Effect of macrophage depletion on immune effector mechanisms during corneal allograft rejection in rats

PURPOSE. In rats, corneal allograft rejection is delayed for at least 100 d ays by clodronate liposomes. These liposomes selectively deplete macrophage s. To investigate the immunologic basis for absence of graft rejection in t reated rats, the effect of these liposomes on the generation of cytotoxic T lymphocytes (CTLs) and antibody production after orthotopic corneal allotr ansplantation was determined. METHODS. Transplantations of corneal buttons from PVG rats were performed i n AO rats. After surgery, one group received clodronate liposomes subconjun ctivally at five time points, and the other group remained untreated. On po stoperative day (POD) 3, 7, 12, or 17, rats were killed, the presence of CT Ls was investigated at three different anatomic locations, and antibodies a gainst donor antigens were tested. RESULTS. NO significant differences were found between the groups tested 3 and 7 days after surgery. But on POD 12 (the time of onset of rejection in the untreated group) and on POD 17, the CTL activities detected in the subm andibular lymph nodes (P less than or equal to 0.008) and the spleen (P les s than or equal to 0.009) were significantly less in the treated groups com pared with the untreated groups. in the untreated groups complement-indepen dent antibodies were present only on POD 17, whereas no antibodies were fou nd in the treated rats. CONCLUSIONS. Local treatment with clodronate liposomes was shown to downreg ulate local and systemic CTL responses and to prevent the generation of ant ibodies. Local depletion of macrophages in the initiation phase of the immu ne response appears to lead to a less vigorous attack on the grafted tissue and therefore to promote graft survival.