Abstract Number: PB0184
Meeting: ISTH 2022 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic
Background: Hemophilia A (HemA) is the most common inherited bleeding disorder, caused by deficiency of coagulation factor VIII (FVIII). Severe affected individuals follow a prophylactic treatment with intravenous replacement therapy of recombinant or plasma derived FVIII. Unfortunately, up to 30% of patients develop inhibitory antibodies (inhibitors) against this protein. Eradication of these inhibitors can be accomplished via immune tolerance induction (ITI) through frequent high-dose administration of FVIII, but tolerance is only achieved in about 70% of patients. The molecular mechanism as well as environmental factors which disrupt this process are mainly unknown.
Aims: The aim of this study is to identify potential environmental effects on tolerance induction within Hemophilia A mice. In detail, the stability of tolerance is analyzed upon an influenza A infection.
Methods: To resemble the ITI process in hemophilic mice, HemA were injected with rFVIII twice a week in contrast to the control group which receives weekly injections. To study the effect of external factors, we additionally induced an infection with influenza in the twice a week treated group.
Results: FVIII immunization induces a robust immune response in HemA mice with FVIII-specific IgG formation and low amounts of active FVIII in serum. In the ITI group a FVIII-tolerogenic phenotype is initiated by increasing the amounts of active FVIII and apoptosis rate of FVIII-specific B cells. In correlation, PD-1 expression on FVIII+ B cells is enhanced too. Moreover, there is an increase in the FVIII-specific amount of FVIII-specific regulatory T cells. On top of that, preliminary results after viral infection during ITI treatment suggest a decrease in tolerance to FVIII, displayed as less active FVIII and significant reduction of FVIII-specific Tregs.
Conclusion(s): The established high dose protocol allows the analysis of molecular mechanisms of tolerance induction. This process is mediated by FVIII-specific Tregs and is altered upon an infection.
To cite this abstract in AMA style:
Jurado-Mestre B, Kotov V, Maione A, Oldenburg J, Kurts C, Becker-Gotot J. FVIII-specific Immune Response in Hemophilia A Mice Upon Infection [abstract]. https://abstracts.isth.org/abstract/fviii-specific-immune-response-in-hemophilia-a-mice-upon-infection/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/fviii-specific-immune-response-in-hemophilia-a-mice-upon-infection/