SUMMARY We have studied the effect of the immunosuppressive agent cyclosporin on collagen induced arthritis in mice. Cyclosporin, when given prophylactically, was capable of suppressing the development of collagen induced arthritis and the immunological response to native type II collagen in a dose dependent manner. Furthermore, treatment with cyclosporin, started on the same day as the booster injection with type II collagen, also resulted in inhibition of development of arthritis and of immunity to collagen. These findings suggest that the time of a booster injection, three weeks after the initial immunisation, might be still within the induction phase of arthritis since reinoculation is required to produce a high incidence of arthritis in mice. In addition, therapeutic treatment with cyclosporin did not affect the clinical course of the disease or the immune response to collagen.Immunisation with native type II collagen induces inflammatory polyarthritis and immunity to collagen in rats and susceptible strains of mice.-The disease, which has been shown to have similarities to human rheumatoid arthritis in many respects,7 can be transferred by immune sera from arthritic rats to naive mice8 and rats.9 Furthermore, we reported previously that a serum concentrate from arthritic rats is capable of inducing arthritis in cyclosporin treated, type II collagen tolerant rats"' and congenitally athymic nude rats. 1 1 These findings suggest that arthritis in rats and mice might be caused by similar mechanisms,8 and that arthritis could be induced by humoral immunity in the absence of cell mediated immunity. " Although pathogenetic mechanisms and the histopathology of collagen induced arthritis in mice are similar to those seen in rats, 3 5there are definite discrepancies in the immune response to collagen between these two species.3 5 In addition, a booster injection and use of complete Freund's adjuvant combined with type II collagen at the time of the primary sensitisation are required to produce a high incidence of arthritis in mice.2 The development of arthritis and immune response to collagen
Collagen arthritis can be induced readily in many strains of rats by immunizing them with heterologous or homologous native type II collagen emulsified in incomplete Freund's adjuvant (1). This disease, which is characterized by the development of both cellular and humoral immune response to type II collagen (2-4), can be passively transferred by sensitized spleen and lymph node cells (5) as well as IgG antibodies to type II collagen (6). These findings are consistent with the proposal that collagen arthritis is the result of immunologic hypersensitivity to type II collagen. In a recent report, Trentham et al. (7) showed that rats with adjuvant arthritis exhibited both humoral and cellular sensitivities to homologous type II collagen, and suggested that an autoimmune response to type I! collagen is a common feature to both collagen arthritis and adjuvant arthritis. However, subsequent studies (8, 9) have produced conflicting results that shed some doubt on this exciting concept, and the discrepancies need further clarification.The present study was intended to determine if an autoimmune response to type II collagen is responsible for the induction of both collagen arthritis and adjuvant arthritis by using a relatively new immunosuppressive agent, cyclosporin, which has been shown to be capable of inducing specific immunologic tolerance in several in vivo and in vitro conditions (10, 1 I).
Materials and MethodsAnimals. Outbred female Sprague-Dawley rats were purchased from Japan Charles River Breeding Laboratories, Kanagawa, Japan. They were allowed 1 wk to adapt to their environment and were used at 6 wk old, weighing 130-160 g at the start of the present experiment. All the animals received standard laboratory chow and water ad libitum.
Preparation of Type II Collagen and Production of Collagen Arthritis.Type II collagen was isolated and purified from bovine articular cartilage as previously described (1). The purity was assessed as described elsewhere (12). Lyophilized type II collagen was dissolved in 0.I M acetic acid at a concentration of 3 mg/ml. Equal volumes of collagen solution and incomplete Freund's adjuvant (Difco Laboratories, Inc., Detroit, MI) were emulsified using a homogenizer (Polytron PT 10-35; Kinematica, Lucerne, Switzerland) and kept cold with an ice bath. Collagen arthritis was produced by intradermal injection of 1 ml of Address correspondence to N. Kaibara,
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