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

Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.
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PMID:Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease. 759 Aug 14

We have proposed the hypothesis that tumour necrosis factor alpha (TNF-alpha) has a pivotal role in the pathogenesis of rheumatoid arthritis, based on in vitro observations that in RA synovial joint cell cultures removal of TNF-alpha, inhibited other potentially pathogenic cytokines such as the equally proinflammatory cytokine interleukin 1 (IL-1) and the macrophage activating factor, GM-CSF. Here we describe that in both rheumatoid (RA) and osteoarthritic (OA) synovial cultures there is a homeostatic mechanism to regulate the activities of TNF-alpha. This concept is based on several observations. First in these synovial joint cell cultures the substantial discrepancy between the levels of bioactive and immunoreactive TNF-alpha indicates the presence of an inhibitor. Second, TNF binding proteins are produced spontaneously, which are the soluble variants of surface p75 and p55 TNF receptor. The amount of soluble TNF receptors (sTNF-R) produced varied between cultures; p75 sTNF-R was more abundant than p55 sTNF-R (as detected by ELISA), and both were produced at higher levels by RA synovial joint cells in culture, compared to OA cultures. These TNF binding proteins act as endogenous inhibitors of TNF-alpha, since blocking their activity in synovial joint cell culture supernatants with MoAb to p55 and p75 sTNF-R enhanced their cytotoxic activity in the TNF bioassay. The regulation of production of these sTNF-R in synovial joint cell cultures is important as the balance between TNF-alpha and sTNF-R production may determine the outcome of the inflammatory process.
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PMID:TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. 763 Nov 38

We characterized the immunophenotype as well as functional properties--phagocytosis, the uptake of acetylated LDL, and the expression of HLA class II antigens, adhesion molecules, and cytokine mRNA--of fibroblast-like synoviocytes from rheumatoid arthritis synovium. Skin fibroblasts (FB) and umbilical vein endothelial cells (HUVEC) were studied in parallel. Cytofluorometric immunophenotyping by use of 84 mAb and 2 lectins and immunofluorescence microscopy indicated a high degree of homology between the three cell types. Only staining with mAb to von Willebrand factor (vWF) and CD31 and the lectin UEA-I appeared specific to HUVEC, whereas the mAb 5B5 to prolyl 4-hydroxylase that has been reported to be specific to FB stained HUVEC as well as synoviocytes and FB. All of the cells phagocytosed fluorescent latex beads of 1.7 and 2.6 microns in size. The uptake of acetylated LDL could be shown by HUVEC and, surprisingly, by synoviocytes, but not by FB. The induction of HLA-DR, -DP, and -DQ by IFN-gamma on the three cell types showed a similar dose-dependence. The upregulation of ICAM-1 by IL-1 alpha, TNF-alpha, and IFN-gamma appeared similar, whereas the induction of VCAM-1 by IL-1 alpha, IL-4, TNF-alpha, and IFN-gamma showed differences between the three cell types. ELAM-1 was expressed only on HUVEC after treatment with IL-1 alpha and TNF-alpha. The capacity of the cells to produce cytokines was studied at the level of mRNA by reverse transcription and PCR. All three cell types expressed the mRNA of IL-1 alpha, IL-6, IL-8, GM-CSF, and TGF-beta 1 spontaneously or after LPS stimulation, but never TNF-alpha mRNA. Our results indicate a high degree of relationship between the three cell types. In contrast to HUVEC, none of the markers and functional properties investigated appear specific to FB. Therefore, the issue of the origin of fibroblast-like synoviocytes and the role of vascular endothelial cells in the inflamed synovium is discussed.
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PMID:Characterization of the immunophenotype and functional properties of fibroblast-like synoviocytes in comparison to skin fibroblasts and umbilical vein endothelial cells. 808 88

Cytokines are decisive for the regulation of the immune system as well as the renewal and maturation of the haematopoietic cells. The most important groups of substances, several of which are already produced by gentechnology, are the interferons, the interleukins and the haematopoietic growth factors. The main indications for the application of alpha-(less often beta-)Interferon in children are the juvenile larynx papillomatosis, chronic hepatitis B, viral encephalitis, and also chronic myeloic leukemia, extended haemangiomas, recurrent Langerhans cell histiocytosis and nasopharynx carcinomas. gamma-Interferon is administered successfully for chronic granulomatous disease and has recorded positive effects in therapy resistant rheumatoid arthritis, in kidney cell carcinoma and in osteopetrosis. G-CSF, GM-CSF and Interleukin 3 are the most effective haematopoietic growth factors currently in use. Through G-CSF congenital agranulocytosis (Kostmann syndrome) has become a treatable disease. Other proven applications are in the reduction of aplastic phases after chemotherapy and in critical situations of primary bone marrow failure as well as myelodysplastic syndromes, for prevention of transplant rejections after bone marrow transplantation and for mobilisation of stem cells into peripheral blood before apheresis. Erythropoietin is established in the treatment of chronic renal anaemia and is currently used in the treatment of anaemia in preterm infants. Finally, Interleukin 2 is also used for adoptive immunotherapy in children with minimal residual tumors. The future will show us, whether the spectrum of indications will expand and whether a definite benefit for sick children will result from a wider application of these substances. As long as the cost/benefit ratio for certain indications is not clear, the use of these drugs should be tested in prospective studies.
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PMID:[Clinical applications of cytokines in pediatrics]. 815 1

We have compared superoxide (O2-) production from cytokine-treated rheumatoid arthritis (RA) vs. control neutrophils (PMN). Exposure of adherent peripheral blood PMN to cytokines known to be present in RA joints (IL-1 beta, TNF-alpha, GM-CSF) resulted in enhanced O2- production from both RA and controls. With few exceptions, we did not find significant differences in enhanced O2- production, between RA and controls. By enhancing O2- production from PMN adherent to articular cartilage, cytokines may influence the potential for joint damage in RA.
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PMID:Superoxide production from cytokine-treated adherent rheumatoid neutrophils. 817 15

To investigate the mechanism of eosinophilia in patients with eosinophilic pleural effusions, we measured the activities of eosinophil colony-stimulating factor (Eo-CSF) and stimulating factor for eosinophil survival in the eosinophilic pleural fluids of six patients (two with tuberculous pleuritis, two with drug allergy, and one each with chronic eosinophilic pneumonia and pleuritis associated with rheumatoid arthritis). The number of eosinophil colonies formed by the pleural fluid of patients with eosinophilic pleural effusions significantly exceeded that of control patients with noneosinophilic pleural effusions (7.5 +/- 1.9 colonies/10(5) bone marrow cells, n = 6, versus 0.3 +/- 0.1 colonies/10(5) bone marrow cells, n = 6, P < 0.01). Similarly, eosinophil survival evaluated on day 4 of culture with pleural fluid of patients with eosinophilic pleural effusions significantly exceeded that of patients with noneosinophilic pleural effusions (83.9 +/- 9.8% versus 46.1 +/- 11.2%, P < 0.001). Both activities were inhibited mainly by anti-IL-5 antibody and partially by anti-GM-CSF antibody and anti-IL-3 antibody. Mononuclear cells obtained from eosinophilic pleural fluid released the activities of Eo-CSF and stimulating factor for eosinophil survival in vitro. These findings suggest that GM-CSF, IL-5, and IL-3 are important to eosinophil accumulation in pleural cavity as stimulators of proliferation and survival of eosinophils.
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PMID:Factors that stimulate the proliferation and survival of eosinophils in eosinophilic pleural effusion: relationship to granulocyte/macrophage colony-stimulating factor, interleukin-5, and interleukin-3. 832 45

Indometacin farnesil (Indo-F) is a prodrug of indomethacin designed to reduce the occurrence of side-effects by esterification of the carboxyl group on indomethacin with farnesol. We have examined the pharmacological kinetics and action of Indo-F in peripheral blood mononuclear cells (PBMNC) and polymorphonuclear leukocytes (PBPNL) from patients with rheumatoid arthritis (RA). PBMNC and PBPNL were obtained from 31 RA patients. Indo-F was incubated with PBMNC or PBPNL in the presence or absence of granulocyte-macrophage colony stimulating factor (GM-CSF) (100 pg/ml) for 3 approximately 7 days, after which the concentrations of Indo-F and indomethacin in the culture supernatants or in the cytoplasm extracts were measured with HPLC. The levels of Indo-F in the culture supernatants were significantly decreased in the presence of PBMNC or PBPNL from either normal individuals or RA patients. Indo-F was found to be taken up by PBMNC as well as by PBPNL from RA patients. Conversion of Indo-F into indomethacin was significantly enhanced by GMCSF in the presence of PBMNC, but not PBPNL. The results indicate that Indo-F is taken up by peripheral blood leukocytes from RA patients. Moreover, the data suggest that monocyte-lineage cells might play an important role in the conversion of Indo-F into indomethacin since GM-CSF markedly facilitated the conversion in the presence of PBMNC, but not PBPNL.
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PMID:Interaction of indometacin farnesil, a new nonsteroidal antiinflammatory drug with peripheral blood mononuclear cells from patients with rheumatoid arthritis. 870 90

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
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PMID:Role of cytokines in rheumatoid arthritis. 871 20

We examined the mRNA levels for various cytokines, including IL-1 alpha, IL-1 beta, TNF alpha, TGF-beta 1, GM-CSF, IL-6, IL-8, bFGF, PDGF-A, PDGF-B and IL-1ra, and IL-1 beta converting enzyme, and the protein levels of some of these cytokines in 19 SV40-transformed synovial cell clones. Among those tested, the mRNA levels for IL-6, bFGF and PDGF-A in rheumatoid arthritis (RA) cell clones were greater than those in non-RA cell clones. Moreover, except for one osteoarthritis (OA) cell clone, the mRNA levels for IL-8 in RA cell clones were also greater than those in non-RA cell clones. Although the protein levels were not always correlated with the mRNA levels, the exception being the same OA cell clone, the protein levels of cytokines, such as IL-1 alpha, IL-1 beta, IL-6 and IL-8, in RA cell clones were greater than those in non-RA cell clones. TNF-a was not detected in any cells tested at either the mRNA or the protein level. TNF-alpha upregulated the expression of GM-CSF mRNA in both RA cell clones and one OA cell clone, but not in the other OA cell clone or the normal cell clone. Taken together, these SV-40 transformed synovial cell clones retained many of the original characteristics in terms of cytokine production.
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PMID:Cytokine production by SV40-transformed adherent synovial cells from rheumatoid arthritis patients. 874 72

While there is an extensive literature on cytokine regulation in vivo using human cell lines or peripheral blood monocytes, very little is known about cytokine regulation within the multicellular environment of inflammatory sites in vivo. We have previously shown that in rheumatoid synovial membrane cultures, a complex, but pathophysiologically relevant mixture of cells, the addition of a neutralizing anti TNF-alpha antibody inhibits the production of IL-1 and GM-CSF, indicating the presence of a cytokine 'cascade' in this inflammatory tissue. In this paper we demonstrate that the interactivities between cytokines in rheumatoid arthritis also extends to other cytokines, such as IL-6 and IL-8, and that within the IL-1 family it is IL-1 beta in particular which is downregulated by neutralizing TNF-alpha activity. The cytokine interactions are unidirectional, in that neutralization of TNF-alpha reduced IL-1 beta, IL-6 and IL-8 production, whereas treatment of the rheumatoid synovial membrane cells with a neutralizing concentration of the IL-1 receptor antagonist (IL-1ra) reduced IL-6 and IL-8 production but not TNF-alpha production. These results suggest a rationale for the profound anti-inflammatory effects and consequent clinical benefit noted in RA patients treated recently in clinical trials with a chimeric anti-TNF-alpha antibody in vivo.
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PMID:Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. 878 87


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