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Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor.

Abstract

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 alphaVbeta3 receptors. We have used monoclonal antibodies (MoAb) directed against alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa) integrins to dissect the role of these integrins in SS RBC adhesion. The murine MoAb 7E3 inhibits both alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa), whereas MoAb LM609 selectively inhibits alphaVbeta3, and MoAb 10E5 binds only to alphaIIbbeta3. 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 alphaVbeta3 may constitute a potential therapeutic approach to prevent SS RBC-endothelium interactions under flow conditions. (Blood. 2000;95:368-374)

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  • Authors+Show Affiliations

    ,

    Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA. kaul@aecom.yu.edu

    , , , ,

    Source

    Blood 95:2 2000 Jan 15 pg 368-74

    MeSH

    Abciximab
    Adult
    Anemia, Sickle Cell
    Animals
    Antibodies, Monoclonal
    Antibodies, Monoclonal, Humanized
    Cecum
    Cell Adhesion
    Endothelium, Vascular
    Erythrocytes
    Humans
    Immunoglobulin Fab Fragments
    Platelet Activating Factor
    Platelet Glycoprotein GPIIb-IIIa Complex
    Rats
    Receptors, Vitronectin
    Reference Values
    Venules

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    10627437

    Citation

    Kaul, D K., et al. "Monoclonal Antibodies to alphaVbeta3 (7E3 and LM609) Inhibit Sickle Red Blood Cell-endothelium Interactions Induced By Platelet-activating Factor." Blood, vol. 95, no. 2, 2000, pp. 368-74.
    Kaul DK, Tsai HM, Liu XD, et al. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood. 2000;95(2):368-74.
    Kaul, D. K., Tsai, H. M., Liu, X. D., Nakada, M. T., Nagel, R. L., & Coller, B. S. (2000). Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood, 95(2), pp. 368-74.
    Kaul DK, et al. Monoclonal Antibodies to alphaVbeta3 (7E3 and LM609) Inhibit Sickle Red Blood Cell-endothelium Interactions Induced By Platelet-activating Factor. Blood. 2000 Jan 15;95(2):368-74. PubMed PMID: 10627437.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. AU - Kaul,D K, AU - Tsai,H M, AU - Liu,X D, AU - Nakada,M T, AU - Nagel,R L, AU - Coller,B S, PY - 2000/1/11/pubmed PY - 2000/1/11/medline PY - 2000/1/11/entrez SP - 368 EP - 74 JF - Blood JO - Blood VL - 95 IS - 2 N2 - 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 alphaVbeta3 receptors. We have used monoclonal antibodies (MoAb) directed against alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa) integrins to dissect the role of these integrins in SS RBC adhesion. The murine MoAb 7E3 inhibits both alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa), whereas MoAb LM609 selectively inhibits alphaVbeta3, and MoAb 10E5 binds only to alphaIIbbeta3. 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 alphaVbeta3 may constitute a potential therapeutic approach to prevent SS RBC-endothelium interactions under flow conditions. (Blood. 2000;95:368-374) SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/10627437/Monoclonal_antibodies_to_alphaVbeta3__7E3_and_LM609__inhibit_sickle_red_blood_cell_endothelium_interactions_induced_by_platelet_activating_factor_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10627437 DB - PRIME DP - Unbound Medicine ER -