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

B. Moghimi, Brandon Wilder, S. Nayak, D. M. Markusic, C. S. Mah, Roland W. Herzog

Research output: Contribution to journalArticle

65 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1524-1533
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume9
Issue number8
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

Fingerprint

Factor VIII
Sirolimus
Hemophilia A
T-Lymphocytes
Antibody Formation
Antigens
Immune Tolerance
Adoptive Transfer
Intravenous Injections
Interleukin-4
Interleukin-10
Mental Competency
Interleukin-2
Interleukin-6
Hemorrhage
Therapeutics
Pharmaceutical Preparations

Keywords

  • Factor VIII
  • Hemophilia
  • Inhibitor
  • Rapamycin
  • T helper cell
  • Tolerance

ASJC Scopus subject areas

  • Hematology

Cite this

Induction of tolerance to factor VIII by transient co-administration with rapamycin. / Moghimi, B.; Wilder, Brandon; Nayak, S.; Markusic, D. M.; Mah, C. S.; Herzog, Roland W.

In: Journal of Thrombosis and Haemostasis, Vol. 9, No. 8, 01.08.2011, p. 1524-1533.

Research output: Contribution to journalArticle

Moghimi, B. ; Wilder, Brandon ; Nayak, S. ; Markusic, D. M. ; Mah, C. S. ; Herzog, Roland W. / Induction of tolerance to factor VIII by transient co-administration with rapamycin. In: Journal of Thrombosis and Haemostasis. 2011 ; Vol. 9, No. 8. pp. 1524-1533.
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