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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037471-03
Application #
3353145
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1986-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
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Kunicki, T J; Plow, E F; Kekomaki, R et al. (1991) Human monoclonal autoantibody 2E7 is specific for a peptide sequence of platelet glycoprotein IIb. Localization of the epitope to IIb231-238 with an immunodominant Trp235. J Autoimmun 4:415-31
Kekomaki, R; Dawson, B; McFarland, J et al. (1991) Localization of human platelet autoantigens to the cysteine-rich region of glycoprotein IIIa. J Clin Invest 88:847-54
Kunicki, T J; Furihata, K; Kekomaki, R et al. (1990) A human monoclonal autoantibody specific for human platelet glycoprotein IIb (integrin alpha IIb) heavy chain. Hum Antibodies Hybridomas 1:83-95
Kunicki, T J; Beardsley, D S (1989) The alloimmune thrombocytopenias: neonatal alloimmune thrombocytopenic purpura and post-transfusion purpura. Prog Hemost Thromb 9:203-32
Kunicki, T J (1988) Platelet glycoprotein antigens and immune receptors. Prog Clin Biol Res 283:87-123
Kunicki, T J; Furihata, K; Nugent, D (1988) Glycoprotein IIb-IIIa as an immunologic target. Curr Stud Hematol Blood Transfus :44-63
Furihata, K; Nugent, D J; Bissonette, A et al. (1987) On the association of the platelet-specific alloantigen, Pena, with glycoprotein IIIa. Evidence for heterogeneity of glycoprotein IIIa. J Clin Invest 80:1624-30
Kunicki, T J; Furihata, K; Bull, B et al. (1987) The immunogenicity of platelet membrane glycoproteins. Transfus Med Rev 1:21-33