Pharmacological studies of antigen-induced arthritis in BALB/c mice. I. Characterization of the arthritis and the effects of steroidal and non-steroidal anti-inflammatory agents.
TL;DR: The optimum conditions for induction of chronic persistent arthritis and the histological characteristics of the arthritic lesion are described and the suppressive effect of the corticosteroids was not due to either suppression of antibody synthesis or alteration of the number of leukocytes in the peripheral circulation.
Abstract: Chronic monoarticular allergic arthritis was induced in BALB/c mice using methylated BSA as antigen and Freund's complete adjuvant, together with Bordetella pertussis as a secondary adjuvant. The optimum conditions for induction of chronic persistent arthritis and the histological characteristics of the arthritic lesion are described. Both the synovitis and erosive progression of the arthritis could be suppressed by daily treatment with prednisolone (1–10 mg/kg) or dexamethasone (0.5–2.5 mg/kg) for 4 weeks commencing 2 weeks after the induction of arthritis. In contrast, daily treatment with the non-steroidal anti-inflammatory agents ibuprofen (50–100 mg/kg), flurbiprofen (1–9 mg/kg) or indomethacin (0.1–3 mg/kg) had no significant effect on either the synovitis or erosions as judged histologically. Synovial fluid differential leukocyte counts were altered by treatment with ibuprofen and indomethacin but not by flurbiprofen or the corticosteroids. The suppressive effect of the corticosteroids was not due to either suppression of antibody synthesis or alteration of the number of leukocytes in the peripheral circulation.
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TL;DR: Data, conduct and features of the various models of these commonly utilized models of RA as well as some transgenic mouse models and less commonly utilized rodent models will be discussed with emphasis on their similarities to human disease.
Abstract: Animal models of arthritis are used to study pathogenesis of disease and to evaluate potential anti-arthritic drugs for clinical use. Therefore morphological similarities to human disease and capacity of the model to predict efficacy in humans are important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability for efficacy in humans include: rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include: corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged dosing periods would preclude dosing in humans at levels that might provide disease modifying effects. Data, conduct and features of the various models of these commonly utilized models of RA as well as some transgenic mouse models and less commonly utilized rodent models will be discussed with emphasis on their similarities to human disease.
343 citations
TL;DR: Animal models of arthritis are used to evaluate potential antiarthritis drugs for clinical use and capacity of the model to predict efficacy in human disease is one of the most important criteria in model selection.
Abstract: Animal models of arthritis are used to evaluate potential antiarthritis drugs for clinical use. Therefore capacity of the model to predict efficacy in human disease is one of the most important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability include rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis, and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged periods would preclude dosing in humans at levels that might provide disease-modifying effects. Animal models of osteoarthritis (OA) include mouse and guinea pig spontaneous OA, meniscectomy and ligament transection in guinea pigs, meniscectomy in rabbits, and meniscectomy and cruciate transection in dogs. None of these models have a proven track record of predictability in human disease because there are no agents that have been proven to provide anything other than symptomatic relief in human OA. Efficacy data and features of the various models of RA and OA are discussed with emphasis on their proven relevance to human disease.
331 citations
TL;DR: It is suggested that interleukin-1 may play a prominent role in the development of some, but not all, forms of arthritis.
Abstract: Objective. To investigate the anti-arthritic effect of recombinant human interleukin-1 receptor antagonist protein (IRAP) in two experimental models of arthritis.
Methods. Recombinant IRAP was administered daily to mice with type II collagen–induced arthritis (CIA) or with antigen-induced arthritis (AIA) provoked by methylated bovine serum albumin (mBSA). Disease incidence and severity were assessed by a clinical index and histologic features. Serum antibody to type II collagen, spleen cell proliferation to mBSA, and anti-IRAP antibodies were measured as indices of immune function.
Results. IRAP reduced the incidence and delayed the onset of CIA and suppressed the antibody response to type II collagen. In contrast, IRAP did not affect the pathogenesis of AIA and had no effect on either humoral or cellular immune responses to mBSA in arthritic mice.
Conclusion. These observations suggest that interleukin-1 may play a prominent role in the development of some, but not all, forms of arthritis.
223 citations
TL;DR: Observations suggest that the SBT leaf extract has a significant anti-inflammatory activity and has the potential for the treatment of arthritis.
147 citations
TL;DR: It was concluded the inner ear mineralocorticoid receptor is a significant target of glucOCorticoids and a factor that should be considered in therapeutic treatments for steroid-responsive hearing loss.
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TL;DR: Antigen-induced arthritis was established in the mouse by immunization with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant with B pertussis vaccine.
Abstract: Antigen-induced arthritis was established in the mouse by immunization with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant with B pertussis vaccine. The knee joint was injected after 21 days with mBSA in saline. The arthritis was chronic, antigen-specific, and T-cell dependent in hypothymic nu/nu mice. C57BL and BALB/c mice were susceptible, whereas CBA mice were relatively resistant. Susceptibility was dominant; one gene was loosely linked to the “b” allele of the H-2 complex of C57BL mice.
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TL;DR: Endogenous factors of this kind take second place as causes of chronicity to those numerous micro-organisms which, by virtue of their structure or their function, or both, are able to establish a sort of symbiotic balance with their host tissues.
Abstract: If inflammation is recognized by its classical cardinal signs, then few would deny that the rheumatoid joint is inflamed. Whether chronicity is assessed by duration in weeks, months, or years, there is equally no denying that rheumatoid arthritis is an example of chronic inflammation. To the student of chronic inflammation the problem of outstanding interest in any particular example is not necessarily what initiated the inflammatory response but the factors responsible for its maintenance. Clues to the conditions responsible for chronicity can to some extent be discovered by a study of the factors interfering with the resolution and healing of what are usually regarded as acute, self-limiting reactions. Thus inadequate drainage of inflammatory exudates, interference with local circulatory dynamics, and the presence of necrotic tissue have long been recognized as major endogenous factors favouring chronicity. Since the joint is a closed space with limited drainage facilities, the ietention of inflammatory products may therefore be an important factor in the maintenance ofinflammation. The success of early synovectomy may well depend upon the removal of such products. Excessive use of an inflamed organ can also seriously impair its powers of recovery. Endogenous factors of this kind, however, take second place as causes of chronicity to those numerous micro-organisms which, by virtue of their structure or their function, or both, are able to establish a sort of symbiotic balance with their host tissues. Examples can be drawn from almost every subgroup of the microbiological world, from viruses to protozoa. Another and distinct group of chronic inflammations is exemplified by gout with its aetiological relationship to a disturbance of uric acid metabolism.
120 citations
"Pharmacological studies of antigen-..." refers background in this paper
...The antigen-induced monoarticular model of arthritis in rabbits described by Dumonde and Glynn [1] bears strong resemblance to rheumatoid arthritis with regard to the pathological changes occurring in both the synovium and cartilage [ 2 ]....
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TL;DR: It is reported here further work, that with ovalbumin or bovine gamma-glotulin as the antigen the authors can produce an arthritis which may still be active for 15 months, after a single intra-articular injection.
Abstract: Dumonde and Glynn (1962) reported the production of a chronic arthritis in rabtits by the intra-articular injection of fibrin in animals previously immunized with this antigen in Freund's complete adjuvant. They commented particularly upon the persistence of the arthritis which was still active after 16 weeks. We report here further work, that with ovalbumin or bovine gamma-glotulin as the antigen we can produce an arthritis which may still be active for 15 months, after a single intra-articular injection. Mr. B. Davis of Glaxo Laboratories Ltd. informs us that, in animals similarly treated, the arthritis has remained active for over 2 years. The mechanism underlying this persistence of the inflammatory process is obviously of great interest for the light it may shed on other chronic arthritides. It is, therefore, essential before invoking such debatable possibilities as auto-immunization, to determine both the amount of the initiating antigen remaining in the joint and the smallest amount of such antigen capable of exciting an inflammatory response. It was our purpose to obtain the necessary data to answer the question whether the persistence of antigen in the joint can alone account for the chronicity of the experimental arthritis.
107 citations
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TL;DR: It would appear that, in addition to enzymatic breakdown of cartilage, other phenomena are important in cartilage destruction: inhibition of proteoglycan synthesis and chondrocyte death, apparently unrelated to pannus formation.
Abstract: The influence of joint inflammation on patellar hyaline articular cartilage was studied in mice Antigen-induced and zymosan-induced arthritis were used as models for immunologically and non-immunologically induced joint inflammation The contribution of newly formed proteoglycan to the cartilage proteoglycan content, as measured by labelling of the cartilage after iv administration of 35S-sulphate, was decreased in parallel with the severity of inflammation during both zymosan-induced and antigen-induced arthritis The decreased 35S content of the cartilage was due to inhibition of synthesis rather than breakdown of newly synthesized proteoglycan, since no accelerated release of 35S from arthritic cartilage could be demonstrated in vitro Antigen-induced arthritis was associated with progressive chondrocyte damage Loss of chondrocytes was consistently found in the central part of the patella, without nearby presence of pannus It would appear that, in addition to enzymatic breakdown of cartilage, other phenomena are important in cartilage destruction: inhibition of proteoglycan synthesis and chondrocyte death, apparently unrelated to pannus formation
82 citations