The platelet-specific alloantigens, P1A and Bak(Lek), are associated with glycoproteins (GP) IIIa and IIb, respectively, the components of the fibrinogen receptor which mediates platelet cohesion. As shown in preliminary studies reported here, additional alloantigens are also associated with platelet glycoproteins: Pen is localized to GPIIIa, and P1E is localized to GPIb, the receptor for von Willebrand factor that mediates platelet adhesion to the vessel wall. Multiply transfused individuals with hereditary defects of the above glycoproteins can produce isoantibodies which react with the respective glycoproteins regardless of allotype, and the relationship of these isoantigenic epitopes to the above alloantigenic epitopes is currently unknown. In view of the importance of certain membrane glycoproteins (GP) in platelet physiology, particularly GPIb and GPIIb/IIIa, the elucidation and further characterization of those structures which make them immunogenic in man will pave the way for studies aimed at the cellular or molecular regulation of platelets immunogenicity. Aside from their localization to specific glycoproteins, platelet-specific antigens are not yet adequately characterized to address such questions. The one aim of our research is to further characterize and compare the structures of human platelet glycoproteins which confer allo- and iso-antigenicity. We have observed that certain platelet alloantigens are expressed by both human endothelial cells and selected human cell lines with erythroid and/or myeloid properties. In view of its relevance to the etiology and clinical manifestations of various disease states in which immunization against platelet antigens is involved, we also propose to investigate the immunobiology of platelet glycoprotein antigens on other cell types which synthesize analogs of these glycoproteins. A final goal is to develop stable, mouse-human heterohybridomas secreting human antibody reactive with platelet glycoprotein allo- and iso-antigens. In addition to their obvious value as laboratory reagents, these human monoclonal antibodies will have potentially valuable in vivo diagnostic or therapeutic applications. Moreover, a comparison of panels of monoclonal allo- or iso-antibodies against a physiologically important platelet glycoprotein will enable us to better understand the molecular basis for immunogenicity of platelet proteins within the human species.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hematology Subcommittee 2 (HEM)
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Bloodcenter of Wisconsin, Inc.
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