LONG-TERM AMELIORATION OF RAT ADJUVANT ARTHRITIS FOLLOWING SYSTEMIC ELIMINATION OF MACROPHAGES BY CLODRONATE-CONTAINING LIPOSOMES

Objective. To determine whether systemic elimination of macrophages by means of clodronate-containing liposomes counteracts inflammation and joint destruction in rats with established adjuvant arthritis (AA). M ethods. Rats with AA received a total of 2.7 mg of clodronate encapsul ated in liposomes in 3 intravenous doses on days 10, 11, and 12 of art hritis, Phosphate buffered saline (PBS), PBS-laden liposomes, or free clodronate were used as negative controls, Clinical, hematologic, and histopathologic signs of AA were monitored, and depletion of macrophag es by clodronate-liposomes was evaluated both in the synovial membrane (SM) and in organs of the mononuclear phagocyte system (MRS). Results . Clodronate-laden liposomes led to significant, long-term amelioratio n of the clinical signs of AA, a reduction in the erythrocyte sediment ation rate (ESR), and counteraction of joint destruction, not only imm ediately after treatment, but also for 2 weeks thereafter. Free clodro nate induced moderate clinical improvement and a significant decrease in the ESR, but only during the late phase of AA, Drug-free vesicles e ven aggravated the joint destruction, Clodronate-laden liposomes did n ot induce significant depletion of resident macrophages in the SM, but rather, in the paracortical region of popliteal lymph nodes, in the l iver, and in the marginal zone and periarteriolar lymphatic sheaths of the spleen. Conclusion. Clodronate-laden liposomes induce long-term a melioration of AA, even if administered for a brief period during the florid phase of the disease, The amelioration is paralleled by the eli mination of macrophages in immunocompetent areas of the spleen and dra ining lymph nodes, but not locally in the SM, This suggests an influen ce of the treatment on the immunoregulatory rather than effector, func tions of macrophages.