The mannose receptor, localization and role in the clearance of tissue-type plasminogen activator

Summary The thrombolytic and antithrombotic effects of tissue-type plasminogen activator (t-PA) depend on its concentration in the blood. The mannose receptor is one of the receptors that mediate the rapid clearance of t-PA from the blood by the liver (Noorman and Rijken, Fibrinolysis & Proteolysis 1997; 11: 173–186). We hypothesized that by blocking the binding of t-PA to this receptor it might be possible to decrease the clearance of t-PA and thereby increase the plasma concentration of endogenous t-PA and exogenous t-PA. Inhibitors of the t-PA-mannose receptor interaction may thus be useful drugs in thrombolytic and antithrombotic therapy. We developed monoclonal antibodies against the human mannose receptor. These antibodies are able to inhibit binding of t-PA to the mannose receptor. By use of the antibodies it was shown that the mannose receptor is expressed by few human cell types. The expression of the mannose receptor on macrophages is highly regulated and depends on the type of macrophage activation. The expression of the mannose receptor in the liver is limited to endothelial cells and Kupffer cells. We developed high affinity ligands of the mannose receptor that are able to inhibit the plasma clearance of therapeutic t-PA doses by maximally 60% in the rat. Therapeutical concentrations of the low affinity mannose receptor ligand and antithrombotic agent dextran partially inhibit t-PA plasma clearance (33%) and thereby increase endogenous t-PA plasma concentrations by 20–60% in the rat. Thus mannose receptor inhibitors can be considered as a new tool to increase the t-PA concentration in blood and thereby increase its thrombolytic and antithrombotic effects.