Activation of T cells recognizing an epitope of heat-shock protein 70 can protect against rat adjuvant arthritis.
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We have previously reported that CD4+ T cells recognizing a peptide comprising residues 234-252 of the heat shock protein (HSP)70 of Mycobacterium tuberculosis (M.tb) in the context of RT1.B MHC class II molecule emerged in the peritoneal cavity during the course of Listeria monocytogenes infection in rats and suppressed the inflammatory responses against listerial infection via IL-10 production. We report in this work that pretreatment with peptide 234-252 of HSP70 derived from M.tb suppressed the development of adjuvant arthritis (AA) in Lewis rats induced using heat-killed M.tb. T cells from rats pretreated with peptide 234-252 produced a significant amount of IL-10 in response to the epitope. T cells from rats pretreated with the peptide and immunized with M.tb produced the larger amount of IL-10 in response to the peptide, but only a marginal level of IFN-gamma in response to purified protein derivative of M.tb. Administration of anti-IL-10 Ab partly inhibited the suppressive effect of pretreatment with peptide 234-252 on the development of AA. Furthermore, transfer of a T cell line specific for the epitope at the time of AA induction markedly suppressed AA. These findings suggested that T cells recognizing peptide 234-252 may play a regulatory role in inflammation during AA via the production of suppressive cytokines including IL-10. (+info)
A proinflammatory role for IL-18 in rheumatoid arthritis.
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IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA. (+info)
Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis.
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Idoxifene, a selective estrogen receptor modulator, was evaluated in male and female rats with adjuvant-induced arthritis (AA). AA was induced in Lewis rats with Mycobacterium butyricum in paraffin oil injected into the base of the tail, and the animals were treated with idoxifene prophylactically (days 0-21) or therapeutically (days 10-21). Efficacy was determined by measurements of paw inflammation, bone mineral content, and bone mineral density (BMD) with dual X-ray absorptiometry and by histological evaluation. Serum interleukin-6 levels were measured as a marker of the anti-inflammatory effects of the compound. Estrogen was included for comparison and was administered at 5 mg/kg, three times a week s.c. Prophylactic treatment of male AA rats with idoxifene at 10, 3, and 1 mg/kg and estrogen at 5 mg/kg significantly inhibited paw inflammation. There was improved joint integrity measured by BMD and reduced serum interleukin-6 levels in animals treated with 10 mg/kg/day idoxifene. Idoxifene and estrogen were as effective for AA in female Lewis rats as in male rats, significantly inhibiting paw inflammation and improving BMD. Histological evaluation of the tibiotarsal joints of female rats treated with 10 mg/kg showed protection of bone, cartilage, and soft tissue. Therapeutic treatment with either idoxifene or estrogen (starting on day 10 of disease) of male and female Lewis rats also was effective in reducing paw inflammation in these animals, although the effect was much less than that observed with the prophylactic dosing protocol. (+info)
Effect of gender on anti-inflammatory and analgesic actions of two kappa-opioids.
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The higher incidence of inflammatory and painful disorders in women and recent reports that have emphasized the importance of gender in nociceptive sensitivity and responsiveness to analgesics prompted us to investigate gender as a factor in the variability in response to opioids. We studied the anti-inflammatory and antinociceptive effects of two kappa-opioid agonists in adjuvant-induced arthritis, one that acts both peripherally and centrally (PNU50488H; 20 mg/kg/day), the other which is peripherally selective (asimadoline; 5 mg/kg/day). Both drugs had equally powerful anti-inflammatory effects in both male and female rats (reducing measures by 60-80%). In contrast, there were gender-based heterogeneities in their analgesic actions, contingent on the method of stimulation (mechanical or thermal); males were insensitive to the analgesic effects of asimadoline with thermal but not mechanical nociceptive stimuli. We also sought evidence for gender influences on the joint content of Substance P (SP), a peptide suggested to have a role in producing inflammation and found that levels were higher in the untreated arthritic females, although there were no gender differences in disease sensitivity or nociception in arthritic animals receiving no drugs. Paradoxically, both drugs elevated SP concentrations in the joints, perhaps as a consequence of an action of kappa-opioids to suppress SP release from peripheral nerves, but the gender differences remained. Further experiments are required to determine exact mechanisms responsible for the gender distinction in analgesic response to kappa-opioids that may involve differential activation of primary afferents. (+info)
Immunogenicity and arthritogenicity of recombinant CB10 in B10.RIII mice.
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Two major T cell determinants are recognized by I-Ar-specific T cells in CII, the immunodominant CII610-618 (GPAGT AGA R) within CB10 and the subdominant CII445-453 (GPAGP AGE R) within CB8. Although the determinants differ by only two residues, CB8 is capable of inducing collagen-induced arthritis (CIA), while CB10 is not. We, therefore, investigated the structural differences between the two determinants that are critical to inducing arthritis. When the CB10 determinant was mutated to that of CB8 using recombinant techniques, the resulting mutant rCB10T614P,A617E product became arthritogenic. Conversely, when the CB8 determinant was mutated to that of CB10, the resulting mutant CB8P449T,E452A was no longer arthritogenic. Comparison of the epitope specificity of the autoantibodies induced by wild-type CB10 and mutant rCB10T614P, A617E revealed no qualitative differences. T cells from mice immunized with either CB10 or mutant rCB10 produced predominantly Th1 cytokines when cultured with the immunizing Ag. In contrast, when cultured with mouse CII, T cells from mice immunized with the nonarthritogenic CB10 produced predominantly Th2 (IL-4 and IL-10) cytokines whereas the arthritogenic mutant rCB10 induced predominantly Th1 (IFN-gamma) cytokines. We conclude that the T cell cytokine response most critical for the induction of CIA is that induced against the corresponding homologous murine T cell determinant and, further, that the structural differences between the T cell determinants in CB8 and -10 are important in breaking self tolerance and inducing autoimmune response. (+info)
Exacerbation of acute inflammatory arthritis by the colony-stimulating factors CSF-1 and granulocyte macrophage (GM)-CSF: evidence of macrophage infiltration and local proliferation.
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CSF-1 and GM-CSF have been implicated in the pathogenesis of rheumatoid arthritis. We report the effects of CSF-1 and GM-CSF in the development of an acute methylated bovine serum albumin (mBSA)-induced murine arthritis model. Examination of histopathological features revealed that the systemic administration of CSF-1 or GM-CSF following mBSA administration into the knee resulted in the exacerbation of arthritis. This included synovial hyperplasia and joint inflammation, most evident at 7 and 14 days post-mBSA administration, and the appearance of erosive pannus tissue. The exacerbation by CSF-1 and GM-CSF was not sustained but declined in incidence and severity by 21 days post-mBSA administration, similar to the effects of IL-1beta in this model, reported here and previously. Macrophages expressing Mac-2 and F4/80 were a prominent feature of the pathology observed, particularly the infiltration of Mac-2+ macrophages seen in all mice administered CSF-1, GM-CSF or IL-1beta. Present in inflamed knees was a locally dividing population of cells which included Mac-2+ and F4/80+ macrophages. These studies demonstrate that CSF-1 and GM-CSF can exacerbate and prolong the histopathology of acute inflammatory arthritis and lend support to monocytes/macrophages being a driving influence in the pathogenesis of inflammatory arthritis. (+info)
Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced in rats by blocking of CD59.
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We investigated the effects of suppression of complement activation at C3 level and inhibition of C5a on acute synovitis in rats. Acute synovitis was induced in Wistar rats by intra-articular (i.a.) injection into one knee of 0.3 mg of MoAb 6D1 (anti-rat CD59 antibody). In the treatment groups, soluble CR1 (sCR1) or C5a receptor (C5aR) antagonist was administered intra-articularly or intravenously and effects on the course of the acute synovitis were monitored. Synovitis induced by 6D1 was characterized by joint swelling, thickening of synovial tissue, cellular infiltration and deposition of membrane attack complex (MAC) on the synovial surface. Neither inflammatory change nor MAC deposition was found in rats which received an i.a. injection of sCR1 to suppress complement activity in the joint. Intra-articular injection of sCR1 did not reduce plasma complement activity. Intravenous administration of sCR1 suppressed plasma complement activity but had no effect on the course of the arthritis and synovitis with MAC deposition was observed. Neither i.a. nor i.v. injection of C5aR antagonist had any suppressive effects on inflammatory change or MAC deposition in synovium. The data show that inflammatory change induced by 6D1 was mediated by local complement activation and was not accompanied by systemic complement activation. C5a generation was not responsible for the observed inflammation, suggesting that other complement activation products, possibly MAC, mediate the inflammatory change observed in this model of acute synovitis in rats. (+info)
Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced th2activity.
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Gene therapy has been explored as a potential method for treating chronic inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of intra-articular IL-4 gene therapy in an animal model of arthritis using a retroviral vector, a retrovirus encoding rat IL-4 (DA-IL-4) was engineered, purified and concentrated to high titer (>/=109 CFU/ml). Infectivity and expression levels were demonstrated in vitro using cultured fibroblast-like synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4 or DA-beta-gal retrovirus was injected into the intra-articular joint space of the right ankle on day 12 after immunization. Three days after joint injection, the injected paw contained increased levels of IL-4 compared with control or with the contralateral uninjected paw, demonstrating successful transgene expression. Surprisingly, 8 days after treatment IL-4 levels continued to increase in the injected and contralateral paw compared with DA-beta-gal-treated animals. Serum IL-4 levels were also elevated in DA-IL-4-treated rats. RT-PCR studies demonstrated that the transgene was expressed in the injected ankle but not in the contralateral joint. IL-4 gene therapy resulted in a significant reduction in paw swelling and decreased radiographic evidence of bone destruction. This is the first demonstration of successful intra-articular retroviral gene treatment using a therapeutic gene. In addition to its anti-inflammatory effect, this study supports the potential application of intra-articular gene therapy as a method for enhancing systemic Th2 function. (+info)