Abstract
Background: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia A mice develop high-titer inhibitors to recombinant human FVIII after a few intravenous injections. Objective: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. Methods: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. Results: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5months). Control mice formed high-titer inhibitors and had CD4 + T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4 +CD25 +FoxP3 + T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4 + T cells from tolerized mice also expressed TGF-β1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. Conclusions: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks.
Original language | English (US) |
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Pages (from-to) | 1524-1533 |
Number of pages | 10 |
Journal | Journal of Thrombosis and Haemostasis |
Volume | 9 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2011 |
Externally published | Yes |
Keywords
- Factor VIII
- Hemophilia
- Inhibitor
- Rapamycin
- T helper cell
- Tolerance
ASJC Scopus subject areas
- Hematology