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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.

Author information

1
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.

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 3.5 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.

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.

PMID:
21585650
PMCID:
PMC3154987
DOI:
10.1111/j.1538-7836.2011.04351.x
[Indexed for MEDLINE]
Free PMC Article

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