Investigation of a Thromboxane A2 Receptor-Based Vaccine for Managing Thrombogenesis.
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BACKGROUND: Despite the well-established role for the thromboxane A2 receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand-binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR-based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity. METHODS AND RESULTS: We used a mouse keyhole limpet hemocyanin/peptide-based vaccination approach rationalized over the TPR ligand-binding domain (ie, the C-terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of invitro and invivo platelet function experiments. Our results revealed that the TPR C-terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C-terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb-IIIa); (3) selectively inhibited TPR-mediated platelet aggregation, platelet-leukocyte aggregation, integrin glycoprotein IIb-IIIa activation, as well as dense and granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis. CONCLUSIONS: Collectively, our findings shed light on TPR's structural biological features, and demonstrate that the C-terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine-based approach that should have therapeutic applications.
