Premium
Induction of tolerance to factor VIII by transient co‐administration with rapamycin
Author(s) -
MOGHIMI B.,
SACK B. K.,
NAYAK S.,
MARKUSIC D. M.,
MAH C. S.,
HERZOG R. W.
Publication year - 2011
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2011.04351.x
Subject(s) - foxp3 , immune tolerance , medicine , immune system , adoptive cell transfer , immunology , antigen , antibody , t cell , il 2 receptor , pharmacology
See also Miao CH. Tilt balance towards regulation: evolving new strategy for treatment of hemophilia inhibitors. This issue, pp 1521–3.DOI: 10.1111/j.1538‐7836.2011.04351.x . Summary. 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.