| title: | Immune response to coagulation factor VIII in haemophilia A |
|---|---|
| reg no: | ETF5454 |
| project type: | Estonian Science Foundation research grant |
| subject: |
1.6-1.9. Chemistry and Molecular Biology 3. Medical Sciences |
| status: | completed |
| institution: | TU Faculty of Medicine |
| head of project: | Ade Kallas |
| duration: | 01.01.2003 - 31.12.2005 |
| description: | Frequent bleedings in haemophilia A patients are treated by replacing the missing coagulation factor VIII by administration of FVIII preparations fractionated from plasma or manufactured by recombinant DNA technology. The most serious consequence of the replacement therapy and also gene therapy is the development of antibodies against exogenous FVIII. The mutations in the FVIII gene lead to the lack of FVIII protein production and the immune system recognises the administered FVIII as the foreign protein. The treatment of haemophilia A patients with FVIII antibodies is complicated since the activity of administered FVIII preparation is inhibited. The immune tolerance can be achieved by the administration of FVIII preparation at higher doses for long time. Mutations in exon 16 or 17 of FVIII gene of mouse results in deficiency of FVIII (FVIII coagulation activity <1% of normal) and haemophilia A like symptoms. Administration of human FVIII to these mouse stops the bleeding and decreases the frequency of bleedings, however, after 4-6 administrations mouse develop FVIII antibodies. So far recombinant FVIII preparations have been used in mouse model studies, but the plasma derived FVIII preparations are still widely in use in replacement therapy of haemophilia A patients. The lower incidence of FVIII antibody development has been observed in patients, which have been treated only with plasma derived FVIII preparations (6-28%) compared to those patients, which have been treated with recombinant FVIII preparation (23-32%). The plasma derived FVIII preparations have been successfully used in immune tolerance treatment. The aim of our study is to investigate the differences in development and production of FVIII-specific T- and B-cells as the response to the administration of plasma derived and recombinant FVIII preparations to haemophilia A mice. Different plasma derived FVIII concentrates are analysed for the presence and activity of von Willebrand factor, the physiological carrier of FVIII and other components of the preparation, which may have immunomodulatory effect. According to the results of in vitro study, the FVIII preparation with the optimal properties will be used for in vivo experiments and its effeciency will be compared with recombinant FVIII preparation in haemophilia A mouse model. Next, the immune tolerance induction by using the same FVIII preparations is investigated in haemophilia A mouse model. The results of our study could be used for the optimization of the immune tolerance treatment protocols in haemophilia A patients and for choosing the appropriate FVIII concentrate with the best outcome. These results can also lead to creating new strategies for immune tolerance treatment. |
| project group | ||||
|---|---|---|---|---|
| no | name | institution | position | |
| 1. | Ade Kallas | TU Faculty of Medicine | Assistant-researcher | |
| 2. | Sulev Kuuse | TU BGMR | Head of the Laboratory Animals' Facility | |
| 3. | Ilvi Rimm | UT, Institute of Cell and Molecular Biology | Senior laboratory assistant | |