Monoclonal antibodies to αVβ3 (7E3 and LM609) inhibit sickle red blood cell–endothelium interactions induced by platelet-activating factor: Presented in part at the INSERM Symposium, Paris, France, September 2, 1995 (ref 24), and at the 40th Annual Meeting of the American Society of Hematology, Miami, FL, December 7, 1998.
2000
Abnormal interaction of sickle red blood cells (SS RBC) with the vascular endothelium has been implicated as a factor in the initiation of vasoocclusion in sickle cell anemia. Both von Willebrand factor (vWf) and thrombospondin (TSP) play important roles in mediating SS RBC–endothelium interaction and can bind to the endothelium via Vβ3 receptors. We have used monoclonal antibodies (MoAb) directed against Vβ3 and IIbβ3 (GPIIb/IIIa) integrins to dissect the role of these integrins in SS RBC adhesion. The murine MoAb 7E3 inhibits both Vβ3 and IIbβ3 (GPIIb/IIIa), whereas MoAb LM609 selectively inhibits Vβ3, and MoAb 10E5 binds only to IIbβ3. In this study, we have tested the capacity of these MoAbs to block platelet-activating factor (PAF)–induced SS RBC adhesion in the ex vivo mesocecum vasculature of the rat. Infusion of washed SS RBC in preparations treated with PAF (200 pg/mL), with or without a control antibody, resulted in extensive adhesion of these cells in venules, accompanied by frequent postcapillary blockage and increased peripheral resistance units (PRU). PAF also caused increased endothelial surface and interendothelial expression of endothelial vWf. Importantly, pretreatment ofthe vasculature with either MoAb 7E3 F(ab′)2 or LM609, but not 10E5 F(ab′)2, after PAF almost completely inhibited SS RBC adhesion in postcapillary venules, the sites of maximal adhesion and frequent blockage. The inhibition of adhesion with 7E3 or LM609 was accompanied by smaller increases in PRU and shorter pressure-flow recovery times. Thus, blockade of Vβ3 may constitute a potential therapeutic approach to prevent SS RBC–endothelium interactions under flow conditions.
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