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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article gives brief history of the advancement of cytokine based therapy and discusses the role of these agents in the future.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Erheumatological autoimmune disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Einflammatory disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EJean-Michel Dayer, MD, University Hospital, Faculty of Medicine, Geneva, presented the Fred Wyss lecture at the 2007 EULAR congress in Barcelona. He gave a brief history of the advancement of cytokine based therapy and discussed the role of these agents in the future.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EThe development of what Prof. Dayer referred to as the \u201ccytokine community\u201d has followed a repeatable sequence. At first, an individual cytokine is identified and associated with a particular function. Later, it is found to have many other functions. At some point, the cytokine is cloned with the assumption that there will be one function associated with one factor, but the result is often that new, unexpected members of the cytokine family are identified and novel functions are revealed. This, in turn, leads to both clinical and biological surprises, species problems, side effects, and antagonists and agonists within the same family. The TNF, IL-1, IL-6 families are excellent examples of this process.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003ETNF was discovered many years ago as a serum factor that causes necrosis of tumors in mice. Years later, the TNF receptor was shown to be expressed by mammalian cells. This led to the discovery of a superfamily of transmembrane proteins and the identification of gene families that include 18 ligands and 28 receptors.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003ETNF has been found to induce collagenase and PGE\u003Csub\u003E2\u003C\/sub\u003E in human synovial cells from patients with RA [Dayer J-M et al. \u003Cem\u003EJ Exp Med\u003C\/em\u003E 1985] and to induce bone resorption [Saklatvala J et al. \u003Cem\u003ENature\u003C\/em\u003E 1986]. It was determined to be involved in collagen-induced arthritis [William RO et al. \u003Cem\u003EProc Natl Acad Sci\u003C\/em\u003E 1982] and was detected in the biological fluids of rheumatoid arthritis (RA) patients [Saxne T et al. \u003Cem\u003EArthritis and Rheum\u003C\/em\u003E 1988]. A key observation was that TNF is very important in the hierarchy of the cytokines, since antibodies to TNF decrease other downstream cytokines [Brennan FM et al. \u003Cem\u003ELancet\u003C\/em\u003E, 1989]. Using a chimeric monoclonal antibody to TNF-\u03b1 as a treatment for RA leads to impressive clinical results [Elliott JM et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 1993].\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe developmental history of cytokines and IL-1 followed a path similar to the TNF developments. Many functions were attributed to IL-1, such aslymphocyte activating factor (LAF) osteaoclast-activating factors (OAF), endogenous pyrogen (EP) and related to RA mononuclear cell factor (MCF) inducing collagenase and PGE\u003Csub\u003E2\u003C\/sub\u003E [Dayer et al. \u003Cem\u003EScience\u003C\/em\u003E 1977]. IL-1 biology still leads to some surprises. For example, in a mouse model, local hippocampal over expression of IL-1 beta in an Alzheimer\u0027s diseased transgenic mouse resulted not in the expected exacerbation of the amyloid beta plaque deposition common in Alzheimer\u0027s disease, but instead in plaque amelioration [Solomon S et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2007]. IL-1 receptor antagonists (IL-1Ra) was shown to inhibit insulin production in cultured rat pancreatic islets [Dayer-M\u00e9troz MD et al. \u003Cem\u003EJ of Autoimmunity\u003C\/em\u003E 1989]. Of great interest was the finding that the expression of the IL-1Ra was reduced in the pancreatic islets of patients with type 2 diabetes mellitus. The blockade of IL-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation [Larsen CM et al. \u003Cem\u003EN Eng J Med\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EProf. Dayer started his EULAR lecture by posing the question \u201cWhy does a patient\u0027s fever regress spontaneously?\u201d He then proposed the following hypothesis: An insult to the system causes an immuno-inflammatory reaction; cytokines are released that cause pain, tissue destruction, and inflammation. A defensive anti-immuno-inflammatory reaction occurs, including the release of anti-cytokines that block the inflammation caused by the originally released cytokines (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E), thus causing the fever to regress.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Spontaneous Fever Regression.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-76323001\u0022 data-figure-caption=\u0022Spontaneous Fever Regression.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1:\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1:\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11183\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1:\u003C\/span\u003E \n               \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003ESpontaneous Fever Regression.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EProof of this can be found in a study conducted by Prieur et al, in which IL-1 activity and inhibition were studied in serum and urine from 9 patients with systemic juvenile chronic arthritis (S-JCA) [Prieur A et al. \u003Cem\u003ELancet\u003C\/em\u003E 1987]. In afebrile patients, IL-1 bio-activity was normal or high. Serum from 2 afebrile S-JCA patients taken during a period of severe disease activity had an enhancing effect on the bio-activity of exogenous IL-1. In contrast, febrile patients\u0027 serum and urine IL-1 bio-activity was low, apparently reflecting the presence of a strong inhibitor of IL-1 activity measured by the inhibition of prostaglandin E2 production by synovial cells. This inhibition was greatest at the time of peak temperature, suggesting the possibility of feedback regulation during fever. Recently, anakinra has been shown to be successful in treating patients with adult-onset Still\u0027s disease [Fitzgerald JD et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2005; Vasques G et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2005] and, surprisingly, in acute gout [So A et al. \u003Cem\u003EArthritis Res Ther\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EWhere are the initial events in RA? Locating the site of disease-initiating events is still under debate. Is it at the systemic level (extra-articular site), or in the bone marrow, or locally (articular site)? Support for systemic localization comes from Binstadt and colleagues [\u003Cem\u003ENat Immunol\u003C\/em\u003E 2006]. Using observations in the K\/BxN murine arthritis model, they uncovered novel pathways underlying the site-specific localization of inflammation driven by immune complexes and triggered by sensitization to non-specific Ag at an extra-articular level. Such a hypothesis has been reviewed by Pitzalis C et al. [\u003Cem\u003ETrend in Immunology\u003C\/em\u003E 2006].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EWithin both the bone marrow and the synovium, fibroblastic stromal cells play an important role in supporting the differentiation and survival of normal cells. They also contribute to the pathologic processes. A possible argument for the localization of the initiating event in the bone marrow could be the presence of nurse cells within the synovium that foster inflammation. These nurse cells may contribute to the localization of inflammation within specific joints. It has also been noted that fibroblastic stromal cells from epiphyseal bone marrow can migrate into the joint space, forming synovial tissue in collagen-induced arthritis [Ochi T et al. \u003Cem\u003EArthritis Res Ther\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EWhat about the local articular site? The overgrowth of synovial tissues is critical in the pathogenesis of rheumatoid arthritis (RA). The expression of Synoviolin (SYN), an E3 ubiquitin ligase, is upregulated in arthritic synovial fibroblasts and is involved in the overgrowth of synovial cells during RA. The proinflammatory cytokines IL-1\u03b2 and TNF\u03b1 induce the overgrowth of synovial cells by upregulating SYN expression via the Erk1\/-ETS1 pathway [Gao B et al. \u003Cem\u003EArthritis Res Ther\u003C\/em\u003E 2006]. Another molecule, Cadherin-11, strongly determines the behavior of synovial cells in their proinflammatory and destructive tissue response in inflammatory arthritis [Lee DM. \u003Cem\u003EScience\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EProf. Dayer also spoke briefly about the new research affecting cytokine understanding, such as cell to cell contact between T lymphocytes and monocytes for IL-1\/TNF production and the environmental influence of Apolipoprotein A\u003Csub\u003E1\u003C\/sub\u003E-HDL blocking [Hyka N. \u003Cem\u003EBlood\u003C\/em\u003E 2001; Dayer JM et al. \u003Cem\u003EAutoimmune Res\u003C\/em\u003E 2004]; on the production of cytokines, and the role of adipose tissue.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EAdipocytokines are cytokines secreted by adipose tissue, the source of production and site of action of several pro- and anti-inflammatory cytokines. White adipose tissues are the major producer of the anti-inflammatory IL-1Ra [Juqe-Aubry CE et al. \u003Cem\u003EJ Clin End Metabol\u003C\/em\u003E 2004]. Some adipocytokines such as adiponectin and leptin affect immune and inflammatory functions. A new proinflammatory adipocytokine (Visfatin) has recently been identified as an adipocytokine that activates human leukocytes and induces cytokine production [Moschen AR et al. \u003Cem\u003EJ Immunol\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EEmerging cytokine targets in RA, eg, IL-6, IL-15, and IL-32, are in multiple stages of development. New cell therapies using T-regulatory cells, hematopoietic stem cell transplantation, and mesenchymal stem cells are also in development.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ENew treatments based upon vaccination with cytokines are emerging. An anti-cytokine induction of autoimmune protection against both acute and chronic hTNF\u03b1 exposure has been demonstrated. Thus, an effective and safe vaccination against a human cytokine may be achievable [Le Buanex H et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2006].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EA number of peptide, and peptidomimetic-based approaches (such as TCR-peptide vaccines and peptides derived from heat shock protein), and antisense oligonucleotide are currently being tested in animal models to treat inflammatory arthritis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003E\u201cWe have learned, and will continue to learn, a great deal about cytokines, a remarkable class of potential disease altering agents that will play a major role in future therapeutics, and lead to more \u2018ad personam\u2019 treatment depending upon the subtypes of diseases and the gene status.\u201d Prof. Dayer concluded.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-76323001\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure2\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure2\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/4\/8\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11184\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2007 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/7\/4\/8.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzm92r\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzm92r\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}