Anti-tumor Necrosis Factor (anti-tumor + necrosis_factor)

Distribution by Scientific Domains


Selected Abstracts


Matrix metalloproteinase inhibitor reduces apoptosis induction of bone marrow cells in MDS-RA

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2004
Kosei Arimura
Abstract:,Background and objectives:,We examined the involvement of apoptosis with myelodysplastic syndrome (MDS) accompanied by peripheral cytopenias despite normo-hypercellular bone marrow. Materials and methods:,Bone marrow smears from 31 patients with MDS-refractory anemia (RA) and five normal controls were stained using the in situ end labeling (ISEL) method. Next, the inhibitory effects of a caspase-3 inhibitor, matrix metalloproteinase inhibitor (MMPI), anti-tumor necrosis factor (TNF)- , or anti-Fas antibody upon the apoptosis induction in overnight cultures of bone marrow cells from the patients were examined. Further, TNF- ,, transforming growth factor (TGF)- , and soluble Fas ligand (sFasL) concentrations in culture supernatants of the cells were assessed by enzyme-linked immunosorbent assay (ELISA). Results:,The incidence of ISEL-positive cells among MDS patients was significantly higher than in normal controls (50.8 ± 14.0% vs. 11.3 ± 2.4%; P < 0.0001). A caspase-3 inhibitor reduced significantly the ISEL-positive rates (32.6 ± 15.2% vs. 50.2 ± 16.5%; P < 0.0001). Anti-TNF- , or anti-Fas antibody reduced the ISEL-positive rates significantly (28.2 ± 6.0%, 29.2 ± 5.8%, vs. 44.2 ± 3.4%, P < 0.001, P = 0.001, respectively). KB-R7785 also significantly decreased the ISEL-positive rates (18.0 ± 9.3% vs. 43.6 ± 14.0%; P < 0.0001). The concentration of TNF- , was significantly reduced by KB-R7785 (P < 0.05), whereas that of TGF- , was not. Concentration of sFasL was under detectable level in the present assay system. The derivatives of KB-R7785 that can be administrated orally showed inhibitory effect on apoptosis induction as well. Conclusions:,These findings suggest that MMPIs inhibits the apoptosis induction of MDS bone marrow cells via the inhibition of TNF- , and probably sFasL secretion, and that MMPIs can be used to control the abnormal induction of apoptosis in MDS. [source]


CD8+ T-cell interaction with HCV replicon cells: Evidence for both cytokine- and cell-mediated antiviral activity

HEPATOLOGY, Issue 6 2003
Chen Liu
The interaction between the host immune response and infected hepatocytes plays a central role in the pathogenesis of hepatitis C virus (HCV). The lack of a suitable animal or in vitro model has hindered our understanding of the host T-cell/HCV interaction. Our aim was to develop an in vitro model to study the mechanisms of HCV-specific T-cell-mediated antiviral and cytolytic function. The HCV replicon was HLA typed and lymphocytes were obtained from an HLA class I-matched subject. CD8+ T cells were expanded with 2 HCV-specific/HLA-restricted peptides for NS3. Lymphocyte preparations were cocultured with HCV replicon (FCA1) and control (Huh7) cells labeled with 51Cr. After a 48-hour incubation, the cells were harvested for RNA extraction. Standard blocking assays were performed in the presence of anti-interferon gamma (IFN-,), anti-tumor necrosis factor , (TNF-,), and anti-FasL. Cytolytic activity was measured by 51Cr release. HCV replicon cells express homozygous HLA-A11 alleles and present HCV nonstructural proteins. HCV-specific expansion of CD8+ cells led to a 10-fold decrease in HCV replication by Northern blot analysis and 21% specific lysis of FCA1 cells (compared with 2% of control Huh7 cells). Twenty percent of this antiviral activity was independent of T-cell binding, suggesting cytokine-mediated antiviral activity. The CD8+ antiviral effect was markedly reduced by blocking either IFN-, or FasL but was unaffected by blocking TNF-,. In conclusion, HCV-specific CD8+ cells inhibit viral RNA replication by cytokine-mediated and direct cytolytic effects. This T-cell/HCV subgenomic replicon system represents a model for the investigation of CD8 cell interaction with HCV-infected hepatocytes. [source]


Mechanism of action of certolizumab pegol (CDP870): In vitro comparison with other anti-tumor necrosis factor , agents

INFLAMMATORY BOWEL DISEASES, Issue 11 2007
Andrew Nesbitt PhD
Abstract Background: Inhibitors of tumor necrosis factor , (TNF,) have demonstrated significant efficacy in chronic inflammatory diseases, including Crohn's disease (CD). To further elucidate the mechanisms of action of these agents, we compared the anti-TNF, agents certolizumab pegol, infliximab, adalimumab, and etanercept in several in vitro systems. Methods: The ability of each anti-TNF, agent to neutralize soluble and membrane-bound TNF,; mediate cytotoxicity, affect apoptosis of activated human peripheral blood lymphocytes and monocytes; induce degranulation of human peripheral blood granulocytes, and modulate lipopolysaccharide (LPS)-induced interleukin (IL)-1, production by human monocytes was measured in vitro. Results: All 4 agents neutralized soluble TNF, and bound to and neutralized membrane TNF,. Infliximab and adalimumab were comparable in their ability to mediate complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and to increase the proportion of cells undergoing apoptosis and the level of granulocyte degranulation. Etanercept generally mediated these effects to a lesser degree, while certolizumab pegol gave similar results to the control reagents. LPS-induced IL-1, production was inhibited by certolizumab pegol, infliximab, and adalimumab, but only partially inhibited by etanercept. Conclusions: In contrast to the other anti-TNF, agents tested, certolizumab pegol did not mediate increased levels of apoptosis in any of the in vitro assays used, suggesting that these mechanisms are not essential for the efficacy of anti-TNF, agents in CD. As certolizumab pegol, infliximab, and adalimumab, but not etanercept, almost completely inhibited LPS-induced IL-1, release from monocytes, inhibition of cytokine production may be important for efficacy of anti-TNF, agents in CD. (Inflamm Bowel Dis 2007) [source]


Effect of the anti-tumor necrosis factor-, antibody infliximab on the ex vivo mucosal matrix metalloproteinase,proteolytic phenotype in inflammatory bowel disease

INFLAMMATORY BOWEL DISEASES, Issue 2 2007
Martin J. Meijer MSc
Abstract Background: Previous studies have shown an upregulation of matrix metalloproteinases (MMPs) in intestinal tissue of patients with inflammatory bowel disease (IBD) and significant clinical improvement after administration of the anti-TNF-, antibody infliximab. The aims of our study were to determine expression and secretion of MMP-1, -2, -3, -9, and their inhibitors TIMP-1, -2 by IBD versus control intestinal mucosa ex vivo and to assess the regulatory capacity by infliximab of the proteolytic phenotype. Methods: Intestinal mucosal explants from 20 IBD and 15 control patients were cultured with or without infliximab and/or the T-cell activator pokeweed mitogen (PWM). Explants and culture supernatants were analyzed for MMPs, TIMPs, and TNF-, protein, activity and/or mRNA levels. All patients were genotyped for functional TNF-,, MMP, and TIMP single nucleotide polymorphism (SNP) loci. Results: Expression of MMP and TIMP protein/activity in basal medium was higher in IBD versus control explants. Dependent on genotype at SNP loci, infliximab downregulated MMP-1, -3, and -9 relative to TIMP-1 and -2 and also decreased MMP-1 and -3 activities, while PWM enhanced these levels, partly counteracted again by infliximab. The expression of MMP-2 relative to TIMP did not change by treatment with infliximab and/or PWM. Conclusions: The high expression of MMPs in patients with IBD suggests a role for these proteinases in the pathogenesis of this disease. Infliximab seems to induce a genotype-associated matrix protective phenotype, which may contribute to the observed therapeutic efficacy of this drug in IBD, particularly at the mucosal surface. (Inflamm Bowel Dis 2007) [source]


Extended indications for anti-tumor necrosis factor-, therapy

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2 2006
Chong-Hyeon YOON
Abstract Tumour necrosis factor-, is a pleiotropic cytokine which has a broad range of actions in inflammation, infection and immunity. TNF-, is supposed to play a crucial role in the pathogenesis of various autoimmune diseases. TNF-, blocking agents have been demonstrated to be highly effective in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. TNF-, inhibitors also have been tried with other rheumatic diseases and have emerged as promising treatments. We here review the current evidences of effectiveness of the anti-TNF-, therapy in various autoimmune diseases. [source]


Immediate anti-tumor necrosis factor-, (etanercept) therapy enhances axonal regeneration after sciatic nerve crush

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2010
Kinshi Kato
Abstract Peripheral nerve regeneration begins immediately after injury. Understanding the mechanisms by which early modulators of axonal degeneration regulate neurite outgrowth may affect the development of new strategies to promote nerve repair. Tumor necrosis factor-, (TNF-,) plays a crucial role in the initiation of degenerative cascades after peripheral nerve injury. Here we demonstrate using real-time Taqman quantitative RT-PCR that, during the time course (days 1,60) of sciatic nerve crush, TNF-, mRNA expression is induced at 1 day and returned to baseline at 5 days after injury in nerve and the corresponding dorsal root ganglia (DRG). Immediate therapy with the TNF-, antagonist etanercept (fusion protein of TNFRII and human IgG), administered systemically (i.p.) and locally (epineurially) after nerve crush injury, enhanced the rate of axonal regeneration, as determined by nerve pinch test and increased number of characteristic clusters of regenerating nerve fibers distal to nerve crush segments. These fibers were immunoreactive for growth associated protein-43 (GAP-43) and etanercept, detected by anti-human IgG immunofluorescence. Increased GAP-43 expression was found in the injured nerve and in the corresponding DRG and ventral spinal cord after systemic etanercept compared with vehicle treatments. This study established that immediate therapy with TNF-, antagonist supports axonal regeneration after peripheral nerve injury. © 2009 Wiley-Liss, Inc. [source]


Understanding and Treating Patients With Alcoholic Cirrhosis: An Update

ALCOHOLISM, Issue 7 2009
Giovanni Addolorato
Alcoholic cirrhosis represents the terminal stage of alcoholic liver disease (ALD) and one of the main causes of death among alcohol abusers. The aim of this review was to provide an update on alcoholic cirrhosis, with an emphasis on recent findings. Increased alcohol consumption in developing countries is expected to increase cirrhosis mortality. There is a need, therefore, to develop new approaches to the prevention of ALD, including more attention to co-factors that may increase risk of ALD (i.e., obesity and diabetes, chronic HCV infection, and smoking). Furthermore, a better understanding of the pathological mechanisms on the basis of alcohol cirrhosis represents a cornerstone in order to develop new pharmacological treatments. Inflammatory and immune responses along with oxidative stress and alterations in adipokine secretion might contribute in different ways to the evolution of alcohol-induced fibrosis/cirrhosis. As of this date, patients with severe alcoholic hepatitis with a Maddrey Discriminant Factor (MDF) 32 should be offered pentoxifylline and/or corticosteroids unless contraindications exist. For ambulatory patients, S-adenosylmethionine (SAMe) may be considered in a motivated patient with nutritional support. Current studies do not support use of anti-tumor necrosis factor (TNF)-alpha antibody. Finally, achieving total alcohol abstinence should represent the main aim in the management of patients affected by any stage of cirrhosis. In the last decades, several drugs able to increase abstinence and prevent alcohol relapse have been evaluated and some of them have obtained approval for alcohol dependence. Patients with alcoholic cirrhosis; however, are usually excluded from such treatments. A recent study demonstrated the efficacy and safety of baclofen in inducing and maintaining alcohol abstinence in cirrhotic alcohol-dependent patients with cirrhosis. All together the information available suggests the need of a multimodal approach in the clinical management of these patients. [source]


Erratum: Golimumab, a human anti-tumor necrosis factor , monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: Twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis

ARTHRITIS & RHEUMATISM, Issue 9 2010
Paul Emery
No abstract is available for this article. [source]