Abstract
Coagulation Factor VIII (FVIII) replacement therapy in hemophilia A patients is complicated by the development of inhibitory antibodies, which often render the treatment ineffective. Previous studies demonstrated a strong correlation between induction of regulatory T cells (Treg) and tolerance to the therapeutic protein. We, therefore, set out to evaluate whether the adoptive transfer of FVIII-specific CD4+ Treg cells prevents inhibitor response to FVIII protein therapy. To this end, we first retrovirally transduced FoxP3+ into FVIII-specific CD4+ cells, which resulted in cells that stably express FoxP3, are phenotypically similar to peripherally induced Tregs and are antigen specific suppressors, as judged by in vitro assays. Upon transfer of the FVIII-specific CD4+ FoxP3+ cells into hemophilia A mice, development of inhibitory antibodies in response to administering FVIII protein was completely suppressed. Suppression was extended for 2 months, even after transferred cells were no longer detectable in the secondary lymphoid organs of recipient animals. Upon co-transfer of FoxP3+-transduced cells with the B cell depleting anti-CD20 into mice with pre-existing inhibitory antibodies to FVIII, the escalation of inhibitory antibody titers in response to subsequent FVIII protein therapy was dramatically reduced. We conclude that reprogramed FoxP3 expressing cells are capable of inducing the in vivo conversion of endogenous FVIII peripheral Tregs, which results in sustained suppression of FVIII inhibitors caused by replacement therapy in recipient hemophilia A animals.
Highlights
Hemophilia A is one of the most common X-linked recessive disorders, affecting 1 in 5,000 male births worldwide
We showed that adoptive transfer of CellTrace Violet+FoxP3GFP+ DO11.10+ CD4+ T cells into recipient animals of the same strain was capable of inducing antigen specific Tregs in the recipient mice, which was dependent on the presence of antigen
For genetic disorders like severe hemophilia A where significant mutations do not allow expression of the protein of interest, central tolerance often cannot be established resulting in very few antigen specific Tregs
Summary
Hemophilia A is one of the most common X-linked recessive disorders, affecting 1 in 5,000 male births worldwide. This blood clotting disorder is caused by mutations in the factor VIII (FVIII) gene, leading to a deficiency in FVIII production. The most challenging issue with conventional factor replacement therapy in the treatment of hemophilia A is the development of antibodies against infused FVIII, which occur in 25–30% of severe hemophilia A patients. Immune tolerance induction (ITI) for the eradication of inhibitors via frequent and high dose exposure to FVIII concentrates for a prolonged period is expensive and not always successful, especially in severe hemophilic patients [8]. There is very little information on the immune interactions that lead to the development of inhibitors, it has been described to be a T helper dependent process involving antigen uptake and presentation that requires the co-operation of multiple macrophage, dendritic cell or B cell subsets of antigen presenting cells (APC) [11,12,13,14,15]
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