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J Thromb Haemost. 2011 Aug;9(8):1524-33. doi: 10.1111/j.1538-7836.2011.04351.x.

Induction of tolerance to factor VIII by transient co-administration with rapamycin.

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Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.



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.


Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII.


A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed.


The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). 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.


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.

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