Type II collagen-induced arthritis in rats.
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Animals↗
Biomedical subjects
A L Oronsky
Publications and source records attributed to A L Oronsky.
Streptococcal cell wall-induced arthritis in rats.
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Animals↗
Synthesis of interleukin-1-like activity by normal rat chondrocytes in culture.
Chondrocytes prepared from the articular cartilage of young rats synthesize and secrete an interleukin-1-like activity into the medium. The physical and biochemical properties of this IL-1-like activity are similar to macrophage-derived IL-1. Immunological studies suggest that this activity is related to IL-1 alpha. Isolated chondrocytes and those grown in culture can express Ia.
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Administration of an aldose reductase inhibitor induces a decrease of collagen fluorescence in diabetic rats.
As a consequence of an increased flux through the sorbitol pathway fructose levels rise in various tissues in diabetes. Also, in vitro nonenzymatic fructosylation of protein induces the generation of fluorescence at a rate 10 times greater than glucosylation. The administration of sorbinil, an aldose reductase inhibitor known to lower tissue fructose concentration, to experimental diabetic rats led to a decrease in the fluorescence related to advanced Maillard products in their skin collagen. This effect is consistent with the in vivo occurrence of nonenzymatic fructosylation of collagen. A potential pathogenetic role for this posttranslational modification in diabetic complications should be considered.
Aldehyde Reductase↗
Passive collagen arthritis induced by anticollagen IgG.
Studies conducted in rats and mice indicate that passive arthritis can be transferred to naive recipients with anticollagen IgG. The passively transferred disease is less severe and is transient. Rats that recover from passive arthritis are resistant to a second phase of clinical disease when administered either anticollagen IgG or type II collagen. Suppressor T cells appear to be responsible for this resistance. Passive arthritis induced by anticollagen IgG is a complement dependent lesion. Deposition of IgG on the cartilage and host complement C3 and C5 activation are essential for the induction of passive disease. Inflammatory cells are necessary for the demonstration of passive arthritis; mice deficient in inflammatory cells or defective in this cell population are resistant to passive arthritis. Monoclonal antibodies reactive to type II collagen or to a renatured TCA fragment can also induce passive arthritis. The disease is subclinical and can be detected only after histological analysis of the joints.
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Methotrexate suppresses passive adjuvant arthritis: studies on the metabolism of methotrexate in mononuclear cells derived from normal and adjuvant arthritic rats.
Passive transfer of adjuvant arthritis by spleen cells is suppressed by methotrexate. Mononuclear cells derived from spleens of normal and adjuvant arthritic Lewis rats were incubated with [3H]-methotrexate and harvested at various periods of time. The amount of methotrexate and its various polyglutamates were quantitated. The results of these studies indicate that the kinetics of uptake of methotrexate by mononuclear cells from normal and adjuvant arthritic rats are similar. However, the amount of methotrexate polyglutamates accumulating in the mononuclear cells of adjuvant arthritic rats was significantly lower than that observed in mononuclear cells derived from normal rats.
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Studies on the effect of methotrexate on macrophage function.
Time course studies in rat adjuvant arthritis have shown that resident peritoneal macrophages synthesize large amounts of interleukin-1 (IL-1) on Day 10-11 postadjuvant immunization. Expression of Ia antigen on these macrophages increased rapidly between Day 15 to Day 20 postadjuvant treatment and remained at these high levels on Day 25. If these adjuvant immunized rats were treated with low doses of methotrexate, resident peritoneal macrophages appeared to synthesize lower amounts of IL-1 and their Ia expression was decreased. Methotrexate, in vitro, has no effect on lipopolysaccharide induced IL-1 synthesis by resident peritoneal macrophages.
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Type II collagen arthritis: identification of arthritogenic epitopes using fractionated anticollagen IgG.
Affinity-purified anticollagen IgG was fractionated on purified cyanogen bromide-derived collagen peptide Sepharose. The antibody fraction bound to the peptides was eluted and tested for its ability to induce passive arthritis in recipients. Anticollagen IgG bound to peptide 5 (alpha 1(II)-CB8-10 and alpha 1(II)CB11-8) and to peptide 6 (alpha 1(II)CB11) were active in inducing passive arthritis. Other peptide bound fractions were inactive. These observations suggest that the arthritogenic domain in Type II collagen is restricted to alpha 1(II)CB11.
Amino Acids↗
Effect of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5a.
When mediators of inflammation such as complement component C5a or leukotriene B4 are introduced into an air pouch created in mice, these mediators induce the migration of neutrophils into the air pouch. Pretreatment of mice with low doses of methotrexate inhibits leukotriene B4 or C5a induced neutrophil migration into the air pouch. Inhibition of neutrophil chemotaxis by methotrexate may, at least in part, account for the rapid onset of antiinflammatory activity that was observed in clinical trials with methotrexate in rheumatoid arthritis.
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Administration of group A streptococcal cell walls to rats induces an interleukin 2 deficiency.
Intraperitoneal administration of group A streptococcal cell walls to Lewis rats induces a chronic arthritis, whereas the Fischer strain is resistant to the development of the lesion. Spleen cells from cell wall-treated rats (Lewis and Fischer) are deficient in the synthesis of IL-2. Using an mAb directed against the rat IL-2-R, the present studies indicate that the expression of IL-2-R on spleens of cell wall-treated rats is normal. However, the addition of exogenous IL-2 to spleen cells cultured with Con A does not stimulate the mitogenic response.
Animals↗
Passive transfer of collagen arthritis: heterogeneity of anti-collagen IgG.
Using a combination of affinity chromatography procedures, anticollagen IgG was fractionated into three distinct populations. One population reacted only to conformational determinants, another population reacted only to structural determinants, and the third population reacted to both conformation and structural determinants. When these populations were tested for their arthritogenicity, only those fractions that reacted to conformational and to conformational and structural determinants were active in inducing clinical arthritis. Immunofluorescence analysis of the hind paw of recipient rats indicated that antibodies directed only to conformational and to both conformational and structural determinants bound to articular cartilage and activated the complement system. Antibodies directed strictly to structural determinants did not bind to articular cartilage and were nonarthritogenic.
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Studies of the effect of mitoxantrone on adjuvant induced arthritis in rats.
When rats with developing or established adjuvant arthritis are treated with mitoxantrone, the hind paw inflammation associated with the disease is inhibited. Radiographic analysis of the hind paws indicates that the agent suppresses joint destruction associated with the lesion. Comparative studies with cyclophosphamide indicate that mitoxantrone is more efficacious and at least 20 times more potent than cyclophosphamide. Mitoxantrone also appeared more effective when given by the subcutaneous route than the peritoneal route of administration.
Animals↗
Studies on type II collagen induced arthritis.
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Animals↗
Studies on the effect of D-penicillamine, gold thioglucose and methotrexate on streptococcal cell wall arthritis.
Intraperitoneal administration of group A streptococcal cell walls to rats induces an acute arthritis that resolves and is followed by a chronic lesion. The effect of low dose methotrexate, D-penicillamine and gold thioglucose has been investigated in this model. Whereas D-penicillamine and gold thioglucose had no effect on the hind paw inflammation and joint destruction (radiological assessment) associated with the lesion, methotrexate treatment suppressed both of these variables. Spleen cells derived from cell wall treated arthritic rats were hyporesponsive to concanavalin A (Con-A) and were deficient in the synthesis of interleukin 2 (IL-2). Spleen cells derived from methotrexate treated rats exhibited an improved response to Con-A and their ability to synthesize IL-2 was significantly enhanced.
Animals↗
Pretreatment of rats with anticollagen IgG renders them resistant to active type II collagen arthritis.
Intravenous administration of 24 mg of affinity-purified rat anticollagen IgG induced a polyarthritis in recipient rats within 48 hr. This polyarthritis was transient and hind paw diameters returned to normal values within 12 days. IgG and C3 could be detected on the articular cartilage by immunofluorescence up to 16 days after antibody administration. Administration of 24 mg of rat anticollagen IgG to these antibody-treated rats did not induce a second phase of polyarthritis. In addition, recovered rats that had been pretreated with antibody were resistant to arthritis when Type II collagen was administered intradermally. In these rats, serum anticollagen IgG levels were significantly lower than in control rats which were not treated with antibody. Pretreatment of rats with anticollagen IgG did not have an effect on the severity or the incidence of adjuvant-induced arthritis. In addition, pretreatment of rats with anticollagen IgG did not have an effect on the development of a humoral response to ovalbumin.
Animals↗
Streptococcal cell wall arthritis: studies with nude (athymic) inbred Lewis rats.
Group A streptococcal cell walls, upon intraperitoneal administration, fail to induce a chronic arthritis in athymic inbred Lewis rats (mu/mu). In contrast, heterozygous euthymic littermates (+/mu) develop a chronic arthritis upon administration of the cell wall material. Chronic arthritis can be readily induced in athymic rats if they are reconstituted intravenously with spleen cells derived from normal heterozygous euthymic littermates. Both athymic and euthymic rats develop the acute arthritis elicited by cell walls. These studies indicate that the requirements in the host for the induction of acute and chronic arthritis are different. Induction of acute arthritis is not dependent on functional T lymphocytes whereas the induction of chronic arthritis is dependent on functional T cells.
Acute Disease↗
Suppression of experimental allergic encephalomyelitis by mitoxantrone.
Treatment of rats with a developing or an established lesion of experimental allergic encephalomyelitis (EAE) with mitoxantrone (Novantrone) suppressed the hind limb paralysis associated with the disease. Histopathological examination of the spinal cords of these rats showed that mitoxantrone-treated rats had reduced vascular lesions that are associated with EAE. Spleen cells derived from immunized rats that had been treated in vivo with mitoxantrone did not transfer disease when these cells were administered to naive syngenic recipients. In addition, spleen cells from diseased rats did not transfer EAE lesions when these cells were administered to recipients that had been treated with mitoxantrone. Recipients treated with mitoxantrone were resistant to EAE lesions induced by sensitized cells in a rapid passive transfer system. Finally, when spleen cells from rats with EAE were incubated, in vitro, with mitoxantrone, these cells did not transfer disease to recipients. Thus the present studies indicate that treatment with mitoxantrone can suppress the lesions associated with both the active and passive forms of EAE.
Animals↗
Synchrotron radiation x-ray scattering in the early stages of in vitro collagen fibril formation.
The time course of in vitro collagen fibril formation was monitored by synchrotron radiation x-ray scattering. Collagen polymerization was induced by a temperature jump from 4 degrees C to 32 degrees C and the solution scattering pattern was recorded continuously with a time resolution of a few seconds. The scattered intensity increased as soon as the final temperature was attained, without discernible lag phase, when the collagen concentration was about 0.56 mg/ml, whereas turbidimetric measurements revealed a lag phase of ca. 2.5 min at 1.05 mg/ml. A direct correlation was found between the temperature and both the rate of formation and the total amount of early aggregates. The formation of these aggregates was only partially reversed by lowering the temperature, except when the collagen had been prevented from forming Schiff base-mediated intermolecular crosslinks by sodium borohydride reduction. In this case, formation of aggregates was completely reversible. We conclude that the aggregates that appear to correspond to the subfibrils proposed on the basis of independent methods are formed and simultaneously crosslinked in the early phases of in vitro collagen self-assembly.
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