Abstract

Quantitative, domain specific assays for inhibitors to factor VIII will be developed. These assays will be used in a comprehensive analysis of inhibitors in hemophilia A patients and patients with autoantibodies to factor VIII. The immunologic response to factor VIII infusions in previously untreated patients will be characterized. The T cell response in inhibitor development will be characterized by the generation of factor VIII-specific T cell lines from peripheral blood mononuclear cells from inhibitor patients. The factor VIII sequences that react with these T cells will be determined. A murine model of hemophilia will be used to study the interaction of factor VIII specific peptides, T cell receptors, and the MHC II complex.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036099-12
Application #
2771257
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1985-09-01
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
2000-08-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20006

  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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