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Tolerization of B10.RIII mice (H-2r) with intravenously injected type II collagen (CII) renders the animals resistant to induction of collagen-induced arthritis (CIA). In order to clarify 11-2r- restricted T-cell responses that modulate CIA, we have analysed the T-cell proliferative response of B10.RIII mice against cyanogen bromide (CB) peptides of CII, and detected the strongest response to α(II)-CB10 (CII 552–897). A panel of chemically synthesized overlapping peptide homologues was used to deduce the minimum structure of this determinant which was found to be CII 610–618. A 15-residue synthetic peptide flanking this region. CII 607–621, was found to effectively suppress arthritis when administered as a tolerogen. Collectively, these data identify the structural component within α1(II)-CB10 which is capable of inducing tolerance in BIO.RIII mice. A similar approach to the treatment of autoimmune arthritis, involving the institution of self-tolerance, has potential applicability to human rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Susceptibility to collagen-induced arthritis (CIA), a murine model of autoimmune arthritis, is strongly linked to only two major histocompatibility complex (MHC) haplotypes, H-2q and H-2r. In order to identify the determinants of type II collagen (CII) required to induce arthritis in H-2rbeating mice, B10.RIII mice were immunized with bovine, chick or human CII. Only bovine Cfi induced significant arthritis and autoantibodies. When the major CNBr peptides of bovine collagen were isolated and used for immunization, only mice immunized with CB8, representing CII 403-551, developed arthritis. To identify immunogenic epitope(s) within CB8, a panel of synthetic peptides representing overlapping sequences of the bovine peptide was generated. When each peptide was cultured with T cells from B10.RIII mice immunized with CII, one peptide, representing CII 430-466, contained a major T-cell epitope. By using an in vitro lymphokine production assay, the T-cell epitope was further narrowed to CII 442-456. These findings suggest that a T-cell determinant important for the initiation of arthritis in B10.RIII (H-2r) mice is located within a 15 amino acid sequence, residues 442-456 of bovine CII. [ABSTRACT FROM AUTHOR]

In vitro data support the view that T cells in adjuvant-induced arthritis (AIA) respond to the proteoglycan (PG) component of articular cartilage; however, an in vivo role for PC in AIA has yet to be shown. To do so, we examined the effects of pretreatment with bovine cartilage high density PG (HDPG) on AIA induced by heat-killed Mycobacterium butyricum in Lewis rats. Purified bovine cartilage HDPG emulsified in Freund's incomplete adjuvant (FIA) was injected intradermally into rats 7 days before challenge with Myco. butyricum. The severity of arthritis was significantly suppressed in rats pretreated with as little as 0.75 mg of HDPG, and the arthritis was completely suppressed in rats pretreated with 30 mg of HDPG. This suppression was specific, as the same treatment did not protect against type 11 collagen-induced arthritis. Suppression of AIA is primarily a property of the HDPG, as suppression of the arthritis was significantly less with pretreatment with 3.0 mg of middle density fractions of PG, and no suppression was observed with pretreatment with the lowest density fraction of PG. Thus we report that pretreatment with cartilage HDPG, but not lower density PG, can induce specific suppression of AIA. These in vivo results support the view that immunity to cartilage HDPG plays a major role in the pathogenesis of AIA, and can induce specific tolerance to this type of arthritis. [ABSTRACT FROM AUTHOR]

We investigated the superior potency of the immunosuppressive agent FK5n6 on collagen-induced arthritis in rats. In our initial studies, we demonstrated that only one shot administration of FK506 at a dose of 10 mg/kg on the same day as type II collagen immunization suppressed the incidence of arthritis completely as well as humoral and delayed-type hypersensitivity (DTH) skin test responses to type II collagen. Yet no major side effects were observed in the rats treated with such a high dose of FK506. Additional studies demonstrated that pretreatment with FK506 on day -7 or day - 3 was effective in suppressing the severity of arthritis and immune responses to type II collagen. The immunosuppressive effect of a single high-dose administration of FK506 continued for at least 1 week in this animal model of arthritis. A single administration of FK506 at a dose of 10 mg/kg on day 12 or 15, after the clinical onset of arthritis, was also effective in suppressing the severity of arthritis and immune response to type II collagen. We conclude that FK506, in this model, possesses an important, curative action when applied therapeutically. The outlook of FK506 treatment in clinical autoimmunity is promising at present. [ABSTRACT FROM AUTHOR]

We have developed a new model of autoimmune arthritis in DBA/1 mice by feeding chick type II collagen (CII) for 2–3 week intervals over a 15 week period. Clinically evident arthritis occurred in 87/10 mice receiving native CII (nCII; 100 μg/mouse) alone at 9–l13 weeks. Arthritis was aggravated by the further ingestion of CII, while remission occurred after withdrawal of the CII. Heat-denatured CII (dCII; 200 μg/mouse) was also arthritogenic if co-administered with ovoinhibitor (OVI; 2 mg/mouse), a proteinase inhibitor. Co-oral administration of lipopolysaccharide (LPS; 10μg/mouse) with CII enhanced the antibody production and T-cell responses to CII, and induced a more chronic arthritis that progressed spontaneously without further administration of CII or LPS. Long-term oral administration of LPS alone also induced a mild arthritis characterized by destruction of bone rather than cartilage. These observations suggest that abnormal gastrointestinal absorption of dietary mimic antigens and intestinal bacterial toxins can potentially disrupt self-tolerance mechanisms, thereby precipitating or exacerbating autoimmune disease in genetically susceptible individuals. [ABSTRACT FROM PUBLISHER]