Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines secreted by cells of the immune system can alter the behavior and properties of immune or other cells. At a site of inflammation, sets of cytokines interact with immune cells, and their combined effect is often more important than the function of one isolated component. Conventional techniques, such as enzyme-linked immunosorbent assays, generally require large quantities of cells to characterize a complete cytokine profile of activated lymphocytes. The Bio-Plex system from Bio-Rad Laboratories combines the principle of a sandwich immunoassay with the Luminex fluorescent-bead-based technology. We developed a multiplex cytokine assay to detect different cytokines simultaneously in culture supernatant of human peripheral blood mononuclear cells stimulated with antigen and with mitogen. Fifteen human cytokines (interleukin 1alpha [IL-1alpha], IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-18, gamma interferon, and tumor necrosis factor alpha) were validated with a panel of healthy individuals, rheumatoid arthritis patients, and juvenile idiopathic arthritis patients. Comparing the multiplex assay with a regular enzyme-linked immunosorbent assay technique with this donor panel resulted in correlation coefficients for all cytokines ranging from 0.75 to 0.99. Intra-assay variance proved to be less then 10%, whereas interassay variability ranged between 10 and 22%. This multiplex system proved to be a powerful tool in the quantitation of cytokines. It will provide a more complete picture in differences between activated lymphocyte cytokine profiles from healthy individuals and those from patients with chronic inflammatory diseases.
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PMID:Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. 1252 51

Production of CCR5 expression and MIP-1alpha, a ligand of CCR5, by CD4+ T cells from patients with rheumatoid arthritis (RA) were studied. We analysed further the influence of IL-15 stimulation, CD40/CD40 ligand (CD40L) interaction and CCR5 promotor polymorphism. One hundred and fifty-five RA patients and another 155 age- and sex-matched healthy individuals were enrolled. Peripheral CD4+ and double negative (DN) T cells from patients had lower portions of CCR5, whereas synovial CD4+ and DN T cells showed a much higher CCR5 expression. IL-15 significantly up-regulated the expression of CCR5 on purified CD4+ T cells. CD40L expression on synovial CD4+ T cells was increased greatly in CCR5+ portions by IL-15. MIP-1alpha production by synovial CD4+ T cells was also enhanced by IL-15. Co-culture of CD40 expressing synovial fibroblasts with IL-15-activated synovial CD4+ T cells significantly increased MIP-1alpha production. Expression of CCR5 on patients' CD4+ T cells was not influenced by the promotor polymorphism of CCR5 gene. Taken together, these data suggest CCR5+CD4+ T cells infiltrate the inflamed synovium and IL-15 up-regulates CCR5 and CD40L expression further and enhance MIP-1alpha production in synovial CD4+ T cells. Production of MIP-1alpha by synovial fibroblasts is significantly increased by engagement of CD40 with CD40L. Synovial microenvironment plays a potential role in regulation of CCR5+CD4+ T cells in rheumatoid joints.
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PMID:Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis. 1269 31

The treatment approach to rheumatoid arthritis has undergone a major evolutionary change in recent years in part as a consequence of growing appreciation of the severity of this condition and in part due to very considerable progress in understanding the important role of cytokines in the immunopathogenesis of this disease. The major focus of this review is on the rationale for targeting TNFalpha and IL-1 in rheumatoid arthritis and the results of clinical studies designed to assess the validity of this therapeutic approach. Recently published studies confirm that the long term use of a several biological agents targeting TNFalpha give rise to sustained improvements in symptoms and signs of rheumatoid disease and, furthermore, that TNFalpha blockade protects joints from structural damage. Although these drugs are well tolerated and have a good overall safety profile, pitfalls to the use of anti-TNFalpha agents apparent with increasing clinical experience include rare cases of tuberculosis. The mechanism of action of anti-TNFalpha therapy is discussed. Clinical trials of interleukin-1 receptor antagonist show relatively modest anti-inflammatory efficacy and an effect on X-ray indicative of retardation of joint damage. Other pro-inflammatory cytokines representing potential therapeutic targets include interferon-beta, interferon-alpha, IL-6, IL-15, IL-17 and IL-18. I will consider preliminary data, where available, arising from clinical trials designed to inhibit the activity of such molecules. In this review I will also discuss the rationale and preliminary data for other potential therapeutic strategies designed to augment the activity of anti-inflammatory cytokines such as IL-4, IL-10, and IL-11 in rheumatoid disease.
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PMID:Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. 1276 49

High-quality monoclonal antibodies (mAbs) with specificity for relevant disease molecules can now be produced in abundance. Anti-tumour necrosis factor-alpha therapies have set a new standard for symptom control in rheumatoid arthritis, and blockade of tumour necrosis factor has the potential to protect joints from structural damage. Other targets for therapeutic antibodies include the cytokines interleukin (IL)-1, IL-6, IL-8, IL-15, IL-17 and IL-18. In addition, there is preliminary evidence for the clinical efficacy of both keliximab, a mAb targeting the T cell antigen CD4, and rituximab, a chimeric mAb against the B cell antigen CD20 and CTLA4-Ig, which blocks the CD28/B7 interaction. Phase III studies have yet to be undertaken for these novel biological agents, and it is unclear whether any of these agents will have true disease-modifying capabilities.
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PMID:Antibody therapy for rheumatoid arthritis. 1281 Feb

Effector T cell responses can be modulated by competing positive or negative signals transduced by natural killer (NK) cell receptors. This raises the possibility that dominant T cell stimulation might promote autoimmune reactions. In rheumatoid arthritis (RA), the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4+CD28- T cells, which are scarce in healthy individuals. For poorly defined reasons, these T cells are autoreactive, implying that they may contribute to disease manifestations. CD4+CD28- T cells in peripheral blood and synovial tissue of RA patients were found to express NKG2D, a costimulatory receptor that is absent on normal CD4 T cells. NKG2D was induced by tumor necrosis factor alpha and IL-15, which are abundant in inflamed synovia and RA patient sera. RA synoviocytes aberrantly expressed the stress-inducible MIC ligands of NKG2D, which stimulated autologous CD4+CD28- T cell cytokine and proliferative responses. Peripheral blood serum samples of RA patients contained substantial amounts of synoviocyte-derived soluble MICA, which failed to induce down-modulation of NKG2D because of the opposing activity of tumor necrosis factor alpha and IL-15. These results suggest that a profound dysregulation of NKG2D and its MIC ligands may cause autoreactive T cell stimulation, thus promoting the self-perpetuating pathology in RA and possibly other autoimmune diseases.
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PMID:Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. 1287 25

IL-1 and its related family member IL-18 are primarily proinflammatory cytokines by their ability to stimulate the expression of genes associated with inflammation and autoimmune diseases. For IL-1 (IL-1alpha and IL-1beta), the most salient and relevant properties are the initiation of cyclooxygenase type 2 (COX-2), type 2 phospholipase A and inducible nitric oxide synthase (iNOS). This accounts for the large amount of prostaglandin-E2 (PGE2), platelet activating factor and nitric oxide (NO) produced by cells exposed to IL-1 or in animals or humans injected with IL-1. Another important member of the proinflammatory IL-1 family is IL-18. IL-18 is also an important player in autoimmune disease because of its ability to induce IFNgamma, particularly in combination with IL-12 or IL-15. Both IL-1 and IL-18 increase the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on mesenchymal cells and vascular-cell adhesion molecule-1 (VCAM-1) on endothelial cells. This latter property promotes the infiltration of inflammatory and immunocompetent cells into the extravascular space. IL-1 and IL-18 are also an angiogenic factors by increasing the expression of vascular endothelial growth factor; IL-1 and IL-18 thus play a role in pannus formation and blood vessel supply. The strongest case for the importance of IL-1 in disease processes come from the administration of the IL-1 receptor antagonist, also a member of the IL-1 family and IL-18 binding protein (IL-18BP), a constitutively expressed and secreted protein that binds and neutralizes IL-18. Data from the human genome project have revealed other members of the IL-1 family. However, these appear to be antagonists rather than agonists. IL-1 also acts as an adjuvant during antibody production and stimulates bone marrow stem cells for differentiation in the myeloid series. IL-1 is distinct from tumor necrosis factor (TNF); IL-1 and TNFalpha share several biological properties but the salient difference is that TNF receptor signaling induces programmed cell death whereas IL-1 receptor signaling does not. In fact, IL-1 is a hematopoietic growth factor and IL-1 was administered to humans to reduce the nadir of white blood cells and platelets in patients during bone-marrow transplantation. This property, of IL-1 is not observed in the responses to TNFalpha. Furthermore, in animal models of destructive rheumatoid arthritis, IL-1 is necessary but TNFalpha is not.
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PMID:The IL-1 family and inflammatory diseases. 1498 23

Recent studies of the pathogenesis of rheumatoid arthritis (RA) have revealed that both synovial fibroblasts and T cells participate in the perpetuation of joint inflammation as dynamic partners in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. In this study, we investigated the role of IL-17, a major Th1 cytokine produced by activated T cells, in the activation of RA synovial fibroblasts. Transcripts of IL-17R (IL-17 receptor) and IL-17RB (IL-17 receptor B) were present in fibroblast-like synoviocytes (FLS) of RA patients. IL-17R responded with increased expression upon in vitro stimulation with IL-17, while the level of IL-17RB did not change. IL-17 enhanced the production of IL-6 and IL-8 in FLS, as previously shown, but did not affect the synthesis of IL-15. IL-17 appears to be a stronger inducer of IL-6 and IL-8 than IL-15, and even exerted activation comparable to that of IL-1beta in RA FLS. IL-17-mediated induction of IL-6 and IL-8 was transduced via activation of phosphatidylinositol 3-kinase/Akt and NF-kappaB, while CD40 ligation and p38 MAPK (mitogen-activated protein kinase) are not likely to partake in the process. Together these results suggest that IL-17 is capable of more than accessory roles in the activation of RA FLS and provide grounds for targeting IL-17-associated pathways in therapeutic modulation of arthritis inflammation.
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PMID:IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. 1505 75

To characterize the molecules responsible for synovial fibroblast-T lymphocyte (TL) cross-talk in rheumatoid arthritis (RA), synovial fibroblasts from patients with established RA (RASFibs) were cocultured with TLs from peripheral blood of early RA patients (RAPBTL). TLs from peripheral blood of healthy controls and from synovial fluid of RA served as controls. Adhesion molecules and cytokines were determined by flow cytometry, ELISA, and real-time PCR. RAPBTL (n = 20) induced an up-regulation of ICAM-1, intracellular IL-8, IL-6, IL-15, and surface IL-15 in cocultured RASFibs. In turn, RAPBTL showed an up-regulation of TNF-alpha, IFN-gamma, IL-17, CD25, and CD69 expression. Responses seen with TLs from peripheral blood of healthy controls (n = 20) were significantly lower, whereas responses with TLs from synovial fluid of RA (n = 20) were maximal. Blocking Abs to IL-15 and CD54, but not an isotype-control Ab, down-regulated the increased TL cytokine and activation marker expression. Abs to CD69, CD11a, IL-17, TNF-alpha, and IFN-gamma significantly decreased the up-regulation of RASFib cytokine and CD54 expression. Cocultures using 0.4- micro m inserts did not result in up-regulation of surface molecules or cytokines. Methotrexate significantly inhibited RASFib/TL cross-talk signals and decreased adhesion of TL to RASFibs. In summary, RASFib production of IL-15 induces the proinflammatory cytokines TNF-alpha, IFN-gamma, and IL-17 in cocultured TLs through a cell contact-dependent mechanism. In turn, these cytokines stimulate the expression of IL-15, IL-8, and IL-6 in RASFibs, thereby creating a feedback loop that favors persistent synovial inflammation. Methotrexate seems to disrupt this loop by decreasing cell adhesion.
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PMID:IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. 1524 Jul 43

Interleukin (IL)-15 is a pleiotropic pro-inflammatory cytokine that is expressed in several inflammatory disorders, including rheumatoid arthritis, psoriasis and pulmonary inflammatory diseases. IL-15 promotes activation of T cells, neutrophils and macrophages, and is critical to dendritic cell function in several model systems. Recent emerging data suggest that IL-15 may serve as a useful therapeutic target across a range of disease states. Advances in the past year highlight the beneficial effect of IL-15 neutralisation in models of psoriasis and diabetes. Further evidence for IL-15 expression and effector function has emerged across a range of rheumatic disorders, including juvenile inflammatory arthritis, rheumatoid arthritis and Kawasaki disease. These data hold promise for therapeutic targeting in ongoing human studies and those in the near future.
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PMID:Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. 1525 Nov 34

Targeting tumor necrosis factor-a has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL) -6, IL-12, IL-15, and IL-18. We review recent data that support the notion that some or all of these moieties offer therapeutic potential. The possibility that some may be useful in partial responders to tumor necrosis factor blocking agents or in synergy with the latter is discussed.
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PMID:Targeting cytokines beyond tumor necrosis factor-alpha and interleukin-1 in rheumatoid arthritis. 1535 45


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