One of the most important problems of transfusion medicine is the induction of the immune response by polymorphic proteins that circulate in plasma or are borne by circulating blood cells and vascular endothelium. A second, very important problem of transfusion medicine is the clinically relevant protein dysfunction that can result from certain protein polymorphisms. In the case of blood coagulation proteins, such dysfunction can compromise hemostasis. The objective of this Program application is to study such t)olvmorphisms in protein structure and expression and their relationship to blood cell function, hematoloitic disease and transfusion medicine. In this Program, both basic science and clinical science related to selected aren of study are interwoven into six mutually supportive, coflabomtive projects. 1) The immunogenicity of human platelet integrins will be studied using platelet glycoprotein Hb- Ma as the prototype. Specific epitopes recognized by human isoantibodies, alloantibodies and autoantibodies will be identified, human monoclonal antibodies will be isolated, and the idiotype repertoires represented by these antibodies will be defined. 2) The molecular biology of humsin platelet integrins will be investigated with major focus upon glycoprotein Ilb-Ma. From platelet messenger RNA, the sequence of allelic forms of glycoproteins Ilb and lUa will be determined, allelic and variant molecules will be expressed in tmnsfected cells, and the genetic basis of inherited defects of platelet integrins will be determined. 3) The regulation of HLA class I antigen expression will be explored. The source of soluble plasma HLA class I antigens will be determined, the role of HLA immune complexes will be evaluated, and the effect of intravenous gamma-globulin upon HLA-mediated refractoriness to transfusion will be studied. 4) The genetic basis for certain variants of von Willebrand's disease will be identified. Emphasis will be placed on those variants wherein important functions of the von Willebrand factor (vWf) are compromised. These functions include vWf binding to coagulation factor VIII or platelet receptors and the multimerization and cellular processing of vWf. 5) The role of DNA polymorphism in the regulation of HLA class II expression on lymphocytes and endothelial cells will be studied. The effects of polymorphism in nontranslated, DNA sequences will be investigated together with the 1 effects of quantitative differences in messenger RNA production and/or degradation. 6) The modulation of TI cell allorecognition at the level of antigen presentation in conjunction with HLA class II antigens will be 'i investigated. The innuence of polymorphism in Class II antigens, T-cell receptors and immunogenic peptides will be incorporated into this analysis. The results of the studies proposed in this Program will contribute significantly to our understanding of the mechanisms whereby proteins in plasma and on blood celts or endothelium become immunogenic in the transfusion setting. Moreover, the results of this work will increase our basic knowledge of human blood protein structure-function relationships and lead to new alternatives for future therapeutic modalities.
Showing the most recent 10 out of 229 publications
