal and medial cell compartments. By day 30, there was concentric intimal thickening, accumulation of alpha-smA+ cells, and collagen deposition. Patchy destruction of the elastic membranes and loss of alpha-smA expression in media were evident. IL-17R:Fc for 6 days decreased MNC infiltration in the intimal and medial compartments at day 7. The endothelium was preserved (completely or partially) in all grafts. The medial compartment showed normal alpha-smA expression. Irrespective of IL-17R:Fc treatment for either 6 days or continuously, allografts harvested at day 30 showed circumferential intimal thickening, with accumulation of alpha-smA+ cells and collagen deposition. There was no effect on circulating alloantibody levels. CONCLUSIONS: These findings support a role for IL-17 in the immunopathogenesis of acute vascular rejection and demonstrate the potential of IL-17 antagonism for therapy. By contrast, IL-17 antagonism does not appear to prevent ensuing chronic graft vascular disease, in particular neointimal formation.


Assuntos
Aorta Torácica/transplante , Rejeição de Enxerto/prevenção & controle , Interleucina-17/imunologia , Receptores de Interleucina/uso terapêutico , Transplante Homólogo/imunologia , Doença Aguda , Animais , Aorta Abdominal/cirurgia , Aorta Torácica/cirurgia , Doença Crônica , Proteínas do Sistema Complemento/imunologia , Humanos , Imunoglobulina G/farmacologia , Interleucina-17/antagonistas & inibidores , Isoanticorpos/sangue , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/uso terapêutico
17.
FASEB J ; 14(13): 1979-87, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11023982

RESUMO

The cytokine IL-6 plays a significant role in liver regeneration in conjunction with additional growth factors (HGF, TNF-alpha, and TGF-alpha). Many IL-6 effects depend on a naturally occurring soluble IL-6 receptor (sIL-6R). Here, the chimeric protein hyper-IL-6, constructed from the human IL-6 protein fused to a truncated form of its receptor, was found to have superagonistic IL-6 properties, and as such, enhanced liver cell regeneration. Hyper-IL-6 reversed the state of hepatotoxicity and enhanced the survival rates of rats suffering from fulminant hepatic failure after D-galactosamine administration. The hyper-IL-6 protein has a significant potential for use in the treatment of severe human liver diseases.


Assuntos
Interleucina-6/agonistas , Interleucina-6/uso terapêutico , Falência Hepática/tratamento farmacológico , Regeneração Hepática/efeitos dos fármacos , Receptores de Interleucina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Modelos Animais de Doenças , Galactosamina/toxicidade , Humanos , Masculino , Ratos , Ratos Endogâmicos F344 , Receptores de Interleucina-6 , Proteínas Recombinantes de Fusão/uso terapêutico , Tioacetamida/toxicidade
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