Long‐term amelioration of rat adjuvant arthritis following systemic elimination of macrophages by clodronate‐containing liposomes

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Abstract
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). Methods. Rats with AA received a total of 2.7 mg of clodronate encapsulated in liposomes in 3 intravenous doses on days 10, 11, and 12 of arthritis. 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 macrophages by clodronate‐liposomes was evaluated both in the synovial membrane (SM) and in organs of the mononuclear phagocyte system (MPS). Results. Clodronate‐laden liposomes led to significant, long‐term amelioration of the clinical signs of AA, a reduction in the erythrocyte sedimentation rate (ESR), and counteraction of joint destruction, not only immediately after treatment, but also for 2 weeks thereafter. Free clodronate induced moderate clinical improvement and a significant decrease in the ESR, but only during the late phase of AA. Drug‐free vesicles even aggravated the joint destruction. Clodronate‐laden liposomes did not induce significant depletion of resident macrophages in the SM, but rather, in the paracortical region of popliteal lymph nodes, in the liver, and in the marginal zone and periarteriolar lymphatic sheaths of the spleen. Conclusion. Clodronate‐laden liposomes induce long‐term amelioration of AA, even if administered for a brief period during the florid phase of the disease. The amelioration is paralleled by the elimination of macrophages in immunocompetent areas of the spleen and draining lymph nodes, but not locally in the SM. This suggests an influence of the treatment on the immunoregulatory rather than effector, functions of macrophages.