The purpose of this study is to determine the risk factors associated with inhibitor formation in hemophilia A and to study the mechanism of tolerance in the murine hemophilia A model. Clinical data on 364 individuals with hemophilia and inhibitors, and stored frozen plasma and white cells on 189 of these, identified in the Hemophilia Malignancy Study (HMS), and the hemophilia A murine model are available for study. Inhibitor formation in individuals with hemophilia is a difficult therapeutic challenge, refractory to standard treatment, potentially life-threatening, costly, and a potential complication of new treatment, such as gene therapy. The major hypothesis of this study is that suppression of immunoregulatory cytokines will prevent factor VIII inhibitor formation in the hemophilia A murine model: if successful, a treatment protocol could be developed for individuals identified to be at highest risk for inhibitor formation. Through this approach to the epidemiology and immunology of inhibitor formation, the investigators may improve the health care of individuals with hemophilia.
The specific aims i nclude: (1) A case-control study comparing prevalent hemophilia patients with inhibitors identified in the HMS Study with three age-matched controls without inhibitors to determine clinical and laboratory characteristics associated with inhibitor development. (2) a histocompatibility study identifying patterns of HLA Class II antigens by molecular typing in hemophilic subjects identified in HMS, with and without inhibitors, which may be linked to inhibitor formation. (3) An animal tolerance study in the hemophilia A murine model, evaluating blockade of T cell costimulatory pathways by CTLA4-Ig and anti-CD40L mAb, to prevent inhibitor formation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061937-03
Application #
6184570
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S2))
Project Start
1998-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$262,335
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ragni, Margaret V; Wu, Wenhu; Liang, Xiaoyan et al. (2009) Factor VIII-pulsed dendritic cells reduce anti-factor VIII antibody formation in the hemophilia A mouse model. Exp Hematol 37:744-54
Ragni, M V; Ojeifo, O; Feng, J et al. (2009) Risk factors for inhibitor formation in haemophilia: a prevalent case-control study. Haemophilia 15:1074-82