title: TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future.
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.
authors.affiliation: 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. Electronic address: Lisa.Sedger@mq.edu.au.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sedger
authors.affiliation: 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. Electronic address: m.mcdermott@leeds.ac.uk.
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D000079424:Tumor Necrosis Factor Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D000079424:Tumor Necrosis Factor Inhibitors
keywords: Inflammation; Monoclonal antibody; Neuropathology; Tumor necrosis factor; Tumor necrosis factor receptor