Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-gamma) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-gamma production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-alpha production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.
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PMID:Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexate-mediated immunosuppression. 993 19

Collagen type II (CII)-induced arthritis (CIA) in mice is a model for rheumatoid arthritis (RA) in which the role of T lymphocytes remains controversial. To clarify this, we have bred a targeted gene deletion of TCR beta or delta loci into two mouse strains susceptible to CIA, the B10.Q and DBA/1 strains. The TCRbeta-/- mice lacked alphabeta T cells, which was compensated by an expansion of B cells, gammadelta T cells and NK cells. The beta-/- mice, but not control beta+/- littermates, were completely resistant to CIA. The production of anti-CII IgG antibodies was also abolished in beta-/- mice, revealing a strict alphabeta T cell dependency. In contrast, beta-/- mice produced reduced, but significant, anti-CII IgM titers after immunization with either CII or ovalbumin, indicating a multispecificity for these alphabeta T cell-independent IgM antibodies. The TCRdelta-/- mice lacked gammadelta T cells but had no other significant changes in lymphocyte or monocyte subsets. The cytokine response (IL-2, IL-4, IL-10 and IFN-gamma) in delta-/- mice, quantified by flow cytometry staining of mitogen-stimulated lymphocytes, was indistinguishable from normal mice. Likewise, no statistically significant differences were observed in CIA between mice lacking gammadelta T cells and control littermates, considering arthritis incidence, day of disease onset, maximum arthritic score, anti-CII IgG titers and disease course. We conclude that alphabeta T cells are necessary for CIA development and for an IgG response towards CII, whereas gammadelta T cells are neither necessary nor sufficient for development of CIA.
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PMID:Collagen-induced arthritis development requires alpha beta T cells but not gamma delta T cells: studies with T cell-deficient (TCR mutant) mice. 1038 39

A strategy of gene therapy using IL-4 or IL-13 xenogeneic transfected cells encapsulated into permeable hollow fibres (HF) was used to treat CIA. Hydrogel-based hollow fibres were obtained from AN-69 copolymer, already known for its biocompatibility and tolerance in rodents. Permeability to IL-4 and lack of cell leakage from the fibres were ascertained in vitro and in vivo. Chinese hamster ovary (CHO) fibroblasts transfected with mouse IL-4 gene were encapsulated in HF (6.25 x 105 cells/HF). IL-4 was detected in vitro in the culture supernatant of filled fibres for at least 19 days. IL-4 or IL-13 transfected CHO cells encapsulated in HF were implanted in the peritoneum of mice on days 11-13 after immunization with type II collagen. Control mice were treated with fibre containing CHO cells transfected with beta-galactosidase (betagal) gene; a positive control group consisted of mice treated by subcutaneous injection of 106 cells on days 10 and 25. Mice were monitored for signs of arthritis by observers unaware of the status of animals. Results of these experiments indicate that severity of the articular disease was significantly reduced in the groups of mice treated with CHO/IL-4 or CHO/IL-13 cells encapsulated in HF, compared with control groups receiving CHO/betagal cells encapsulated in HF. Histological analysis confirmed these data and extended them to a better inhibitory effect of encapsulated cells compared with free cells on inflammatory and destructive joint disease. Moreover, such long-term treatment with HF was well tolerated; macroscopic and histological aspects of peritoneal cavity were moderately inflammatory. Thus, our results may have important implications for clinical use of gene transfected cells as therapeutic agents in the treatment of autoimmune diseases.
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PMID:Encapsulation in hollow fibres of xenogeneic cells engineered to secrete IL-4 or IL-13 ameliorates murine collagen-induced arthritis (CIA). 1044 73

Cromoglicate lisetil (CL) is an orally deliverable prodrug of cromoglycic acid, having diethyl promoieties and a lysyl promoiety for its optimum drug-delivery. We examined the effects of CL on bovine type II collagen (CII)-induced arthritis (CIA) of male DBA/1J mice, an experimental model for human rheumatoid arthritis, and its action mechanism. CL (100 mg/kg/day) was given by gavage to CII-immunized mice once daily for 6 weeks, starting when arthritic symptoms became evident. Symptomatic scores of arthritis obviously elevated in non-treated CIA mice at week 6.5 after initial immunization and continued elevated thereafter throughout the experiment, the elevation which was reduced by CL. CL also improved radiographic score of phalangeal destruction and pathohistological indexes at the end of treatment period. Serum anti-CII antibody titer was increased in non-treated CIA mice and the elevation was reduced by CL treatment. Mast cells (MCs) number in arthritic region was increased in non-treated CIA mice but not by CL treatment. In conclusion, oral CL treatment proved beneficial in CIA mice. Observed correlation between the CL effect on CIA and that on MCs number suggests the potential contribution of MCs to accelerate chronic arthritic processes and may further implicate potential action mechanism of CL, which may act by regulating MC functions for chronic inflammation.
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PMID:[Effects of orally available prodrug of cromoglycic acid on collagen-induced arthritis mice]. 1062 73

The effects of chondroitin sulfate-C (CAS 25322-46-7, Chondroitin ZS Tab) on type II collagen (CII)-induced arthritis (CIA) in mice were evaluated. DBA/1J mice were immunized with bovine CII emulsified in Freund's complete adjuvant, followed by a booster injection 21 days later. Chondroitin sulfate-C at doses of 100, 300 and 1000 mg/kg was administered orally once daily beginning 14 days before initial immunization. An arthritis index and hind paw edema were examined from day 0 to day 49, when the mice were killed by ether anesthesia for histopathological examination. The delayed-type hypersensitivity (DTH) reaction, serum anti-CII antibody titer, and histopathologic characteristics of both synovitis and destruction of articular cartilage were analyzed. Both the arthritis index and the serum anti-CII antibody titer were reduced by treatment with chondroitin sulfate-C in a dose-dependent manner. Chondroitin sulfate-C (1000 mg/kg) significantly inhibited hind paw edema, synovitis and destruction of the articular cartilage, but not DTH reaction.
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PMID:Effects of chondroitin sulfate-C on articular cartilage destruction in murine collagen-induced arthritis. 1071 18

We studied the effects of local IL-10 application, introduced by a recombinant human type 5 adenovirus vector, in the mouse knee joint during the early phase of CIA. One intra-articular injection with the IL-10-expressing virus (Ad5E1mIL-10) caused substantial over-expression of IL-10 in the mouse knee joint, using virus dosages which did not induce distracting inflammation. High expression of IL-10 was noted for a few days, being maximal at day 1. One intra-articular injection of Ad5E1mIL-10 in the knee joints of collagen type II (CII)-immunized mice, before onset of CIA was noted, reduced the incidence of collagen arthritis in that knee. Of high interest, the protective effect of local IL-10 expression by Ad5E1mIL-10 was not restricted to the knee joint alone. The arthritis incidence in the ipsilateral paw was highly suppressed. In contrast, local IL-10 over-expression was not effective when treatment was started after onset of CIA. Further analysis in the acute streptococcal cell wall-induced arthritis model revealed that local IL-10 over-expression markedly suppressed the production of tumour necrosis factor-alpha (TNF-alpha) and IL-1alpha, but had no significant effect on IL-1beta and IL-12 production in the inflamed synovium. These data indicate that local over-expression of IL-10 in the knee joint of mice regulates the expression of collagen arthritis, probably through down-regulation of TNF-alpha.
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PMID:Intra-articular IL-10 gene transfer regulates the expression of collagen-induced arthritis (CIA) in the knee and ipsilateral paw. 1079 91

Bone destruction is the most difficult target in the treatment of rheumatoid arthritis (RA). Here, we report that local overexpression of IL-4, introduced by a recombinant human type 5 adenovirus vector (Ad5E1mIL-4) prevents joint damage and bone erosion in the knees of mice with collagen arthritis (CIA). No difference was noted in the course of CIA in the injected knee joints between Ad5E1mIL-4 and the control vector, but radiographic analysis revealed impressive reduction of joint erosion and more compact bone structure in the Ad5E1mIL-4 group. Although severe inflammation persisted in treated mice, Ad5E1mIL-4 prevented bone erosion and diminished tartrate-resistant acid phosphatase (TRAP) activity, indicating that local IL-4 inhibits the formation of osteoclast-like cells. Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production. Osteoprotegerin ligand (OPGL) expression was markedly suppressed by local IL-4, but no loss of OPG expression was noted with Ad5E1mIL-4 treatment. Finally, in in vitro studies, bone samples of patients with arthritis revealed consistent suppression by IL-4 of type I collagen breakdown. IL-4 also enhanced synthesis of type I procollagen, suggesting that it promoted tissue repair. These findings may have significant implications for the prevention of bone erosion in arthritis.
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PMID:IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. 1086 85

When the immune system is stimulated there is a concomitant decrease in drug biotransformation and elimination that may results in unwanted drug response and toxic side effects. We investigated the subacute toxicity of a hydroalcoholic extract of Pterodon pubescens seeds (HEPp) to DBA1/J mice with collagen II-induced arthritis. The oral treatment with HEPp reduced the arthritic index without any concomitant alteration in their hematological examination, histopathological analysis and relative or absolute weight of several organs and in several clinical biochemical parameters when compared with the control group. We concluded that daily administration of anti-arthritic doses of HEPp did not induce any detectable subacute toxic side-effect in mice whose host defense mechanisms is active as we can observe in mice with CIA.
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PMID:Subacute toxicity evaluation of a hydroalcoholic extract of Pterodon pubescens seeds in mice with collagen-induced arthritis. 1153 59

Evidence from animal models convincingly supports the fact that gene therapy can be an advantageous strategy in the treatment of chronic destructive RA. In this article, we review the state of the art in anticytokine gene transfer into the synovial arthritic joint with the emphasis on IL-1Ra, IL-4, and IL-10 effects on CIA in mice. In CIA, only high and continuous release of IL-1Ra protein systemically by mini-osmotic pumps could prevent disease onset and was curative in mice. Local gene transfer seemed to be the obvious way to reach the high local levels that are demanded for protection. It was shown that local IL-1Ra overexpression reduced arthritis incidence and severity as well as tissue destruction. In line with observations about neutralizing antibodies and soluble receptors, gene therapy with TNF soluble receptors provided anti-inflammatory activity in early arthritis but not in advanced arthritis. The limited efficacy at later stages and poor protection against destruction imply that the combination of gene constructs for TNF and IL-1 inhibitors is the obvious direction for future therapy. Apart from targeting of proinflammatory cytokines, adenoviral overexpression of IL-10 and IL-4 may have therapeutic applicability. Local injection of AdIL-10 in the knee joint was effective at the site, but also highly reduced spreading to ipsilateral sites. High local dosages caused suppression in contralateral sites as well. The reports on the anti-inflammatory effect of AdIL-4 are conflicting; however, all present data showed that IL-4 overexpression provides impressive protection against cartilage and bone erosion. Apart from the local effects in the injected joint, it is becoming more and more clear that local treatment also affects arthritis in nearby joints. This is an intriguing general finding, which may enlarge the therapeutic applicability of gene transfer in human arthritis. Proving the feasibility of gene therapy in experimental arthritis, most research efforts are now focused on improving local gene delivery by enhanced viral infection of synovial cells, using RGD-modified adenovirus, or achieving prolonged persistence and regulated expression with AAV. Elegant future alternatives are the application of in vitro engineered T cells as a vehicle capable of specific homing to joint tissues. The feasibility of viral transduction of chondrocytes to obtain a tissue-specific approach to treat articular cartilage damage in arthritis needs further attention.
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PMID:Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators. 1184 Jun 94

An experimental study was performed to investigate the influence of chronic inflammation in peripheral target tissue on recovery of the sciatic nerve after crush injury. Thirty-four male Wistar rats, weighing 300-370 g were used. The sciatic nerve was crushed unilaterally with an aneurysm clip (250 gf; holding force; 5 min). One week before the operation, chronic inflammation, localized in the tibiotarsal joint of one hind limb, was produced by the intraarticular injection of complete Freund's adjuvant. The animals were divided into five groups, as follows: CIA (crush injury with ipsilateral arthritis), CCA (crush injury with contralateral arthritis), C (crush injury without arthritis), A (sham operation and ipsilateral arthritis), and S (sham operation without arthritis). Specimens for histological examination were taken from the nerve at a site 5 mm distal to the crush injury 4 weeks postoperatively. Histological study showed that the diameters of the axons in group CIA were significantly smaller than those in group CCA and those in group C. No significant differences were observed between group CCA and group C. In conclusion, peripheral nerve recovery after crush injury was suppressed by chronic inflammation in peripheral target tissue.
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PMID:Influence of chronic inflammation in peripheral target tissue on recovery of crushed nerve injury. 1184 51


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