Induction Of Adjuvant Arthritis Research Articles

Induction of adjuvant arthritis in rats by muramyl dipeptide (MDP)

Induction of adjuvant arthritis in rats by muramyl dipeptide (MDP)

Lack of correlation between induction of adjuvant arthritis and changes in metabolism and disposition of phenylbutazone in rats.

Phenylbutazone disposition after intravenous injection of 50 mg/kg was studied in Lewis and AVN rats treated by mycobacterial adjuvant in comparison with untreated animals. Although the arthritic lesions, body weight loss and decline in albumin concentration developed only in the Lewis strain, an increase of the extrapolated volume of distribution, decline in total body clearance and prolongation of the biological half-life of phenylbutazone were found in both strains of rats. Also the content of cytochromes P-450 and b5 was reduced in both Lewis and AVN rats.

Chemical structure required for immunoadjuvant and arthritogenic activities of cell wall peptidoglycans

Water-soluble glycopeptides isolated from Lactobacillus plantarum cell walls by the use of Streptomyces L-3 enzyme were purified by gel filtration and ion-exchange column chromatography and were shown to be potently adjuvant-active and arthritogenic in the rat. Although these peptidoglycans contained non-peptidoglycan components (ribitol-teichoic acid and polysaccharide) attached to them in different proportions, the potency of both activities did not seem to be dependent upon the presence of these non-peptidoglycan components. Furthermore, the peptidoglycans of Staphylococcus epidermidis cell walls, which were essentially free from non-peptidoglycan components also showed potent immunoadjuvant and arthritogenic activities. These results indicated the importance of the peptidoglycan portion, but not of the non-peptidoglycan portion for both of these activities. Fractions containing peptidoglycans with an average glycan chain length of more than 5 disaccharide units were more potent than the peptidoglycan fractions with shorter glycan chains of 2–3 disaccharide units. Synthetic N- acetylmuramyl- l-alanyl- d-isoglutamine also exhibited an adjuvant activity as evaluated by its effect on the induction of experimental allergic encephalomyelitis in the PVG/c strain rat, although it was less active than the natural products with longer glycan chains. However, this synthetic compound failed to produce arthritis in the rat, suggesting that the minimal structure required for adjuvant activity is not sufficient for induction of adjuvant arthritis. A purified fraction with low ratio of peptide to glycan content seemed to be less potent in both arthritogenicity and immunoadjuvant activity despite the presence of an average glycan chain length of 8 disaccharide units. These findings suggest that polymerization of the minimal effective structure potentiates each of adjuvant and arthritogenic activities.

Role of T Lymphocytes in Adjuvant Arthritis

Abstract The effects of treatments with cyclophosphamide (CY), hydrocortisone and anti-thymocyte sera (ATS) on the development of adjuvant arthritis (AA) were examined in WKA rats inoculated with wax D to induce AA. A single injection of 25 to 50 mg/kg of CY given 2 to 3 days before wax D inoculation caused severe arthritis with high incidence, whereas larger doses of CY were less efficient. Furthermore, the enhancing effect of CY pretreatment was abolished by passively transferred normal syngeneic thymocytes 1 day before wax D inoculation, but not by thymocytes that had been treated with ATS and guinea pig C. On the basis of these results and the previous observations on the effect of adult thymectomy and low-dose irradiation, we concluded that this enhancing effect of CY pretreatment was caused by selective depletion of suppressor T lymphocytes. Pretreatment with 12.5 mg of hydrocortisone also caused severe arthritis. This enhancing effect of hydrocortisone could also be due to the elimination of those suppressor cells. In contrast, in vivo pretreatment with ATS showed striking inhibition on the development of AA, suggesting that ATS could eliminate T lymphocytes that were responsible for eliciting this disease. Thus it appears that at least two T cell subpopulations are involved in the development of AA, one is an ATS-sensitive T2 subpopulation that is effective for induction of AA and the other is a T1 subpopulation that regulates this disease process.

Synergism of immunogenic and adjuvant-active components of mycobacterial wax D in the induction of adjuvant arthritis.

Two derivatives of wax D, one possessing immunogenicity and the other adjuvant activity, were tested for the possible role in the induction of adjuvant arthritis (AA) in rats. The former, a water-soluble arthritogenic and immunogenic component (WAC), in incomplete Freund's adjuvant, was able to induce delayed hypersensitivity (DH) and mild AA, but failed to function as an adjuvant in rats. The latter, an acetylated wax D (AD) and its subfraction, AD6, did exert adjuvant activity, but were free from immunogenicity and arthritogenicity. The addition of AD or AD6 to the WAC in incomplete Freund's adjuvant, when injected into inguinal lymph nodes, resulted in the production of severe AA with high incidence. Other adjuvants such as pertussis vaccine and lipopolysaccharide could not replace AD6; they failed to enhance AA when combined with the WAC. Also, other mycobacterial antigen, PPD, could not replace wax D-derived WAC; it did not induce AA when coupled with AD6, although it did induce DH to PPD.

Induction of adjuvant arthritis in the rat by various bacterial cell walls and their water-soluble components.

A number of purified cell walls of various gram-positive bacteria had arthritogenic activity in the rat. The water-soluble adjuvant-active component(s), which were isolated from some of these cell walls by utilizing a peptidoglycan-degrading enzyme, did produce severe adjuvant arthritis. However, the components obtained by digestion with glycan-degrading enzymes failed to produce arthritis. Thus, the present finding indicates the importance of a peptidoglycan portion, especially its intact glycan chain, for induction of adjuvant arthritis.

Effect of degradation of the arabinogalactan portionof a water-soluble component from M. tuberculosis wax D on polyarthritis induction in the rat.

In order to explore a possible role of the arabinogalactin (AG) portion of the water-soluble arthritogenic component (WAC) from M. tuberculosis wax D for induction of adjuvant arthritis (AA) in the rat, this component was digested with an AG-degrading enzyme. The enzyme-digested WAC was able to produce AA. The severity of AA was almost comparable to that of the nondigested WAC. This finding suggests that the AG portion of the WAC does not seem to be essential for AA induction and indirectly points the importance of the peptidoglycan portion.

Animal model to study the relationship between immunoreactive gastrin and inflammatory arthritis.

THE observation of raised concentrations of radioimmunoreactive gastrin in the plasma of patients with rheumatoid arthritis1 has directed attention to the role of this foregut hormone in the inflammatory response. Evaluation of the significance of this relationship would be simplified if a suitable animal model were available. We have studied immunoreactive gastrin in rats following the induction of adjuvant arthritis in an attempt to establish such a model.

Letter: Experimental arthritis in thymectomized rats with an impaired humoral immune response.

ADJUVANT-induced arthritis in rats shares many of the clinical and pathological features of human rheumatoid arthritis1. Cell-mediated immune mechanisms are believed to be of importance in the experimentally induced arthritis2. Although this experimental disease can be transferred by thoracic duct lymphocytes from sensitized to non-sensitized syngeneic recipient rats3, it has been reported that neonatal thymectomy does not prevent subsequent induction of adjuvant arthritis4. We recently observed induction of adjuvant arthritis in rats subjected to neonatal thymectomy, but not in sham thymectomized rats. The accompanying finding that the severity of the arthritis was related to depression of an apparently thymus dependent antibody response may be a clue to the immunopathological mechanism involved in this arthritis model.

Fatty acid nature and adjuvant activity of wax D from Mycobacterium tuberculosis.

SUMMARY: Wax D, a chloroform-soluble and boiling-acetone-insoluble fraction extracted from various human strains of mycobacteria, showed characteristic biological activities such as Freund-type adjuvant activity (Raffel, 1950; White, Jolles, Samour & Lederer, 1964) and the induction of adjuvant arthritis in rats (Pearson, 1959; Pearson, Wood, McDaniel & Daft, 1963). Wax D from human strains was found to be peptidoglycolipid consisting of unsaturated fatty acid (mycolic acid) esters of mucopolysaccharide containing a peptide moiety of alanine, glutamic acid and meso-α-α'-diaminopimelic acid (Asselineau, 1951; Asselineau, Buc, Jolles & Lederer, 1958). Previous work from this laboratory has shown the importance of fatty acid content for the adjuvant activity of the wax D of a human strain, Peurois (Hiu, Amiel & Jolles, 1969). This communication reports an increase in adjuvant activity after hydrogenation of the fatty acids forming the lipid portion of the wax D from the human strains Peurois and Canetti.

The effects of adjuvant-induced arthritis on the liver metabolism of drugs in rats

During a period of 15 days following induction of adjuvant arthritis in rats, the liver microsomal N-demethylase and NADPH 2-oxidase enzyme activity and levels of cytochrome P-450 are greatly reduced. This implies a reduced capacity for the oxidative metabolism of steroids and foreign compounds in adjuvant arthritic rats which should influence the toxicity and half-life of any administered compound. The ability of the liver to form β-glucuronide conjugates is also reduced. These effects on microsomal metabolism are associated principally with the onset of adjuvant arthritis rather than with delayed hypersensitivity to the injected tuberculin which occurs at the same time.