RESUMO
BACKGROUND: Understanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identification of precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therapeutic approaches for pain management. Our recent studies had identified an inflammation-amplifying (Inf-A) cell population that is expanded in human OA cartilage and is distinctive in the expression of both IL1R1 and TNF-R2 receptors and active Jnk signaling cascade. METHODS: In this study, we have tested the function of the cartilage-resident IL1R1+TNF-R2+ Inf-A cells in OA. We have identified that the IL1R1+TNF-R2+ Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in InfA through competitive inhibition of Jnk signaling in mice and human OA explants and tested the effects on joint structure and gait in mice. RESULTS: Modulation of Jnk signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint architecture. Interestingly, Jnk inhibition and lowered CCL2 and 7 are sufficient to significantly improve the gait parameters in treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with JNK inhibitor did not improve human OA cartilage explants. CONCLUSION: These studies demonstrate that Inf-A, an articular-cartilage resident cell population, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.
Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Camundongos , Animais , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/farmacologia , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Modelos Animais de Doenças , Osteoartrite/metabolismo , Cartilagem Articular/metabolismo , Dor/etiologia , Dor/metabolismo , Inflamação/metabolismoRESUMO
Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Current anti-TNF MS therapies are shown to be detrimental to patients due to pleiotropic effects on both pro- and anti-inflammatory functions. Using a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, we systemically administered a TNFR2 agonist (p53-sc-mTNFR2) to investigate behavioral and pathophysiological changes in both female and male mice. Our data shows that TNFR2 activation alleviates motor and sensory symptoms in females. However, in males, the agonist only alleviates sensory symptoms and not motor. nPTX EAE induction in TNFR2 global knockout mice caused exacerbated motor symptoms in females along with an earlier day of onset, but not in males. Our data demonstrates that TNFR2 agonist efficacy is sex-specific for alleviation of motor symptoms, however, it effectively reduces mechanical hypersensitivity in both females and males. Altogether, these data support the therapeutic promise TNFR2 agonism holds as an MS therapeutic and, more broadly, to treat central neuropathic pain.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Humanos , Masculino , Feminino , Camundongos , Animais , Receptores Tipo II do Fator de Necrose Tumoral/agonistas , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Camundongos Endogâmicos C57BL , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Proteínas da Mielina , Fator de Necrose Tumoral alfa/metabolismo , Camundongos KnockoutRESUMO
BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer's disease (AD). Therapies that block TNF-α proved ineffective as therapeutic for neurodegenerative diseases, which might be explained by the opposing functions of the two receptors of TNF (TNFRs): while TNFR1 stimulation mediates inflammatory and apoptotic pathways, activation of TNFR2 is related to neuroprotection. Despite the success of targeting TNFR2 in a transgenic AD mouse model, research that better mimics the human context is lacking. OBJECTIVE: The aim of this study is to investigate whether stimulation of TNFR2 with a TNFR2 agonist is effective in activating human TNFR2 and attenuating AD neuropathology in the J20xhuTNFR2-k/i mouse model. METHODS: Transgenic amyloid-ß (Aß)-overexpressing mice containing a human extracellular TNFR2 domain (J20xhuTNFR2-k/i) were treated with a TNFR2 agonist (NewStar2). After treatment, different behavioral tests and immunohistochemical analysis were performed to assess different parameters, such as cognitive functions, plaque deposition, synaptic plasticity, or microglial phagocytosis. RESULTS: Treatment with NewStar2 in J20xhuTNFR2-k/i mice resulted in a drastic decrease in plaque load and beta-secretase 1 (BACE-1) compared to controls. Moreover, TNFR2 stimulation increased microglial phagocytic activity, leading to enhanced Aß clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity. CONCLUSION: Our findings demonstrate that activation of human TNFR2 ameliorates neuropathology and improves cognitive functions in an AD mouse model. Moreover, our study confirms that the J20xhuTNFR2-k/i mouse model is suitable for testing human TNFR2-specific compounds.
Assuntos
Doença de Alzheimer , Receptores Tipo II do Fator de Necrose Tumoral , Camundongos , Humanos , Animais , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Doença de Alzheimer/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Transgênicos , Peptídeos beta-Amiloides/metabolismo , Plasticidade NeuronalRESUMO
We have shown that KRAS-TP53 genomic coalteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating KRAS-TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry. Silencing of cell-intrinsic Cxcl1 in LSL-KrasG12D/+;Trp53R172H/+;Pdx-1Cre/+(KPC) cells reprograms the trafficking and functional dynamics of neutrophils to overcome T-cell exclusion and controls tumor growth in a T cell-dependent manner. Mechanistically, neutrophil-derived TNF is a central regulator of this immunologic rewiring, instigating feed-forward Cxcl1 overproduction from tumor cells and cancer-associated fibroblasts (CAF), T-cell dysfunction, and inflammatory CAF polarization via transmembrane TNF-TNFR2 interactions. TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell-neutrophil cross-talk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC. SIGNIFICANCE: By decoding connections between high-risk tumor genotypes, cell-autonomous inflammatory programs, and myeloid-enriched/T cell-excluded contexts, we identify a novel role for neutrophil-derived TNF in sustaining immunosuppression and stromal inflammation in pancreatic tumor microenvironments. This work offers a conceptual framework by which targeting context-dependent TNF signaling may overcome hallmarks of chemoresistance in pancreatic cancer. This article is highlighted in the In This Issue feature, p. 1275.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neutrófilos , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Inflamação/genética , Microambiente Tumoral/fisiologia , Quimiocina CXCL1/genética , Neoplasias PancreáticasRESUMO
In rare cases, clinical inhibitors of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) can induce symptoms of lupus erythematosus (drug-induced lupus, DIL), but this adverse response usually resolves rapidly upon drug withdrawal. We report the case of a 25-year-old Asian woman with rheumatoid arthritis exhibiting severe prolonged DIL even after the termination of TNF-α inhibitor treatment. The patient had been treated intermittently using Traditional Chinese Medicine for 11 years, but this therapy failed to effectively control her clinical symptoms. Subsequently, methotrexate and hydroxychloroquine were prescribed, but a reduced white blood cell count was detected. Finally, the TNF-α inhibitor Anbainuo was prescribed. However, after 2 months of treatment, the patient exhibited elevated serum creatinine, anti-double-stranded DNA (+++), anti-nuclear antibody (1:1000), and urine protein (+++) accompanied by buccal erythema, hair loss, and hand shaking, consistent with Anbainuo-induced lupus, lupus nephritis, and lupus encephalopathy. Moreover, her serum creatinine level remained high after Anbainuo withdrawal and prolonged steroid and immunosuppressive therapy. Careful and sustained monitoring for adverse reactions to Anbainuo (and other TNF-α inhibitors) is recommended.
Assuntos
Antirreumáticos , Artrite Reumatoide , Lúpus Eritematoso Sistêmico , Adulto , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Metotrexato/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão , Fator de Necrose Tumoral alfaRESUMO
The objective of the study was to evaluate the efficacy and safety of etanercept (Anbainuo) treatment in Chinese moderate to severe rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR); 600 patients (360 in phase III-1 and 240 in phase III-2) poorly responding to MTX were enrolled in the study and randomized at a ratio of 2:1 into an Anbainuo treatment or control group. The study was designed as a 12-week double-blind, placebo-controlled period followed by a 12-week open-label study. The primary endpoint was the ACR20 response rate at week 12. Secondary endpoints included the ACR50, ACR70, ACR-N, and safety. At week 12, ACR20 response was observed in 60.9 % of the Anbainuo group-significantly higher than that of the control group (20.6 %). At week 24, the ACR20 response in the Anbainuo group increased to 70.2 %; there was no significant difference compared with that of the control group (61.8 %, P > 0.05). At week 12, the ACR50 and ACR70 responses of the Anbainuo group increased to 25.6 and 6.8 %, compared to 4 and 1 % in the control group (P < 0.001, P = 0.002). The ACR-N was 2.85 ± 6.73 vs. -3.24 ± 8.78 % in the control group (P < 0.001). During the first 12 weeks of treatment, 66 adverse events (AE) were reported in the Anbainuo group (15.6 %) and 21 AEs (10.5 %) occurred in the control group, whereby the rate of the Anbainuo group was slightly higher than the control group (P = 0.042). Severe adverse events (SAEs) occurred in the Anbainuo group (1.3 %) and one (SAE) occurred in the control group (0.5 %) (P = 0.19). Anbainuo displays a rapid onset of efficacy as well as good tolerance and safety in MTX-IR patients having moderate to severe RA.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Metotrexato/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Método Duplo-Cego , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Receptores Tipo II do Fator de Necrose Tumoral/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Retratamento , Índice de Gravidade de Doença , Falha de Tratamento , Resultado do TratamentoRESUMO
We developed a novel trimeric sTNFRII fusion protein, named sTNFRII-gAD, which exhibited a higher in vitro antagonistic efficacy for TNFα in comparison with sTNFRII-Fc. This study aimed to investigate the arthritic protection of sTNFRII-gAD in a rat collagen-induced arthritis (CIA). The rats were injected intradermally with collagen type II at days 0 and 7. Three days after the second injection (day 10), the rats were intraperitoneally given sTNFRII-gAD or sTNFRII-Fc, or PBS. Effects of treatments were examined with respect of CIA incidence, severity and pathological changes. Serum TNFα, IL-17A and regulatory T cell (Treg) in periphery were determined at days 10 and 16, respectively. Our results showed that sTNFRIIgAD significantly reduced CIA incidence and severity (p < 0.05); meanwhile it led to a dramatic improvement in cartilage and bone damage. Moreover, the increase in serum anti-CII and IL-17A, and the reduction in Treg population were inhibited (p < 0.05) by sTNFRII-gAD or sTNFRII-Fc. Serum TNFα was found to be accumulated in the groups treated with sTNFRII-gAD or sTNFRII-Fc compared with the group treated with PBS (p < 0.05). It is noteworthy that sTNFRII-gAD displayed a better efficacy than sTNFRII-Fc in CIA incidence, pathological changes in cartilage and the elevation of anti-CII antibody, indicating that sTNFRII-gAD is potentially a more efficacious anti-TNFα agent for rheumatoid arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Animais , Anticorpos/sangue , Artrite Experimental/sangue , Artrite Experimental/patologia , Cartilagem/patologia , Colágeno Tipo II/imunologia , Colágeno Tipo II/toxicidade , Avaliação Pré-Clínica de Medicamentos , Feminino , Injeções Intraperitoneais , Interleucina-17/sangue , Articulação do Joelho/patologia , Contagem de Linfócitos , Ratos , Ratos Wistar , Receptores Tipo II do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/uso terapêutico , Solubilidade , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/análiseRESUMO
Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown etiology where tumor necrosis factor-α (TNFα) plays a critical role. Etanercept, a recombinant fusion protein of human soluble tumor necrosis factor receptor II (hsTNFR) linked to the Fc portion of human IgG1, is used to treat RA based on the rationale that sTNFR binds TNFα and blocks TNFα-mediated inflammation. We compared hsTNFR protein delivery from genetically engineered human mesenchymal stem cells (hMSCs) with etanercept. Blocking TNFα-dependent intercellular adhesion molecule-1 expression on transduced hMSCs and inhibition of nitric oxide production from TNFα-treated bovine chondrocytes by conditioned culture media from transduced hMSCs demonstrated the functionality of the hsTNFR construction. Implanted hsTNFR-transduced mesenchymal stem cells (MSCs) reduced mouse serum circulating TNFα generated from either implanted TNFα-expressing cells or lipopolysaccharide induction more effectively than etanercept (TNFα, 100%; interleukin [IL]-1α, 90%; and IL-6, 60% within 6 hours), suggesting faster clearance of the soluble tumor necrosis factor receptor (sTNFR)-TNFα complex from the animals. In vivo efficacy of sTNFR-transduced MSCs was illustrated in two (immune-deficient and immune-competent) arthritic rodent models. In the antibody-induced arthritis BalbC/SCID mouse model, intramuscular injection of hsTNFR-transduced hMSCs reduced joint inflammation by 90% compared with untransduced hMSCs; in the collagen-induced arthritis Fischer rat model, both sTNFR-transduced rat MSCs and etanercept inhibited joint inflammation by 30%. In vitro chondrogenesis assays showed the ability of TNFα and IL1α, but not interferon γ, to inhibit hMSC differentiation to chondrocytes, illustrating an additional negative role for inflammatory cytokines in joint repair. The data support the utility of hMSCs as therapeutic gene delivery vehicles and their potential to be used in alleviating inflammation within the arthritic joint.
Assuntos
Células-Tronco Adultas/citologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Engenharia Genética , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Células-Tronco Adultas/metabolismo , Animais , Artrite Experimental/patologia , Bovinos , Diferenciação Celular , Condrogênese , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/complicações , Inflamação/patologia , Inflamação/terapia , Mediadores da Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Ratos , Solubilidade , Transdução Genética , Resultado do TratamentoRESUMO
AIM: To investigate the therapeutic effects of BF02 on adjuvant arthritis (AA) in rats and the regulatory effects of BF02 on T lymphocyte function. METHODS: SD rats received a single intradermal injection of Freund's complete adjuvant emulsion into the right hind metatarsal footpad. After the onset of AA, the rats were injected BF02 (1, 3, or 9 mg/kg, sc) every 3 d for a total of 15 d. Intragastric administration of methotrexate (MTX, 0.5 mg/kg, every 3 d for a total of 15 d) was taken as the positive control drug. Arthritis index, swollen joint count, ankle joint histopathology, spleen histopathology and the paw radiography were used for evaluating the drug effects on AA rats. T lymphocyte function was assessed by measuring T lymphocyte cytokine levels, IL17 and TNF-α mRNA expression levels, and percentage of T lymphocyte subsets. RESULTS: In the AA rats, remarkable secondary inflammatory responses exhibited, accompanied by significantly higher levels of IL-1, IL-6, TNF-α, IL-17, LTα, RANKL, and MMP-13. The expression of IL17 and TNF-α mRNAs was also substantially higher than in normal rats. The percentages of CD3(+)CD4(+) and CD4(+)CD25(+) T lymphocytes were increased, whereas the percentages of CD4(+)CD62L(+) and CD4(+)CD25(+)FoxP3(+) T lymphocytes were decreased. Treatment of the AA rats with BF02 (9 mg/kg) or MTX significantly decreased the arthritis index, swollen joint count and arthritis global assessment. Moreover, both BF02 (9 mg/kg) and MTX significantly inhibited T lymphocyte proliferation, and blocked the above mentioned aberrance in T lymphocyte cytokine levels, IL17 and TNF-α mRNA expression, and percentages of T lymphocyte subsets. CONCLUSION: BF02 exerts therapeutic effects on AA rats via the regulation of T lymphocytes.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Antirreumáticos/administração & dosagem , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Experimental/radioterapia , Artrografia , Proliferação de Células/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Articulações/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Tipo II do Fator de Necrose Tumoral/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Timo/efeitos dos fármacos , Timo/imunologia , Timo/patologiaRESUMO
This study aims to evaluate the clinical and radiological efficacy as well as safety profiles of Anbainuo, a recombinant human TNFRII:Fc fusion protein, combined with methotrexate (MTX) versus MTX alone or Anbainuo alone in the treatment of Chinese patients with moderate to severe rheumatoid arthritis (RA). In this 24-week, multicenter, double-blind, active comparator-controlled study, 396 RA patients were randomized into combination therapy group (Anbainuo plus MTX), Anbainuo group, or MTX group. Clinical response was assessed using the American College of Rheumatology (ACR)-N, ACR20, ACR50, ACR70, and van der Heijde modification of Sharp score, among which ACR-N and ACR20 were defined as primary major endpoints. After 24 weeks of treatment, the ACR-N in the combination therapy group (12.79 ± 9.24 %) was significantly higher than that in Anbainuo group (9.56 ± 11.16 %) and in MTX group (5.08 ± 11.1 %) (p = 0.00 and p = 0.00, respectively). Patients in Anbainuo group had significantly higher ACR-N than those in MTX group (p = 0.02). More patients in the combination therapy group (53.6 %) achieved ACR50 improvement response than those in the MTX group (30.8 %). ACR70 of combination therapy group (27.7 %) was significantly higher than that of Anbainuo group (15.8 %) and MTX group (7.70 %), with no significant difference between Anbainuo group and MTX group. DAS28-ESR in the combination therapy group was significantly reduced compared to either monotherapy groups. Moreover, DAS28-ESR was significantly lower in Anbainou group than in MTX group. The combination therapy group also showed significantly less radiographic progression than the MTX group (p = 0.03). The total adverse events (AE) in the combination group (40.9 %) was significantly higher than those in the MTX group (28.8 %) (p < 0.05). Anbainuo combined with MTX therapy can effectively control the disease activity and radiographic progression of RA, while the incidence of AE also increased compared to either Anbainuo or MTX.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunoglobulina G/uso terapêutico , Metotrexato/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/etnologia , Povo Asiático , China/etnologia , Método Duplo-Cego , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Hiperalgesia/patologia , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
TNF α plays a central role in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and murine acute liver injury induced by injection of D-galactosamine and subsequent LPS. Recombinant Fc-fused soluble TNF receptor II (sTNFRII-Fc) has been used in the treatment of rheumatoid arthritis for a decade. We have recently constructed a novel fusion protein sTNFRII-gAD, which is composed of a soluble TNF receptor II and a globular domain of adiponectin. Utilizing the inclination of gAD to form homologous trimer naturally, we sought to explore TNFα antagonism of the novel trimerized sTNFRII-gAD and meantime compare TNFα-neutralizing effects in vitro and in vivo between sTNFRII-Fc and sTNFRII-gAD. Here, we evaluated the TNFα-antagonizing activity of sTNFRII-gAD with TNFα-induced L929 cytotoxicity assay. Furthermore, sTNFRII-Fc or sTNFRII-gAD was administered simultaneously with d-galactosamine 1h prior to LPS injection in the murine model of acute liver injury. Serum TNFα and TNFα-sTNFRII-gAD complex were measured by ELISA and the liver injury was assessed through alanine transaminase measurement and liver histological analysis. sTNFRII-gAD was shown to have higher TNFα-neutralizing activity than sTNFRII-Fc (p<0.05) in the L929 cytotoxicity assay. With a significant attenuation of murine lethality (p<0.05), sTNFRII-gAD showed more protective effects than sTNFRII-Fc in the murine model of acute liver injury. These results demonstrated that sTNFRII-gAD was more efficacious than sTNFRII-Fc as a TNFα antagonist, highlighting the potential of sTNFRII-gAD for the treatment of diseases associated with excessive TNFα.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Adiponectina/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Adiponectina/biossíntese , Adiponectina/sangue , Animais , Células CHO , Linhagem Celular Tumoral , Sobrevivência Celular , Cricetinae , Cricetulus , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores Tipo II do Fator de Necrose Tumoral/biossíntese , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/sangue , Solubilidade , Análise de Sobrevida , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Tumor necrosis factor (TNF)-α is a pivotal inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). TuNEX, a recombinant TNF-α receptor protein, can effectively bind TNF-α. The purpose of this phase I/II dose-escalation study was to assess the safety and preliminary efficacy of three dose levels of TuNEX in Taiwanese patients with RA. METHODS: Eighteen patients with active RA from three medical centers who had failed previous therapy with at least one disease modifying antirheumatic drug (DMARD) were enrolled. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology criteria (ACR20) in the fourth week. The occurrence of treatment-emergent adverse events (TEAEs) was the primary safety variable. RESULTS: The highest percentage of TuNEX 25-mg- and 35-mg-treated patients achieved an ACR20 response (60% and 100%, respectively) for the first time at Week 2 during the 4-week treatment period. There was a strong trend toward a superior ACR20 response rate in the TuNEX 15-mg group (83.3%) in comparison with the TuNEX 25-mg group (40.0%) and the TuNEX 35-mg group (50.0%) at week 4. Patients who received 15-mg TuNEX, 25-mg TuNEX, and 35-mg TuNEX had 35.99%, 16.85%, and 21.86% reduction of disability indices of Health Assessment Questionnaire after drug treatment, respectively. The most commonly reported adverse event was injection-site reaction. The TEAEs were comparable between the three TuNEX-treated groups. CONCLUSION: TuNEX reduced the signs and symptoms of RA and improved physical function, with clinically acceptable safety and tolerability in patients who had previously received DMARDs.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Feminino , Humanos , Imunoglobulina G/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversosRESUMO
OBJECTIVE: To evaluate the efficacy, radiographic changes and safety of the combination of recombinant human tumor necrosis factor-α receptor II IgG Fc fusion protein (rhTNFR:Fc) and methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: 30 RA patients were treated with rhTNFR:Fc (25 mg subcutaneously twice weekly) and oral MTX (up to 15 mg weekly) in an open-label manner. Clinical response was assessed by American College of Rheumatology (ACR) criteria and Disease Activity Score in 28 joints (DAS28). Radiographs of hands and wrist were assessed by the modified Sharp score. RESULTS: At Week 24, ACR20, ACR50 and ACR70 responses were achieved by 90%, 76.67% and 46.67% respectively. At Week 24, the mean DAS28 was 3.65 ± 1.26 versus 6.41 ± 0.61 at baseline (P < 0.001). And 20% patients achieved remission and 16.67% patients had a low disease activity. At week 24, EULAR good and moderate responses were attained by 36.67% and 60% respectively. Similarly, Health Assessment Questionnaire (HAQ) improved significantly, declining from 1.12 at baseline to 0.36 at week 24 (P < 0.001). No radiographic progression (based on change of total Sharp score) was found in 27 cases. Adverse events were mild. CONCLUSION: rhTNFR:Fc in combination with MTX shows an excellent efficacy of reduced disease activity, improved function and slowed radiographic progression through 24 weeks. A combination therapy for 24 weeks can lead to disease remission and an inhibition of radiographic progression. Further study is warranted.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Artrite Reumatoide/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the influence of the recombinant human type II tumor necrosis factor receptor-antibody Fc fusion protein (rhTNFR:Fc) on cytokines and bone metabolism in patients with juvenile idiopathic arthritis (JIA). METHODS: This was a prospective, non-randomized, controlled and open-label study. Thirty-one patients with JIA in active state were enrolled at our hospital from December 2006 to June 2009. The mean age was 12.7 ± 2.3 years. Exclusive criteria included infection with tuberculosis and hepatitis B etc., abnormal renal or hepatic function. Study consists of two phases. During the first phase (0-3 months), according to the economic status, all JIA patients were divided into treatment and control groups. The treatment group consisted of 18 patients (enthesitis-related arthritis, n = 15; polyarticular-onset arthritis, n = 2; systemic-onset type, n = 1) on a regimen of rhTNFR:Fc 0.4 mg/kg, subcutaneously injected twice weekly. The control group contained 13 patients (enthesitis-related arthritis, n = 9; polyarticular-onset arthritis, n = 2; systemic-onset type, n = 2) on a regimen of MTX 10 mg × m(-2) × w(-1). Two intolerance patients were given sulfasalazine (SASP) 30-50 mg × kg(-1) × d(-1). During the second phase (3-6 months), the responding patients continued the original therapy. The rhTNFR:Fc group received a reduced dosage of 0.4 mg × kg(-1) × w(-1). All patients of both groups who became complicated with peripheral arthritis or were non-responding had the addition of SASP. Follow-up was conducted at baseline, 1 month, 3 months and 6 months. And TNF-α, MMP-3, IL-1ß, osteocalcin (BGP), ß-collagen fragment (ß-CTx), alkaline phosphatase, erythrocyte sedimentation rate (ESR), c-reactive protein (CRP) and bone mineral density dynamic changes were examined respectively in the treatment process. RESULTS: Alkaline phosphatase and lumbar spine bone mineral density increased while TNF-α, IL-1ß, ESR and CRP decreased significantly in two groups (P < 0.05). ESR were 16 ± 8.0 mm/h vs 60 ± 38 mm/h, CRP 10 ± 7 mg/L vs 47 ± 37 mg/L and ß-CTx 2.1 ± 0.8 vs 1.1 ± 0.9 µg/L at 1 month in two groups respectively with statistic difference (P < 0.05). BGP increased and MMP-3 decreased in both groups with no statistic difference. Femur Ward's triangular area and forearm bone mineral density had no statistic difference between two groups. Interestingly, one case with bone fracture for two years has healed after a 6-month therapy of rhTNFR:Fc as proved by X-ray. CONCLUSION: Both rhTNFR:Fc and traditional DMARDs both can reduce the levels of TNF-α, IL-1ß, ESR and CRP and increase lumbar spine bone mineral density and ALP significantly. RhTNFR: Fc improves the acute phase index and bone metabolism index earlier than the traditional therapy. Thus disease and bone destruction are controlled more earlier.
Assuntos
Artrite Juvenil/metabolismo , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Artrite Juvenil/tratamento farmacológico , Densidade Óssea , Criança , Pré-Escolar , Humanos , Interleucina-1/biossíntese , Metaloproteinase 3 da Matriz/biossíntese , Estudos Prospectivos , Proteínas Recombinantes de Fusão/uso terapêuticoAssuntos
Antirreumáticos/uso terapêutico , Proteínas de Neoplasias/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Austrália , Humanos , Assistência Farmacêutica/economia , Receptores Chamariz do Fator de Necrose TumoralAssuntos
Antirreumáticos/efeitos adversos , Imunoglobulina G/efeitos adversos , Sarcoidose/induzido quimicamente , Idoso , Antirreumáticos/uso terapêutico , Citocinas/fisiologia , Etanercepte , Granuloma/etiologia , Granuloma/fisiopatologia , Humanos , Imunoglobulina G/uso terapêutico , Masculino , Proteínas de Neoplasias/efeitos adversos , Proteínas de Neoplasias/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Sarcoidose/fisiopatologia , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/fisiopatologia , Receptores Chamariz do Fator de Necrose TumoralRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF-alpha therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P = 0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2 = 0.701; P < 0.0001). Aortic PWV was reduced significantly by anti-TNF-alpha therapy (8.82+/-2.04 versus 7.94+/-1.86 versus 7.68+/-1.56 m/s at weeks 0, 4, and 12, respectively; P < 0.001); concomitantly, endothelial function improved. CONCLUSIONS: RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF-alpha therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.
Assuntos
Aorta/fisiopatologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Aterosclerose/fisiopatologia , Proteínas de Neoplasias/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Aorta/efeitos dos fármacos , Artrite Reumatoide/fisiopatologia , Aterosclerose/etiologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea , Suscetibilidade a Doenças/fisiopatologia , Elasticidade , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/farmacologia , Receptores do Fator de Necrose Tumoral/uso terapêutico , Análise de Regressão , Fatores de Risco , Receptores Chamariz do Fator de Necrose TumoralRESUMO
OBJECTIVE: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha. METHODS: A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha-/- mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis. RESULTS: The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively). CONCLUSION: These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha.