EXACERBATION OF MDP-LYS (L18)-INDUCED ARTHRITIS BY CYCLOSPORIN A IN RATS

Abstract

The mechanisms of MDP-Lys (L18)-induced arthritis in rats and exacerbating effect of cyclosporin A (CsA) on the arthritis were examined. Consecutive subcutaneous injections of MDP-Lys (L18) for 14 days increased tarsal joint thickness from day 7 up to day 15, with marked recovery after cessation of the treatment. Histological examination, however, revealed multilayered arrangement of synovial lining cells with vesicular cytoplasms and mild neutrophil (NEU) infiltration in the synovial membrane 6 hr after a single injection (early stage). From day 8 (late stage), the lesion progressed in association with chronic signs, such as fibroblast proliferation, infiltration of mononuclear cells and Imphocytes (LYMs), and necrosis of the synovial membrane. However, exudative changes and NEU infiltration were seen throughout the course of the treatment. Rat macrophage-conditioned medium (M∅-CM) stimulated with MDP-Lys (1-18) produced NEU chemotactic factor (NCF), which was also detected in the synovial fluid from dogs with MDP-Lys (L18)-induced arthritis (MIA). The NCF was determined to be one of chemokines by partial purification, and cytokine-induced NEU chemoattractant [CINC, rat interleukin-8 (IL-8)] was detected in the rat M∅-CM. Examination of spleen T cell subsets revealed a decrease in CD8⁺ cell population in the later stage. Therefore, the chemokine, at least CINC, is thought to contribute to the early and later development of MIA, and the decreased population of CD8⁺ cells is to the later development. Cyclosporin A (CsA) markedly exacerbated MIA in the later but not early stage, and this was suggested to be caused by its additive effect to decrease CD8⁺ T cell population with MDP-Lys (L18).