The aim of this project is to define the platelet membrane changes which lead to autoantibody mediated clearance of activated or senescent platelets. Both aged and thrombin activated platelets have increased levels of membrane bound immunoglobulin (Ig) which facilitates clerance of these cells from circulation. However, the polyclonal nature of these antibodies has precluded a precise definition of the specific antigenic changes expressed with aging or activation. Using lymphocytes from normal individuals and from patients with decreased platelet survival, I will isolate Epstein Barr Virus (EBV) transformed B cell lines which secrete human monoclonal autoantibodies specific for aged or activated platelets. These monoclonal autoantibodies will be used to identify and characterize platelet membrane neoantigens revealed as platelets age or become activated. Our long term goal is to define the events leading to immune mediated platelet clearance in man and develop strategies to prolong platelet survival in disease states associated with shortened platelet survival. Specifically I intend to: 1.) Isolate human EBV transformed B cell lines which secrete monoclonal autoantibodies specific for aged or activated platelets. 2.) Biochemically characterize the platelet membrane changes that occur with aging or activation as recognized by these human monoclonal autoantibodies. 3.) Characterize the pattern of antigen expression: during normal platelet aging in vitro and in vivo, following platelet activation in vivo and in vitro, and in disease states associated with shortened platelet survival.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Research Manpower Review Committee (MR)
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Fred Hutchinson Cancer Research Center
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Kunicki, T J; Annis, D S; Gorski, J et al. (1991) Nucleotide sequence of the human autoantibody 2E7 specific for the platelet integrin IIb heavy chain. J Autoimmun 4:433-46
Hiraiwa, A; Nugent, D J; Milner, E C (1990) Sequence analysis of monoclonal antibodies derived from a patient with idiopathic thrombocytopenic purpura. Autoimmunity 8:107-13
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
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Kunicki, T J; Nugent, D J; Staats, S J et al. (1988) The human fibroblast class II extracellular matrix receptor mediates platelet adhesion to collagen and is identical to the platelet glycoprotein Ia-IIa complex. J Biol Chem 263:4516-9
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