Suppression Of Adjuvant-induced Arthritis Research Articles

Intraarticular gene delivery of CTLA4-FasL suppresses experimental arthritis

T lymphocytes are key inflammatory cells contributing significantly to the pathogenesis of Rheumatoid arthritis (RA). Biological treatments targeting T lymphocytes may provide an efficient approach for treatment of RA. CTLA4-FasL, a fusion product of extracellular domains of CTLA4 and FasL, integrating two inhibitory elements against T cells into one molecule, might be a desirable derivative of engineered soluble FasL or CTLA4 and have therapeutic potential in RA. The aim of this study was to investigate whether simultaneous induction of Fas-mediated apoptosis and blockade of co-stimulation signal by CTLA4-FasL gene delivery has a suppressive effect on adjuvant-induced arthritis (AIA) in Lewis rats. Recombinant adeno-associated virus (rAAV) vectors encoding rat CTLA4-FasL fusion gene (rAAV.CTLA4-FasL) or enhanced green fluorescent protein (rAAV.EGFP) were injected intraarticularly into both ankle joints after immunization. The ankles were monitored by measures of clinical, histological and inflammatory cytokines' changes. Treatment using rAAV.CTLA4-FasL resulted in a significant suppression of AIA compared with rAAV.EGFP control, as reflected in the mainly clinical signs including articular index, ankle joint thickness and paw swelling and typically histological characters of arthritic joints including synovial hyperplasia, inflammatory cells infiltration and cartilage degradation. Treatment with rAAV.CTLA4-FasL also significantly decreased the levels of key proinflammatory cytokines in AIA joints. Moreover, local productions of transgene mRNA and protein of CTLA4-FasL were found in injected joints without systemic distribution. Our results indicate that rAAV.CTLA4-FasL profoundly suppressed experimental model of RA, implicating the potential therapeutic applications for suppression of RA by local joint delivery of CTLA4-FasL.

The preventive effects of incomplete Freund's adjuvant and other vehicles on the development of adjuvant-induced arthritis in Lewis rats.

The present study showed a novel finding that the development of adjuvant-induced arthritis (AA) in Lewis rats was completely prevented by incomplete Freund's adjuvant (IFA) injected 21 or 28 days before complete Freund's adjuvant (CFA) challenge. Hexadecane also completely prevented AA and squalane, methyl oleate and pristane moderately prevented AA, though pristane by itself induced mild arthritis in two out of five rats. Concanavalin A-stimulated lymph node cells (LNCs) isolated from AA rats were able to adoptively transfer the severe polyarthritis to all the naive recipients or even to the IFA pretreated recipients with earlier onset and more rapid progression than those of AA. The LNCs from the donors who had been pretreated with IFA and subsequently challenged with CFA could induce mild arthritis in only two out of eight naive recipients, whereas all the recipients who were challenged with CFA immediately after intravenous injection of these LNCs developed significantly less severe arthritis. However, the LNCs from IFA-pretreated donors failed to prevent AA. According to the T helper type 1 (Th1)/Th2 paradigm, it was suggested that the adjuvant-active vehicles such as IFA, hexadecane, squalane, methyl oleate and pristane, can affect and deviate the Th1/Th2 balance of immune responses in host. CFA could promote the propagation of Th2 cells rather than Th1 cells in these vehicle-pretreated rats through as yet undetermined mechanisms, eventually resulting in the prevention of AA. Finally, we discussed a regulatory role of adjuvant vehicles for induction and suppression of AA.

Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase

Adjuvant-induced arthritis is a model of chronic inflammation that exhibits several pathological changes similar to those occurring in rheumatoid arthritis, an autoimmune disease in humans characterized by chronic inflammation of the joints. We have examined the role of inducible nitric oxide synthase in producing the pathological changes associated with adjuvant-induced arthritis. Plasma nitrite concentrations were maximally elevated 14 days following adjuvant administration compared to untreated control animals. Arthritic changes in the paw were first observed between days 10–12 and were maximally elevated 21 days following adjuvant administration. Inducible nitric oxide synthase immunoreactivity was found localized in the synovial tissue from adjuvant-treated rats, while untreated controls exhibited no inducible nitric oxide synthase staining. Two selective inducible nitric oxide synthase inhibitors, aminoguanidine and N-iminoethyl- l-lysine, suppressed the increase in plasma nitrite levels and joint inflammation associated with adjuvant-induced arthritis in a dose-dependent manner. N-Iminoethyl- l-lysine attenuated the inducible nitric oxide synthase immunoreactivity in adjuvant-treated rats. Blood pressure was not affected by the highest dose of N-iminoethyl- l-lysine administered in the drinking water, indicating a lack of inhibition of constitutive nitric oxide synthase.

Efficacy and Possible Mechanisms of the Chinese Herbs Suching-Huo-Hsuei-Tang in the Treatment of Adjuvant-Induced Arthritis in Rats

The Chinese herbal formula suching-huo-hsuei-tang (SHT) was studied to evaluate its efficacy and possible mechanism on adjuvant-induced arthritis (AIA) in rats. SHT was extracted with water, butanol and chloroform into 5 different layers. The top 3 layers of SHT showed a significant suppression of AIA and writhing reaction; the top 2 layers suppressed neutrophil chemotaxis and platelet aggregation. The results suggest that SHT is very promising in the treatment of rheumatoid arthritis (RA) by way of its anti-inflammatory and analgesic action. The possible mechanisms for arthritis are multifactorial.

The toxicity of three gold compounds in laboratory animals.

Compounds of gold have been used in the treatment of human rheumatoid arthritis for several decades, and their effectiveness is generally accepted. The compounds currently used (Myochrysine@ and Solganal? are poorly absorbed by the gastrointestinal tract and consequently are administered by deep intramuscular injection. The toxic effects of these two drugs in laboratory animals are not well known; there are no published reports of studies by currently accepted procedures. The series of papers which follow is intended to provide a profile of the toxicology of gold-containing compounds used in the treatment of arthritis. They are based on our studies of 2 gold-containing compounds that are effective after oral administration in the suppression of adjuvant-induced arthritis in rats,'. and on Myochrysine, which is given parenterally. Throughout the reports in this series of papers the doses are given as amount of compound, followed by the gold content in parentheses. Comparisons between doses of the three compounds dealt with are not appropriate. This is obviously so where the routes of administration and frequency of dosing differ. However, it also applies to the two orally administered compounds, because of differing percentages of absorption, excretion and tissue distribution; there may be other, unknown differences as well. Only qualitative comparisons are appropriate. For both the oral and injectable gold compounds ionic gold, Ag, is being administered and not molecular gold, Ag2. The effects of molecular gold (e.g., as used in dental restorations) are not considered herein. Comprehensive monitoring of many parameters, typical of toxicity studies of pharmaceutical agents, was done. To have included the raw data or comment on parameters that were not significantly altered would have obscured the major features of the toxicologic profiles which emerged from the studies. Some small changes of minor interest are mentioned only once, although they occurred in subsequent similar studies. Furthermore, some entire studies are not reported at all since no significant compound-related effect occurred. Despite the omission herein of the many details submitted in the dossiers to governments, considerable repetition of findings from

Mechanisms underlying the suppression of adjuvant-induced arthritis by 6-mercaptopurine.

Daily oral administration of 6-mercaptopurine suppressed the development of the secondary (immune) lesions of adjuvant arthritis in a dose-related manner. The degrees of arthritis suppression corresponded closely to suppressions of concurrent development of the humoral and the cellular immune response to El4 cells. A short course of therapy during the sensitization period (day - 1 to day 5 when the day of adjuvant injection is designated as day 0) appeared to be almost as effective as continued daily dosing (day - 1 to day 15). The drug did not influence the development of the primary (nonimmune) lesions of adjuvant arthritis at all dosage levels investigated. Chronic pretreatment with 10 mg/kg/day PO for 17 days had no effect on the development of carrageenin-induced acute inflammation in the rat. The suppression of adjuvant arthritis by 6-mercaptopurine, unlike suppression by cyclophosphamide, appears to result primarily from its suppressive action on the immune response.

Suppression of adjuvant-induced arthritis in the rat by gold sodium thiomalate.

Suppression of adjuvant-induced arthritis in the rat by gold sodium thiomalate.