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1
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Ha R, Keynan Y, Rueda ZV. Increased susceptibility to pneumonia due to tumour necrosis factor inhibition and prospective immune system rescue via immunotherapy. Front Cell Infect Microbiol 2022; 12:980868. [PMID: 36159650 PMCID: PMC9489861 DOI: 10.3389/fcimb.2022.980868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/15/2022] [Indexed: 11/22/2022] Open
Abstract
Immunomodulators such as tumour necrosis factor (TNF) inhibitors are used to treat autoimmune conditions by reducing the magnitude of the innate immune response. Dampened innate responses pose an increased risk of new infections by opportunistic pathogens and reactivation of pre-existing latent infections. The alteration in immune response predisposes to increased severity of infections. TNF inhibitors are used to treat autoimmune conditions such as rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, transplant recipients, and inflammatory bowel disease. The efficacies of immunomodulators are shown to be varied, even among those that target the same pathways. Monoclonal antibody-based TNF inhibitors have been shown to induce stronger immunosuppression when compared to their receptor-based counterparts. The variability in activity also translates to differences in risk for infection, moreover, parallel, or sequential use of immunosuppressive drugs and corticosteroids makes it difficult to accurately attribute the risk of infection to a single immunomodulatory drug. Among recipients of TNF inhibitors, Mycobacterium tuberculosis has been shown to be responsible for 12.5-59% of all infections; Pneumocystis jirovecii has been responsible for 20% of all non-viral infections; and Legionella pneumophila infections occur at 13-21 times the rate of the general population. This review will outline the mechanism of immune modulation caused by TNF inhibitors and how they predispose to infection with a focus on Mycobacterium tuberculosis, Legionella pneumophila, and Pneumocystis jirovecii. This review will then explore and evaluate how other immunomodulators and host-directed treatments influence these infections and the severity of the resulting infection to mitigate or treat TNF inhibitor-associated infections alongside antibiotics.
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Affiliation(s)
- Ryan Ha
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Yoav Keynan
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Department of Community-Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Facultad de Medicina, Universidad Pontificia Bolivariana, Medellin, Colombia
| | - Zulma Vanessa Rueda
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Facultad de Medicina, Universidad Pontificia Bolivariana, Medellin, Colombia
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2
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Freitas MO, Fonseca APR, de Aguiar MT, Dias CC, Avelar RL, Sousa FB, Alves APNN, de Barros Silva PG. Tumor necrosis factor alpha (TNF-α) blockage reduces acute inflammation and delayed wound healing in oral ulcer of rats. Inflammopharmacology 2022; 30:1781-1798. [PMID: 35948810 DOI: 10.1007/s10787-022-01046-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/26/2022] [Indexed: 11/05/2022]
Abstract
Oral traumatic ulcers (OTU) are common in dental routine, and the control of proinflammatory cytokines, such as the tumor necrosis factor-alpha (TNF-α), may interfere with OTU repair. Our aim was to evaluate the role of TNF-α in the healing process of OTU in rats. Wistar male rats were divided into six groups: a control-group (treated with 0.1 mL/kg of saline) and five groups treated with anti-TNF-α infliximab (INF) at 1, 3, 5, 7, and 10 mg/kg immediately before OTU production. The animals were weighed (day 0) and euthanized on days 1, 3, 7, 14 and 21 after ulceration. The ulcers were clinically measured, and the mucosa samples were histologically (scores 0-4), histochemically (collagen assay (pircrosirius)), histomorphometrically (cell counting), and immunohistochemically (TNF-α, α-smooth-muscle-actin (α-SMA), monocyte-chemoattractive-protein-1 (MCP-1), interleukin-8 (IL-8), and fibroblast-growth-factor (FGF)) analyzed. The Evans blue assay was used to measure the vascular permeability. ANOVA-1-2-way/Bonferroni, Kruskal-Wallis/Dunn, and correlation analyses were performed (GraphPad Prism 5.0, p < 0.05). High doses of INF reduced the OTU area (p = 0.043), body mass loss (p = 0.023), vascular permeability (p < 0.001), and reduced delayed histologic scores (p < 0.05), polymorphonuclear (p < 0.001) and mononuclear (p < 0.001) cells, blood vessel counting (p = 0.006), and total (p < 0.001), type-I (p = 0.018), and type-III (p < 0.001) collagen. INF treatment reduced TNF-α immunostaining and delayed MPC-1, FGF, and α-SMA expression, with little/none influence in IL-8 immunostaining. TNF-α blockage by INF reduced acute inflammation in OTU but delayed cell migration and wound healing.
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Affiliation(s)
- Milena Oliveira Freitas
- Department of Dentistry, Unichristus, Rua João Adolfo Gurgel, 133, Cocó, Fortaleza, Ceará, CEP 60192-345, Brazil.,Division of Oral Pathology, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | | | - Maria Thaynara de Aguiar
- Department of Dentistry, Unichristus, Rua João Adolfo Gurgel, 133, Cocó, Fortaleza, Ceará, CEP 60192-345, Brazil
| | - Camila Costa Dias
- Department of Dentistry, Unichristus, Rua João Adolfo Gurgel, 133, Cocó, Fortaleza, Ceará, CEP 60192-345, Brazil
| | - Rafael Linard Avelar
- Division of Oral Pathology, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Fabrício Bitu Sousa
- Department of Dentistry, Unichristus, Rua João Adolfo Gurgel, 133, Cocó, Fortaleza, Ceará, CEP 60192-345, Brazil.,Division of Oral Pathology, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Ana Paula Negreiros Nunes Alves
- Division of Oral Pathology, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Paulo Goberlânio de Barros Silva
- Department of Dentistry, Unichristus, Rua João Adolfo Gurgel, 133, Cocó, Fortaleza, Ceará, CEP 60192-345, Brazil. .,Division of Oral Pathology, Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Ceará, Fortaleza, Ceará, Brazil.
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3
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EKİNCİ B, YAŞAR H, ARSLAN YK. Evaluation of Peripheral Nerves In Patients Receiving Anti -Tnf- α Drug Therapy. ARCHIVES OF CLINICAL AND EXPERIMENTAL MEDICINE 2021. [DOI: 10.25000/acem.870894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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4
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Patel S, Wadhwa M. Therapeutic use of specific tumour necrosis factor inhibitors in inflammatory diseases including COVID-19. Biomed Pharmacother 2021; 140:111785. [PMID: 34126316 PMCID: PMC8162906 DOI: 10.1016/j.biopha.2021.111785] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has caused significant devastation globally. Despite the development of several vaccines, with uncertainty around global uptake and vaccine efficacy, the need for effective therapeutic agents remains. Increased levels of cytokines including tumour necrosis factor are significant in the pathogenesis of COVID-19 and associated with poor outcomes including ventilator requirement and mortality. Repurposing tumour necrosis factor blocker therapy used in conditions such as rheumatoid arthritis and inflammatory bowel disease seems promising, with early feasibility data showing a reduction in circulation of pro-inflammatory cytokines and encouraging the evaluation of such interventions in preventing disease progression and clinical deterioration in patients with COVID-19. Here, we examine the biological activities of tumour necrosis factor inhibitors indicative of their potential in COVID-19 and briefly outline the randomised control trials assessing their benefit-risk profile in COVID-19 therapy.
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Affiliation(s)
- Serena Patel
- Downing College, Regent Street, Cambridge CB2 1DQ, UK; Ipswich Hospital, Heath Road, Ipswich IP4 5PD, UK
| | - Meenu Wadhwa
- NIBSC, MHRA, Blanche Lane, South Mimms, Hertfordshire EN6 3QG, UK.
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5
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Attwood MM, Jonsson J, Rask-Andersen M, Schiöth HB. Soluble ligands as drug targets. Nat Rev Drug Discov 2020; 19:695-710. [PMID: 32873970 DOI: 10.1038/s41573-020-0078-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases.
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Affiliation(s)
- Misty M Attwood
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Jörgen Jonsson
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Mathias Rask-Andersen
- Medical Genetics and Genomics, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Helgi B Schiöth
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden. .,Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
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6
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Bufan B, Jančić I, Stojić-Vukanić Z. Inhibitors of tumor necrosis factor-a and mechanisms of their action. ARHIV ZA FARMACIJU 2020. [DOI: 10.5937/arhfarm2003109b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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7
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Lim KJ, Lee SJ, Kim S, Lee SY, Lee MS, Park YA, Choi EJ, Lee EB, Jun HK, Cho JM, Lee S, Kwon KS, Lim BP, Jeon MS, Shin EC, Choi YS, Fudim E, Picard O, Yavzori M, Ben-Horin S, Chang SJ. Comparable Immune Function Inhibition by the Infliximab Biosimilar CT-P13: Implications for Treatment of Inflammatory Bowel Disease. J Crohns Colitis 2017; 11:593-602. [PMID: 28453766 DOI: 10.1093/ecco-jcc/jjw183] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 10/06/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS CT-P13 is the first biosimilar monoclonal antibody to infliximab, and was recently approved in the European Union, Japan, Korea, and USA for all six indications of infliximab. However, studies directly assessing the biologic activity of CT-P13 versus inflximab in the context of inflammatory bowel disease [IBD] are still scanty. In the present study, we aimed to compare the biological activities of CT-P13 and infliximab with specific focus on intestinal cells so as to gain insight into the potential biosimilarity of these two agents for treatment of IBD. METHODS CT-P13 and infliximab were investigated and compared by in vitro experiments for their neutralisation ability of soluble tumour necrosis factor alpha [sTNFα] and membrane-bound tumour necrosis factor alpha [mTNFα], suppression of cytokine release by reverse signalling, induction of regulatory macrophages and wound healing, and antibody-dependent cell cytotoxicity [ADCC]. RESULTS CT-P13 showed similar biological activities to infliximab as gauged by neutralisation of soluble TNFα, as well as blockade of apoptosis and suppression of pro-inflammatory cytokines in intestinal Caco-2 cells. Infliximab and CT-P13 equally induced apoptosis and outside-to-inside signals through transmembrane TNFα [tmTNFα]. Moreover, regulatory macrophage induction and ensuing wound healing were similarly exerted by CT-P13 and infliximab. However, neither CT-P13 nor infliximab exerted any significant ADCC of ex vivo-stimulated peripheral blood monocytes or lamina propria mononuclear cells from IBD patients. CONCLUSIONS These findings indicate that CT-P13 and infliximab exert highly similar biological activities in intestinal cells, and further support a mechanistic comparability of these two drugs in the treatment of IBD.
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Affiliation(s)
- Ki Jung Lim
- R&D Division, Celltrion Inc., Incheon, Korea
| | - So Jung Lee
- R&D Division, Celltrion Inc., Incheon, Korea
| | | | - Su Yeon Lee
- R&D Division, Celltrion Inc., Incheon, Korea
| | | | - Yoon A Park
- R&D Division, Celltrion Inc., Incheon, Korea
| | | | | | | | | | | | | | | | - Myung-Shin Jeon
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon, Korea
| | - Eui Cheol Shin
- Laboratory of Immunology and Infectious Disease, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Yong Sung Choi
- Department of Gastroenterology, Daehang Hospital, Seoul, Korea
| | - Ella Fudim
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Orit Picard
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Miri Yavzori
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Shomron Ben-Horin
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
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8
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Chang S, Hanauer S. Extrapolation and Interchangeability of Infliximab and Adalimumab in Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2017; 15:53-70. [PMID: 28164249 DOI: 10.1007/s11938-017-0122-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OPINION STATEMENT Infliximab and adalimumab biosimilars have been approved by the FDA and European Medicines Agency and have already been introduced to the international market. Availability into the US market is imminent. Biosimilars are highly similar to the reference biologic product but should not be referred to as, nor equated with, generic medications as no two biosimilars can ever be identical. Regulatory pathways for biosimilar approval consider the totality of evidence for biosimilar approvals, but the preponderance of development relies on analytic and functional testing and allows extrapolation between indications to reduce the financial burden of completing comparative clinical trials for each indication. Neither CT-P13 (infliximab biosimilar) nor ABP 501 (adalimumab biosimilar) was clinically tested in patients with inflammatory bowel disease prior to being submitted for approval by regulatory agencies. The body of available evidence suggests that these drugs will perform similarly to their originators. The pathway for interchangeability of biosimilars has yet to be clarified by federal regulators and currently remains determined by states within the USA. However, preliminary data suggests that switching from originator to biosimilar is safe with minimal differences in clinical efficacy.
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Affiliation(s)
| | - Stephen Hanauer
- Northwestern University Feinberg School of Medicine, 676 N. St Clair, Suite 1400, Chicago, IL, 60611, USA.
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9
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Szondy Z, Pallai A. Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications. Pharmacol Res 2017; 115:124-132. [DOI: 10.1016/j.phrs.2016.11.025] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 11/21/2016] [Indexed: 12/25/2022]
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10
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Abstract
BACKGROUND Infliximab (IFX), an anti-tumour necrosis factor alpha (TNFα) monoclonal antibody, provides clinical benefits in treating Crohn's disease (CD) but its mechanisms of action are not fully elucidated. This study investigated blood monocyte repertoires and the acute effects of IFX infusion on monocyte subset phenotype and function in IFX-treated patients with CD. METHODS Monocytes and monocyte subsets were enumerated and phenotypically characterized by multicolor flow cytometry in freshly isolated blood from healthy controls (n = 21) and patients with CD treated with (IFX, n = 24) and without (non-IFX, n = 20) IFX. For the IFX-CD group, blood was sampled immediately before (tough-IFX) and after (peak-IFX) infusion. Monocyte responses to lipopolysaccharide were analyzed by whole-blood intracellular cytokine staining. RESULTS Non-IFX and IFX-CD patients had increased numbers of intermediate (CD14CD16) monocytes compared with healthy controls, whereas classical (CD14CD16) and nonclassical (CD14CD16) monocytes were numerically reduced in the IFX-CD group alone. In all groups, monocyte subsets expressed high surface levels of transmembrane (tm)TNFα. After IFX infusion, a significant reduction in monocyte numbers occurred. Post-IFX monocytopenia was proportionately greatest for classical and intermediate subsets, correlated with postinfusion IFX levels and was not associated with monocyte apoptosis. In contrast, lipopolysaccharide-induced production of TNFα and IL-12 by monocytes was significantly reduced in peak-IFX compared with trough-IFX blood samples. CONCLUSIONS Actively managed CD is associated with monocyte repertoire skewing suggestive of chronic inflammatory stimulation. Infused IFX acutely targets monocytes, likely by binding to tmTNFα, resulting in a non-apoptosis-related decline in circulating monocyte numbers and blunting of the inflammatory response of monocytes remaining in the blood.
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11
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Zhao XL, Tian LF, Zhang SJ, Li JM, Feng H, Wang LM, Wang S, Wang J, Wang T, Chen WQ. Novel Human Three-Domain Antibody Fragments Against sTNFα as Well as tmTNFα with High Affinity Generated by the Combination of Ribosome Display and E. coli Expression System. Scand J Immunol 2016; 83:267-78. [PMID: 26860639 DOI: 10.1111/sji.12417] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 01/30/2016] [Indexed: 12/31/2022]
Abstract
Human tumour necrosis factor α (hTNFα) has been proved to be a validated therapeutic target in a number of immune-mediated inflammatory diseases (IMIDs). Fully human monoclonal antibodies (mAbs) that can neutralize soluble hTNFα (sTNFα) as well as transmembrane hTNFα (tmTNFα) are more desirable hTNFα antagonists. Here, we report that novel anti-hTNFα human low-molecular-weight MAbs have been selected and identified using both sTNFα and tmTNFα as target antigens by the combination of ribosome display and E. coli expression system for the first time. As a newly born engineering small molecular antibody, three-domain antibody fragment (VH /κ) provides an alternative promising molecular principle to generate biological agents for TNFα-dependent IMIDs. In this study, a panel of novel human VH /κs (F09, F21, F49 and F409) with high affinity (10(-10) -10(-9) mol/l) to neutralize sTNFα as well as tmTNFα was generated by the combination of ribosome display and E. coli expression system. Among the four clones, F21 and F409 could reduce cytotoxicity on L929 cells induced by sTNFα as well as tmTNFα effectively, and both of them had great potential to inhibit hTNFα-mediated NF-κB activation. Soluble F21 and F409 were also able to inhibit the binding of hTNFα to TNFR1 and TNFR2. The new human antibodies described here have desirable capability to neutralize sTNFα as well as tmTNFα effectively with high affinity and reasonable stability; this may provide an alternative approach for patients who are not responding adequately to currently available anti-TNFα agents.
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Affiliation(s)
- X-L Zhao
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China.,New York University School of Medicine, New York, NY, USA
| | - L-F Tian
- 1st hospital of ShanXi Medical University, Taiyuan, China
| | | | - J-M Li
- 254th Hospital, Tianjin, China
| | - H Feng
- Tianjin College of Physical Education, Tianjin, China
| | - L-M Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - S Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - J Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - T Wang
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
| | - W-Q Chen
- Tianjin Institute of Health and Environmental Medicine, Tianjin, China
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Olesen CM, Coskun M, Peyrin-Biroulet L, Nielsen OH. Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol Ther 2016; 159:110-9. [PMID: 26808166 DOI: 10.1016/j.pharmthera.2016.01.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α but with varying efficacies in IBD. The variations in efficacy probably are caused by structural differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF inhibitors in order to identify mechanisms of importance for their efficacy in IBD. Thus, a better understanding of the mechanistic basis for clinical efficacy can lead to a more rational use of TNF inhibitors in the management of IBD.
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Affiliation(s)
- Caroline Meyer Olesen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre, France
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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13
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Pallai A, Kiss B, Vereb G, Armaka M, Kollias G, Szekanecz Z, Szondy Z. Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-β: Therapeutic Implications. THE JOURNAL OF IMMUNOLOGY 2016; 196:1146-57. [PMID: 26729808 DOI: 10.4049/jimmunol.1501573] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 12/01/2015] [Indexed: 12/14/2022]
Abstract
TNF-α, a potent proinflammatory cytokine, is generated in a precursor form called transmembrane (m)TNF-α that is expressed as a type II polypeptide on the surface of certain cells. mTNF-α was shown to act both as a ligand by binding to TNF-α receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into the mTNF-α-bearing cells. In this study, we show that nonactivated macrophages express basal levels of mTNF-α and respond to anti-TNF-α Abs by triggering the MAPK kinase 4 signaling pathway. The pathway induces TGF-β. Based on inhibitory experiments, the production of TGF-β1 is regulated via Jun kinases, whereas that of other TGF-βs is regulated via p38 MAPKs. Exposure to LPS further induced the expression of mTNF-α, and triggering of mTNF-α strongly suppressed the LPS-induced proinflammatory response. Neutralizing TGF-β by Abs prevented the mTNF-α-mediated suppression of LPS-induced proinflammatory cytokine formation, indicating that the immune-suppressive effect of mTNF-α is mediated via TGF-β. Although apoptotic cells are also known to suppress LPS-induced proinflammatory cytokine formation in macrophages by upregulating TGF-β, we show that they do not use the mTNF-α signaling pathway. Because TGF-β possesses a wide range of immune-suppressive effects, our data indicate that upregulation of TGF-β synthesis by those TNF-α-targeting molecules, which are able to trigger mTNF-α, might contribute to their therapeutic effect in the treatment of certain inflammatory diseases such as Crohn's disease, Wegener's granulomatosis, or sarcoidosis. Additionally, none of the TNF-α-targeting molecules is expected to interfere with the immune-silencing effects of apoptotic cells.
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Affiliation(s)
- Anna Pallai
- Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Hungary
| | - Beáta Kiss
- Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Hungary
| | - György Vereb
- Department of Biophysics and Cell Biology, Research Center of Molecular Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| | - Marietta Armaka
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece
| | - George Kollias
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece; Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, 15771 Athens, Greece; and
| | - Zoltán Szekanecz
- Division of Rheumatology, Department of Internal Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| | - Zsuzsa Szondy
- Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Hungary;
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14
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Slevin SM, Egan LJ. New Insights into the Mechanisms of Action of Anti-Tumor Necrosis Factor-α Monoclonal Antibodies in Inflammatory Bowel Disease. Inflamm Bowel Dis 2015; 21:2909-20. [PMID: 26348448 DOI: 10.1097/mib.0000000000000533] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor necrosis factor alpha (TNF-α) has been widely accepted as a therapeutic target for inflammatory disorders including inflammatory bowel disease. Anti-TNF-α monoclonal antibodies (mAbs) including infliximab, adalimumab, golimumab, and certolizumab pegol have revolutionized therapy for these chronic inflammatory disorders. These agents are potent inhibitors of TNF-α, but significant evidence points to the fact that their actions extend beyond simple neutralization of the cytokine. Recent advances in understanding the mechanism of action of anti-TNF-α mAbs has discovered a number of previously unrecognized actions that are likely to be relevant in mediating their anti-inflammatory effects. Many of those actions are mediated by the binding of the antibodies to transmembrane TNF-α (tmTNF-α) and involve complex interactions with other molecular factors and cells. In this review, we have highlighted new information on the mechanism of actions of anti-TNF-α mAbs, from in vitro and in vivo studies. Despite obvious benefits in many patients, the clinical use of these antibodies are hampered by the fact that some patients do not respond to them, and among patients who do respond, many will develop recurrent disease despite continued dosing. Although pharmacokinetic factors explain some of the observed cases of partial or complete resistance to the effects of anti-TNF-α mAbs, other nonresponder patients may be resistant to those agents mechanism of action. A more thorough understanding of the mechanism of action of anti-TNF-α mAbs may allow the development of strategies to individualize therapy and to overcome resistance.
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Affiliation(s)
- Stephanie M Slevin
- *Immunology Research Group, REMEDI, National University of Ireland, Galway, Ireland; and †Department of Pharmacology and Therapeutics, Clinical Science Institute, National University of Ireland, Galway, Ireland
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Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21:12519-12543. [PMID: 26640330 PMCID: PMC4658608 DOI: 10.3748/wjg.v21.i44.12519] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.
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16
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Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders. Antibodies (Basel) 2015. [DOI: 10.3390/antib4040369] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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17
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Chighizola CB, Favalli EG, Meroni PL. Novel mechanisms of action of the biologicals in rheumatic diseases. Clin Rev Allergy Immunol 2015; 47:6-16. [PMID: 23345026 DOI: 10.1007/s12016-013-8359-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF-α) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-α agent does not imply a non-response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-α. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-α therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-α blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-α plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-α blocking action. The efficacy of an anti-C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects.
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Sonar S, Lal G. Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity. Front Immunol 2015; 6:364. [PMID: 26257732 PMCID: PMC4507150 DOI: 10.3389/fimmu.2015.00364] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/05/2015] [Indexed: 12/18/2022] Open
Abstract
Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor-ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor-ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity.
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Reverse Signaling Contributes to Control of Chronic Inflammation by Anti-TNF Therapeutics. Antibodies (Basel) 2015. [DOI: 10.3390/antib4020123] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Ronda N, Greco D, Adorni MP, Zimetti F, Favari E, Hjeltnes G, Mikkelsen K, Borghi MO, Favalli EG, Gatti R, Hollan I, Meroni PL, Bernini F. Newly Identified Antiatherosclerotic Activity of Methotrexate and Adalimumab: Complementary Effects on Lipoprotein Function and Macrophage Cholesterol Metabolism. Arthritis Rheumatol 2015; 67:1155-64. [DOI: 10.1002/art.39039] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 01/15/2015] [Indexed: 12/13/2022]
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Ivana Hollan
- Lillehammer Hospital for Rheumatic Diseases; Lillehammer Norway
| | - Pier Luigi Meroni
- University of Milan and IRCCS Istituto Auxologico Italiano; Milan Italy
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Sennikov SV, Alshevskaya AA, Shkaruba NS, Chumasova OA, Sizikov AE, Lopatnikova JA. Expression of TNFα membrane-bound receptors in the peripheral blood mononuclear cells (PMBC) in rheumatoid arthritis patients. Cytokine 2015; 73:288-94. [PMID: 25828588 DOI: 10.1016/j.cyto.2015.01.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 01/18/2015] [Accepted: 01/21/2015] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To investigate the expression of TNFα membrane-bound receptors: the percentage of cells expressing these receptors and the number of molecules expressed on different immune cell subsets, and to evaluate serum concentrations of soluble TNFα and its receptors (sTNFRI and sTNFRII) in patients with rheumatoid arthritis in acute stage and after response to treatment compared to healthy donors. METHODS The objects of the study are peripheral blood mononuclear cells (PBMC) of healthy donors (n=150) and RA patients (n=40) subjected to hospital treatment with either biological agents (Rituximab) or glucocorticosteroids (methylprednisolone). To determine PBMC phenotype antibodies anti-hCD3-APC, anti-hCD19 PECy7, anti-hCD14 FITC (eBioscience), as well as anti-hTNFRI-PE and anti-hTNFRII-PE (R&D Systems) were used. To determine receptor number on the cells Quantibrite PE Beads (BD) were used. RESULTS Cells obtained from patients who responded to therapy and achieved disease remission exhibited either an increase in the percentage of TNFRI+ cells or elevated expression density of this receptor type. CONCLUSION Subsets of immunocompetent cells from RA patients show variation in the percentage of membrane-bound receptor positive cells and receptor expression density, which influences the development and progression of the pathological processes in RA. Response to therapy and achievement of disease remission are associated with an increase of TNFRI expression.
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Affiliation(s)
- Sergey V Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology", Yadrintsevskaya Str., 14, Novosibirsk 630099, Russia.
| | - Alina A Alshevskaya
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology", Yadrintsevskaya Str., 14, Novosibirsk 630099, Russia.
| | - Nadezhda S Shkaruba
- Rheumatology Department, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology", Yadrintsevskaya Str., 14, Novosibirsk 630099, Russia.
| | - Oksana A Chumasova
- Rheumatology Department, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology", Yadrintsevskaya Str., 14, Novosibirsk 630099, Russia.
| | - Aleksey E Sizikov
- Rheumatology Department, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology", Yadrintsevskaya Str., 14, Novosibirsk 630099, Russia.
| | - Julia A Lopatnikova
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology", Yadrintsevskaya Str., 14, Novosibirsk 630099, Russia.
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22
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Siebert S, Tsoukas A, Robertson J, McInnes I. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev 2015; 67:280-309. [PMID: 25697599 DOI: 10.1124/pr.114.009639] [Citation(s) in RCA: 239] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti-interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/adverse effects
- Anti-Inflammatory Agents/therapeutic use
- Anti-Inflammatory Agents, Non-Steroidal/adverse effects
- Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
- Antirheumatic Agents/adverse effects
- Antirheumatic Agents/therapeutic use
- Arthritis, Psoriatic/drug therapy
- Arthritis, Psoriatic/immunology
- Arthritis, Psoriatic/metabolism
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/metabolism
- Crohn Disease/drug therapy
- Crohn Disease/immunology
- Crohn Disease/metabolism
- Cytokines/antagonists & inhibitors
- Cytokines/metabolism
- Drugs, Investigational/adverse effects
- Drugs, Investigational/therapeutic use
- Humans
- Interleukin-1/antagonists & inhibitors
- Interleukin-1/metabolism
- Interleukin-6/antagonists & inhibitors
- Interleukin-6/metabolism
- Models, Biological
- Molecular Targeted Therapy/adverse effects
- Psoriasis/drug therapy
- Psoriasis/immunology
- Psoriasis/metabolism
- Spondylitis, Ankylosing/drug therapy
- Spondylitis, Ankylosing/immunology
- Spondylitis, Ankylosing/metabolism
- Tumor Necrosis Factor Inhibitors
- Tumor Necrosis Factors/metabolism
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Affiliation(s)
- Stefan Siebert
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom (S.S., J.R., I.M.); and Division of Rheumatology, McGill University Health Centre, Montreal, Quebec, Canada (A.T.)
| | - Alexander Tsoukas
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom (S.S., J.R., I.M.); and Division of Rheumatology, McGill University Health Centre, Montreal, Quebec, Canada (A.T.)
| | - Jamie Robertson
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom (S.S., J.R., I.M.); and Division of Rheumatology, McGill University Health Centre, Montreal, Quebec, Canada (A.T.)
| | - Iain McInnes
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom (S.S., J.R., I.M.); and Division of Rheumatology, McGill University Health Centre, Montreal, Quebec, Canada (A.T.)
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23
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TNF receptors: signaling pathways and contribution to renal dysfunction. Kidney Int 2014; 87:281-96. [PMID: 25140911 DOI: 10.1038/ki.2014.285] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/28/2014] [Accepted: 03/06/2014] [Indexed: 12/19/2022]
Abstract
Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological activities from cell proliferation, cell death and differentiation to induction of inflammation and immune modulation. TNF exerts its biological responses via interaction with two cell surface receptors: TNFR1 and TNFR2. (TNFRs). These receptors trigger shared and distinct signaling pathways upon TNF binding, which in turn result in cellular outputs that may promote tissue injury on one hand but may also induce protective, beneficial responses. Yet the role of TNF and its receptors specifically in renal disease is still not well understood. This review describes the expression of the TNFRs, the signaling pathways induced by them and the biological responses of TNF and its receptors in various animal models of renal diseases, and discusses the current outcomes from use of TNF biologics and TNF biomarkers in renal disorders.
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24
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Sedger LM, McDermott MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor Rev 2014; 25:453-72. [PMID: 25169849 DOI: 10.1016/j.cytogfr.2014.07.016] [Citation(s) in RCA: 566] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF - now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or individual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
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Affiliation(s)
- Lisa M Sedger
- Australian School of Advanced Medicine, Macquarie University, North Ryde, NSW 2109, Australia; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia.
| | - Michael F McDermott
- Experimental Rheumatology, National Institute for Health Research - Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), and Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James University, Beckett Street, West Yorkshire, Leeds LS9 7TF, UK.
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25
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Juhász K, Buzás K, Duda E. Importance of reverse signaling of the TNF superfamily in immune regulation. Expert Rev Clin Immunol 2014; 9:335-48. [DOI: 10.1586/eci.13.14] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Different changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders. Mol Psychiatry 2013; 18:767-73. [PMID: 22801413 DOI: 10.1038/mp.2012.95] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The growing body of evidence implicating tumor necrosis factor-α (TNFα) in the pathophysiology of psychiatric disorders led us to measure levels of that protein in the cortex of subjects with major depressive disorders (MDD). Having reported an increase (458%) in the levels of the transmembrane (tmTNFα), but not the soluble (sTNFα), form of the protein in Brodmann's area (BA) 46, but not 24, in people with the disorder, we decided to examine additional components of TNFα-related pathways in the same regions in people with MDD and extend our studies to the same cortical regions of people with schizophrenia (Sz) and bipolar disorders (BD). Using postmortem tissue, western blots and quantitative PCR, we have now shown there is a significant increase (305%) in tmTNFα in Brodmann's area 24, but not 46, from subjects with BD, and that levels of the protein were not altered in Sz. Levels of sTNFα were not altered in BD or Sz. In addition, we have shown that levels of TNF receptor 1 (TNFR1) mRNA are increased in BA 24 (53%) and BA 46 (82%) in people with Sz, whereas levels of TNFR2 mRNA was decreased in BA 46 in people with mood disorders (MDD=-51%; BD=-67%). Levels of proteins frequently used as surrogate markers of neuronal, astrocytic and microglia numbers, as well as levels of the pro-inflammatory marker (interleukin 1β), were not changed in the cortex of people with mood disorders. Our data suggest there are differential changes in TNFα-related markers in the cortex of people with MDD, BD and Sz that may not be related to classical inflammation and may cause changes in different TNFα-related signaling pathways.
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28
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To KW, Reino JJG, Yoo DH, Tam LS. Tumour necrosis factor antagonist and tuberculosis in patients with rheumatoid arthritis: An Asian perspective. Respirology 2013; 18:765-73. [PMID: 23627398 DOI: 10.1111/resp.12106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 04/01/2013] [Accepted: 04/17/2013] [Indexed: 12/31/2022]
Affiliation(s)
- Kin Wang To
- Division of Respiratory Medicine; Prince of Wales Hospital, The Chinese University of Hong Kong; Hong Kong, SAR; China
| | - Juan J Gomez Reino
- Department of Medicine and Rheumatology Unit; Hospital Clínico Universitario, USC; Santiago de Compostela; Spain
| | - Dae Hyun Yoo
- Division of Rheumatology, Department of Internal Medicine; Hanyang University Hospital, Hanyang University College of Medicine; Seoul; Korea
| | - Lai Shan Tam
- Division of Rheumatology; Department of Medicine and Therapeutics; Prince of Wales Hospital, The Chinese University of Hong Kong; Hong Kong, SAR; China
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29
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Chimenti MS, Saraceno R, Chiricozzi A, Giunta A, Chimenti S, Perricone R. Profile of certolizumab and its potential in the treatment of psoriatic arthritis. Drug Des Devel Ther 2013; 7:339-48. [PMID: 23620660 PMCID: PMC3633576 DOI: 10.2147/dddt.s31658] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab' fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn's disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.
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Affiliation(s)
- Maria Sole Chimenti
- Unit of Rheumatology, Allergology, and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy.
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Dreschers S, Gille C, Haas M, Grosse-Ophoff J, Schneider M, Leiber A, Bühring HJ, Orlikowsky TW. Infection-induced bystander-apoptosis of monocytes is TNF-alpha-mediated. PLoS One 2013; 8:e53589. [PMID: 23349721 PMCID: PMC3547953 DOI: 10.1371/journal.pone.0053589] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 12/03/2012] [Indexed: 01/30/2023] Open
Abstract
Phagocytosis induced cell death (PICD) is crucial for controlling phagocyte effector cells, such as monocytes, at sites of infection, and essentially contributes to termination of inflammation. Here we tested the hypothesis, that during PICD bystander apoptosis of non-phagocyting monocytes occurs, that apoptosis induction is mediated via tumor necrosis factor-alpha (TNF-α and that TNF-α secretion and -signalling is causal. Monocytes were infected with Escherichia coli (E. coli), expressing green fluorescent protein (GFP), or a pH-sensitive Eos-fluorescent protein (EOS-FP). Monocyte phenotype, phagocytic activity, apoptosis, TNF-receptor (TNFR)-1, -2-expression and TNF-α production were analyzed. Apoptosis occured in phagocyting and non-phagocyting, bystander monocytes. Bacterial transport to the phagolysosome was no prerequisite for apoptosis induction, and desensitized monocytes from PICD, as confirmed by EOS-FP expressing E. coli. Co-cultivation with non-infected carboxyfluorescein-succinimidyl-ester- (CFSE-) labelled monocytes resulted in significant apoptotic cell death of non-infected bystander monocytes. This process required protein de-novo synthesis and still occurred in a diminished way in the absence of cell-cell contact. E. coli induced a robust TNF-α production, leading to TNF-mediated apoptosis in monocytes. Neutralization with an anti-TNF-α antibody reduced monocyte bystander apoptosis significantly. In contrast to TNFR2, the pro-apoptotic TNFR1 was down-regulated on the monocyte surface, internalized 30 min. p.i. and led to apoptosis predominantly in monocytes without phagocyting bacteria by themselves. Our results suggest, that apoptosis of bystander monocytes occurs after infection with E. coli via internalization of TNFR1, and indicate a relevant role for TNF-α. Modifying monocyte apoptosis in sepsis may be a future therapeutic option.
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Affiliation(s)
- Stephan Dreschers
- Department of Neonatology, University Children’s Hospital, Aachen, Germany
| | - Christian Gille
- Department of Neonatology, University Children’s Hospital, Tuebingen, Germany
| | - Martin Haas
- Department of Neonatology, University Children’s Hospital, Aachen, Germany
| | | | - Marion Schneider
- Department of Experimental Anesthesiology, University Hospital, Ulm, Germany
| | - Anja Leiber
- Department of Neonatology, University Children’s Hospital, Tuebingen, Germany
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Davignon JL, Hayder M, Baron M, Boyer JF, Constantin A, Apparailly F, Poupot R, Cantagrel A. Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2012. [PMID: 23204551 DOI: 10.1093/rheumatology/kes304] [Citation(s) in RCA: 166] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Biotherapies have revolutionized the treatment of RA. However, much work is needed to understand all the mechanisms of these biotherapies, and alternatives are needed to circumvent adverse effects and the high cost of these long-lasting treatments. In this article we outline some of the approaches we have used to target monocytes/macrophages as major components of inflammation and bone homeostasis. We also discuss how anti-TNF-α antibodies target monocytes/macrophages in the complex mechanisms contributing to inhibition of inflammation.
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Thalayasingam N, Isaacs JD. Anti-TNF therapy. Best Pract Res Clin Rheumatol 2012; 25:549-67. [PMID: 22137924 DOI: 10.1016/j.berh.2011.10.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Accepted: 10/11/2011] [Indexed: 12/17/2022]
Abstract
There are now five anti-tumour necrosis factor (TNF) drugs licenced for use in rheumatoid arthritis. This chapter examines the similarities and differences between the drugs and looks for clues with regard to their rational prescribing. The major difference is between the monoclonal antibody-based drugs and the soluble receptor etanercept. Etanercept exhibits the best drug survival and is also associated with a lower risk of opportunistic infections, particularly tuberculosis. Immunogenicity should explain some of the differences between the different drugs but the lack of standardised assays has hindered this area of research. The optimal approach to the patient who has failed their first anti-TNF remains unclear and awaits appropriate clinical trials. The safety profile of anti-TNFs has become clearer, largely through registry data. There is a small increase in serious and opportunistic infections but there does not appear to be a heightened cancer risk, and cardiovascular risk is probably reduced.
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Sivamani RK, Goodarzi H, Garcia MS, Raychaudhuri SP, Wehrli LN, Ono Y, Maverakis E. Biologic Therapies in the Treatment of Psoriasis: A Comprehensive Evidence-Based Basic Science and Clinical Review and a Practical Guide to Tuberculosis Monitoring. Clin Rev Allergy Immunol 2012; 44:121-40. [DOI: 10.1007/s12016-012-8301-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Essien BE, Kotiw M. Anti-inflammatory activity of hyperimmune plasma in a lipopolysaccharide-mediated rat air pouch model of inflammation. Inflammation 2012; 35:58-64. [PMID: 21213030 DOI: 10.1007/s10753-010-9289-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumour necrosis factor-α (TNFα) and polymorphonuclear neutrophils play key and interrelated roles in the inflammatory response against infectious agents. However, these entities can mediate significant tissue damage if their biological activity becomes deregulated. We have previously shown that canine hyperimmune frozen plasma (HFP) contains anti-TNFα activity that is attributable to elevated levels of soluble TNFα receptor 1 (sTNFR1). The aim of this study was to determine the effect of HFP on TNFα levels and neutrophil infiltration in a lipopolysaccharide (LPS)-mediated rat air pouch model of inflammation. Rats were administered either HFP, HFP which had been pre-incubated with anti-sTNFR1 antibody (5 ng/ml), fresh frozen plasma (FFP), physiological saline (PS) at 2 ml/day or Carprofen at 5 mg/kg for 3 days prior to LPS challenge. Pouch fluid was withdrawn at 1, 6, 12, 24 and 48 h post-LPS challenge and assayed for TNFα by ELISA, and for total leukocytes and neutrophils by microscopic examination. At 6 h post-LPS challenge, both TNFα levels and neutrophil counts were significantly lower in HFP-treated rats than was found in FFP, PS or Carprofen treated animals (p<0.05). In a sTNFR1 blocking experiment, incubation of HFP with anti-sTNFR1 antibody resulted in significant increases in neutrophil numbers and TNFα levels, which suggests that the anti-TNFα activity observed in HFP may be due to elevated levels of sTNFR1. The data also revealed a significant inverse correlation between total leukocyte counts and sTNFR1 levels present in pouch fluid (r= -0.73, p<0.0001). Our observations suggest that HFP warrants further investigation as a possible means for modulating acute inflammatory processes where TNFα is a key mediator.
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Affiliation(s)
- Bryan E Essien
- Centre for Systems Biology, Faculty of Sciences, University of Southern Queensland, Toowoomba, Queensland, 4350, Australia
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Biologics and infections: lessons from tumor necrosis factor blocking agents. Infect Dis Clin North Am 2012; 25:895-910. [PMID: 22054762 DOI: 10.1016/j.idc.2011.08.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
In the decade since tumor necrosis factor α (TNF-α) antagonists were first approved for clinical use, they have proven invaluable for the treatment of specific types of chronic inflammation. Currently licensed TNF blockers fall into two classes, monoclonal antibody (or antibody fragments) and soluble receptor. Although they are equally effective in rheumatoid arthritis and psoriasis, important differences have emerged with regard to efficacy in granulomatous inflammation and risks of granulomatous infections, particularly tuberculosis. This article focuses on recent studies that inform prevention and management of infections in this susceptible patient population.
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Coulthard LR, Taylor JC, Eyre S, Robinson JI, Wilson AG, Isaacs JD, Hyrich K, Emery P, Barton A, Barrett JH, Morgan AW, McDermott MF. Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis 2011; 70:98-103. [PMID: 20805296 DOI: 10.1136/ard.2010.133249] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Rheumatoid arthritis (RA) does not always respond to available treatments, including tumour necrosis factor (TNF) antagonists. A study was undertaken to investigate whether genetic variation within genes, encoding proteins in the p38 signalling network, contributes to the variable response to TNF antagonists. METHODS 1102 UK Caucasian patients with RA receiving anti-TNF therapy (infliximab, adalimumab and etanercept) were genotyped for 38 pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 12 candidate genes from the p38 network. Regression analyses were performed to test association between genotype and treatment response at 6 months using both absolute change in DAS28 (Disease Activity Score across 28 joints) and European League Against Rheumatism (EULAR) improvement criteria. Stratified analyses were performed to investigate association with individual therapies. RESULTS Seven SNPs, in five genes, were associated with improvement in DAS28 at 6 months at a nominal 0.1 significance level, jointly explaining 3% of variance in outcome in a model adjusting for other predictors. These encoded proteins both upstream (MKK6) and downstream (MAPKAPK2, MSK1, MSK2) of p38, and MAPK14, the p38-α isoform of p38 MAPK. One SNP (rs2716191 in MAP2K6) was associated with EULAR response at the 0.1 level. SNPs generally showed greater correlation with response to infliximab and adalimumab, but not to etanercept. CONCLUSIONS More SNPs than would be expected by chance, mapping to the p38 signalling network, showed association with the anti-TNF response as a whole, and particularly with the response to infliximab and adalimumab. Validation of these findings in independent cohorts is warranted.
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Affiliation(s)
- Lydia R Coulthard
- NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), University of Leeds, Leeds, UK
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Khera TK, Dick AD, Nicholson LB. Mechanisms of TNFα regulation in uveitis: Focus on RNA-binding proteins. Prog Retin Eye Res 2010; 29:610-21. [DOI: 10.1016/j.preteyeres.2010.08.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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McGirt LY, Thoburn C, Hess A, Vonderheid EC. Predictors of response to extracorporeal photopheresis in advanced mycosis fungoides and Sézary syndrome. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2010; 26:182-91. [PMID: 20626820 DOI: 10.1111/j.1600-0781.2010.00514.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) has been utilized for more than 20 years to treat cutaneous T-cell lymphoma (CTCL), but a clinical response can take up to 9 months to manifest. This study was undertaken to determine whether clinical features, laboratory values, cytokine levels, or gene expression levels of tumor markers are useful to predict the subsequent response to ECP in CTCL patients with blood involvement. METHODS Twenty-one patients with CTCL treated with ECP as monotherapy for at least 6 months were retrospectively identified. Laboratory and clinical data and blood obtained at baseline, 3, and 6 months of treatment were used for analysis. RESULTS In pretreatment blood specimens, a lower percentage of Sézary cells and a higher absolute eosinophil count were associated with a favorable clinical response. Clinical evidence of an early response after 3 months of ECP did not reliably predict a favorable response at 6 months or beyond. Comparison of cytokines, gene transcripts, and other laboratory measures of disease did not correlate with the subsequent clinical response, although lactate dehydrogenase levels tended to decrease progressively in ECP-responsive cases and increase progressively in ECP-non-responsive cases. Additionally, serum levels of TNF-alpha significantly increased from baseline to 6 months of ECP, but was not found to correlate with the clinical response. CONCLUSIONS Although we found that increased eosinophils and decreased percentage of Sézary cells were associated with a favorable clinical response to ECP, we were not able to identify the predictors of ECP response within the first 3 months of treatment.
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Affiliation(s)
- Laura Y McGirt
- Dermatology, Johns Hopkins Medical Institutes, Baltimore, MD, USA.
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Bouchaud G, Mortier E, Flamant M, Barbieux I, Plet A, Galmiche JP, Jacques Y, Bourreille A. Interleukin-15 and its soluble receptor mediate the response to infliximab in patients with Crohn's disease. Gastroenterology 2010; 138:2378-87. [PMID: 20188102 DOI: 10.1053/j.gastro.2010.02.044] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2009] [Revised: 02/05/2010] [Accepted: 02/26/2010] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Infliximab is a monoclonal antibody against tumor necrosis factor that is used to treat patients with inflammatory bowel disease. We investigated serum levels and cellular expression of interleukin (IL)-15 and its receptor (sIL-15Ralpha) in patients with Crohn's disease (CD) treated with infliximab; and the effect on sIL-15Ralpha secretion by epithelial cells. METHODS CD patients were given infliximab (n = 40; 3 infusions); 37 healthy controls were studied. Serum levels of IL-15, sIL-15Ralpha, and complex were determined by radioimmunoassay and cytokine levels by enzyme-linked immunosorbent assay. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 levels were assessed by immunohistochemistry. Epithelial cell lines (HT-29 and Caco-2) were cultured with infliximab, adalimumab, or etanercept. Patients were classified as responders and nonresponders according to their Crohn's Disease Activity Index and clinical observations. RESULTS Before infliximab, IL-15 was higher in responders than in controls and nonresponders. After infliximab, IL-15 decreased in responders while remaining stable in nonresponders. sIL-15Ralpha and IL-15/sIL-15Ralpha complex levels were higher in CD than in controls and increased only in responders after infliximab. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 colocalized in epithelial cells and were higher in CD patients. In vitro, infliximab but not adalimumab and etanercept induced sIL-15Ralpha secretion by epithelial cells. CONCLUSIONS Serum level of sIL-15Ralpha and the IL-15/sIL-15Ralpha complex increased in responder patients and the response was associated with a decrease of IL-15. Infliximab induced the release of the IL-15 receptor alpha, suggesting a specific modulation of IL-15 and its soluble receptor by reverse signaling through transmembrane tumor necrosis factor alpha.
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El Fakhry Y, Alturaihi H, Diallo D, Merhi Y, Mourad W. Critical role of lipid rafts in CD154-mediated T cell signaling. Eur J Immunol 2010; 40:770-9. [PMID: 20039299 DOI: 10.1002/eji.200939646] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although signal pathways triggered via the CD40 molecule are well characterized, those induced via CD154 are less known. This study demonstrates that engagement of CD154 in Jurkat D1.1 cells with soluble CD40 leads to PKC alpha and delta activation, calcium mobilization, and phosphorylation of the Map kinases ERK1/2 and p38. Such response is accompanied by significant recruitment of CD154 into lipid rafts. Disruption of lipid rafts integrity with nystatin or methyl beta-cyclodextrin abrogated PKCalpha PKCdelta and p38 phosphorylation, but had no effect on ERK1/2 phosphorylation. Inhibition of PKC activation completely abolished p38 phosphorylation but had no effect on ERK1/2 phosphorylation, suggesting that localization of CD154 within lipid rafts is an absolute requirement for CD154-induced PKCalpha- and PKCdelta-dependent p38 phosphorylation. Furthermore, CD154 acts as co-stimulator for the production of IL-2 in an APC-superantigen-T-cell activation model. The results obtained demonstrate for the first time, that lipid rafts are of immunological relevance for CD154-triggered signals, and reinforce the importance of CD154 in T-cell activation.
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Affiliation(s)
- Youssef El Fakhry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Saint Luc, Montréal, Que., Canada H2X 1P1
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Meusch U, Rossol M, Baerwald C, Hauschildt S, Wagner U. Outside-to-inside signaling through transmembrane tumor necrosis factor reverses pathologic interleukin-1β production and deficient apoptosis of rheumatoid arthritis monocytes. ACTA ACUST UNITED AC 2009; 60:2612-21. [DOI: 10.1002/art.24778] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Abstract
PURPOSE OF REVIEW Our understanding of the infection risks posed by tumor necrosis factor (TNF) antagonists has continued to evolve in the 10 years since these drugs were first introduced. This review summarizes recent data regarding infection risk, examines potential structure-function relationships that may account for the differences, and discusses their implications with regard to tuberculosis prevention and management. RECENT FINDINGS Recent prospective studies have confirmed the risk of tuberculosis reactivation posed by TNF antibodies to be several fold greater than soluble TNF receptor. Certolizumab pegol, a monovalent anti-TNF Fab' fragment appears to share this risk, despite its lack of Fc and its inability to cross-link transmembrane TNF. Screening and initiation of treatment for latent tuberculosis (TB) infection can greatly reduce the TB risk of anti-TNF treatment in western countries. However, alternative strategies to prevent TB because of new transmission may be required as these therapies become available worldwide. Current recommendations for withdrawal of anti-TNF therapy when TB is diagnosed place patients at risk for paradoxical worsening because of recovery of TNF-dependent inflammation. Recent case reports suggest reinstitution of TNF blockade may be safe and effective adjunctive treatment in such cases, but prospective studies are needed to confirm these observations. SUMMARY TNF blockers have transformed treatment of several chronic inflammatory conditions. Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infection diseases.
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Kontermann RE, Scheurich P, Pfizenmaier K. Antagonists of TNF action: clinical experience and new developments. Expert Opin Drug Discov 2009; 4:279-92. [DOI: 10.1517/17460440902785167] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Kato K, Kikuchi S, Shubayev VI, Myers RR. Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience 2009; 160:492-500. [PMID: 19250961 DOI: 10.1016/j.neuroscience.2009.02.038] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 02/05/2009] [Accepted: 02/12/2009] [Indexed: 12/31/2022]
Abstract
Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine that is implicated in the initiation of neuropathic pain. Locally administered TNF antagonist etanercept offers a promising new treatment approach to target neuropathic pain. Here we evaluate the distribution and binding specificity for TNF isoforms of locally administered etanercept into injured and uninjured rat sciatic nerve. Distribution and co-localization of etanercept and TNF in the injured and uninjured nerve was evaluated at 1, 24, 48 and 96 h after etanercept local application using immunohistochemistry. In addition, binding specificity of etanercept for TNF isoforms was analyzed using immunoblot assay system in nerve lysates. A new observation was that locally administered etanercept reached the endoneurium of the injured but not the uninjured nerve 1 h after its application and mainly co-localized with TNF-positive structures, morphologically similar to Schwann cells and macrophages. We further noticed that immunoblot analyses for etanercept demonstrated its preferential binding to transmembrane and trimer TNF isoforms. Finally, locally administered etanercept inhibited pain-related behaviors in a rat sciatic nerve crush model. We conclude that locally administered etanercept reaches the endoneurial space in the injured nerve and preferentially binds to transmembrane and bioactive trimer TNF isoforms to modulate neuropathic pain. Locally administered etanercept has potential as a targeted immunomodulating agent to treat local pathogenesis in neuropathic pain after peripheral nerve injury.
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Affiliation(s)
- K Kato
- Department of Anesthesiology, University of California, San Diego and the VA Medical Center, 9500 Gilman Drive, La Jolla, CA 92093-0629, USA.
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Lionaki S, Siamopoulos K, Theodorou I, Papadimitraki E, Bertsias G, Boumpas D, Boletis J. Inhibition of tumour necrosis factor alpha in idiopathic membranous nephropathy: a pilot study. Nephrol Dial Transplant 2009; 24:2144-50. [DOI: 10.1093/ndt/gfn771] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Yu M, Shi W, Zhang J, Niu L, Chen Q, Yan D, Liu T, Jing W, Jiang X, Wei F, Yin B, Zhang W, Li Q, Li Z. Influence of reverse signaling via membrane TNF-alpha on cytotoxicity of NK92 cells. Eur J Cell Biol 2008; 88:181-91. [PMID: 18950896 DOI: 10.1016/j.ejcb.2008.09.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2008] [Revised: 09/11/2008] [Accepted: 09/15/2008] [Indexed: 11/28/2022] Open
Abstract
Membrane tumor necrosis factor-alpha (mTNF-alpha) serves as a receptor transducing signals into mTNF-alpha-bearing cells. Among human peripheral blood mononuclear cells, natural killer (NK) cells have been reported to be the only cell type constitutively expressing mTNF-alpha, which is involved in the cytotoxicity of resting NK cells. Using an IL-2-dependent human NK cell line, NK92, which constitutively expresses mTNF-alpha, we examined the effect of reverse signaling via mTNF-alpha on cellular activities. When the cells were prestimulated with soluble TNFR1 (sTNFR1) which activated mTNF-alpha-mediated reverse signaling, the cytotoxicity of NK92 cells was significantly increased. Further investigation demonstrated that prestimulation with sTNFR1 augmented exocytosis and mRNA transcription of two cytotoxic molecules, perforin and granzyme B, which could serve as underlying molecular mechanisms by which mTNF-alpha-mediated reverse signaling promoted cytotoxicity of NK cells toward K562 cells. On the other hand, pretreatment of NK92 with sTNFR1 boosted the expression of FasL and TNF-alpha, including both the secretory and membrane forms. These molecules also contribute to the NK-mediated cytotoxicity, although K562 cells are Fas-negative and sTNF-alpha-resistant. Interestingly, the mTNF-alpha reverse signaling was found to act synergistically with IL-2 on NK-mediated cytotoxicity. This synergy markedly promoted the production of secretory as well as membrane cytotoxic molecules which may be responsible for the enhanced NK92-mediated cytotoxicity. Our observations suggest that, via reverse signaling, constitutively expressed mTNF-alpha may sensitize NK cells to activating stimuli, such as IL-2, resulting in increased NK-mediated cytotoxicity through promoting the production of multiple cytotoxic effector molecules.
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Affiliation(s)
- Mingxia Yu
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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Wallis RS. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks. THE LANCET. INFECTIOUS DISEASES 2008; 8:601-11. [PMID: 18922482 DOI: 10.1016/s1473-3099(08)70227-5] [Citation(s) in RCA: 182] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Mata M, Hao S, Fink DJ. Gene therapy directed at the neuroimmune component of chronic pain with particular attention to the role of TNF alpha. Neurosci Lett 2008; 437:209-13. [PMID: 18403116 PMCID: PMC2668118 DOI: 10.1016/j.neulet.2008.03.049] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Revised: 02/28/2008] [Accepted: 03/19/2008] [Indexed: 01/17/2023]
Abstract
Identification that neuroimmune activation in the spinal cord is an important factor in the development of chronic pain has opened the possibility that gene transfer of anti-inflammatory peptides may be used to reduce pain neurotransmission. We review the published evidence regarding gene transfer to meninges to express the anti-inflammatory peptide interleukin 10, and gene transfer to dorsal root ganglia using replication incompetent HSV vectors to express interleukin 4, interleukin 10, or the soluble (p55) tumor necrosis factor receptor (sTNFR). The results of these experiments suggest a novel role for "reverse signaling" through the full-length membrane form of TNFalpha in spinal glia in the modulation of chronic pain.
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Affiliation(s)
- Marina Mata
- Department of Neurology, University of Michigan, 1914 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0316, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI 48109-0316, USA
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