The impact of von Willebrand factor on factor VIII memory immune responses

Abstract

Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis were used to study FVIII-primed CD4+ T cells. When CD4+ T cells from primed FVIIInull mice were restimulated with recombinant human FVIII (rhF8) plus recombinant human VWF (rhVWF) in vitro, the percentages of daughter CD4+ T cells were significantly decreased compared with the groups cultured with rhF8 only. Levels of interferon-γ and interleukin 10 were significantly lower in the rhF8 plus rhVWF groups than in the rhF8 groups. When memory B-cell pools from primed FVIIInull mice were cultured with rhF8 with or without rhVWF to induce differentiation of memory B cells into antibody-secreting cells (ASCs), the number of ASCs was significantly lower in the rhF8 plus VWF group than in the rhF8 group. When memory B-cell pools were transferred into NSGF8KO mice followed by rhF8 immunization with or without rhVWF, the titers of anti-F8 inhibitors and total immunoglobulin G were significantly higher in the rhF8 group than in the rhF8 plus rhVWF group, with an average difference of 2.23- and 2.04-fold. Together, our data demonstrate that VWF attenuates FVIII memory immune responses in HA mice.

Platelet-Targeted FVIII Gene Therapy Restores Hemostasis and Induces Immune Tolerance for Hemophilia A

“…Chen et al reported that VWF could attenuate FVIII-primed CD4 T cell proliferation in response to rhFVIII restimulation. Their studies showed that VWF could mitigate FVIII-specific memory B cell maturation and anti-FVIII antibody production both ex vivo in a memory B cell-based ELISPOT assay and in vivo in an immunocompromised FVIII deficient animal model upon rhFVIII restimulation (37). Results from this study support the notion that FVIII stored together with VWF in platelets may be less immunogenic compared to plasma FVIII in a milieu of preexisting anti-FVIII immunity.…”

Pharmacokinetic Studies of Factor VIII in Chinese Boys with Severe Hemophilia A

“…VWF, the binding partner for FVIII, protect FVIII from protease degradation in the circulation as a protector protein for FVIII. [ 22 ] The low level or nonfunctional of VWF could lead to the FVIII activity decrease. All PK parameters had a correlation with VWF:Ag in the study.…”

Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice

“…The titers of anti-FVIII inhibitors were determined by a modified Bethesda assay, as described in our previous reports. 31,32 C57BL/6J WT and mixed bone marrow (BM) chimeric mice, which had normal levels of endogenous murine FVIII, were immunized with recombinant human full-length FVIII (rhfF8, Kogenate FS; Bayer Pharma, Whippany, NJ) at a dose of 200 U/kg weekly for 4 weeks. One week after the last immunization, blood samples were collected for assays.…”