Abstract

This research proposal seeks information about the nature of human antibodies that inactivate factor VIII procoagulant (antihemophilic factor) activity and the antigenic determinants with which they react. It is based on the contention that effective means for treatment and/or prevention of inhibitors to factor VIII are not likely to be developed until this basic information is available. There are five specific goals: 1. Immunochemical characterization of the structure and function of factor VIII procoagulant protein (VIII:C) using high-titer human anti-VIII:C and hybridoma anti-VIII:C as probes. 2. Preparation of monoclonal antibodies to the factor VIII procoagulant protein by both murine-murine fusions and human-murine fusions. 3. Preparation of anti-idiotype antibodies that react with specific determinants of human anti-VIII:C antibodies. These antibodies will be obtained by both conventional (rabbit immunization followed by antiserum adsorption) and hybridoma methods. The anti-idiotype antibodies will be used with a panel of high titer human anti-VIII:C to determine if there are common determinants shared by different human anti-VIII:C. 4. Immunochemical analysis of human anti-VIII:C to determine heavy and light chain classes by methods that are independent of coagulation assays. 5. Identification of the organ and cell type responsible for VIII:C synthesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036099-03
Application #
3350742
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1985-09-01
Project End
1990-03-31
Budget Start
1987-09-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20037

  Publications

Qian, J; Collins, M; Sharpe, A H et al. (2000) Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 95:1324-9
Qian, J; Burkly, L C; Smith, E P et al. (2000) Role of CD154 in the secondary immune response: the reduction of pre-existing splenic germinal centers and anti-factor VIII inhibitor titer. Eur J Immunol 30:2548-54
Saenko, E L; Loster, K; Josic, D et al. (1999) Effect of von Willebrand Factor and its proteolytic fragments on kinetics of interaction between the light and heavy chains of human factor VIII. Thromb Res 96:343-54
Young, M; Inaba, H; Hoyer, L W et al. (1997) Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. Am J Hum Genet 60:565-73
Saenko, E L; Scandella, D (1997) The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von willebrand factor. J Biol Chem 272:18007-14
Koshihara, K; Qian, J; Lollar, P et al. (1995) Immunoblot cross-reactivity of factor VIII inhibitors with porcine factor VIII. Blood 86:2183-90
Hoyer, L W; Scandella, D (1994) Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients. Semin Hematol 31:1-5
Hoyer, L W (1994) Hemophilia A. N Engl J Med 330:38-47
Hoyer, L W (1993) Characterization of dysfunctional factor VIII molecules. Methods Enzymol 222:169-76
McGinniss, M J; Kazazian Jr, H H; Hoyer, L W et al. (1993) Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A. Genomics 15:392-8

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