A role for thrombin in the initiation of the immune response to therapeutic factor VIII

Skupsky, Jonathan; Zhang, Aihong; Su, Yan; Scott, David W.

doi:10.1182/blood-2008-10-186452

Cited by 43 publications

(52 citation statements)

References 44 publications

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“…ELISA and Bethesda assays for measuring anti-FVIII IgG titer and for the FVIII inhibitor titer, respectively, were performed as previously described [14,25]. Anti-trinitrophenyl and anti-uX174 titers were performed by ELISA on haptenated-BSA and uX174-coated plates, respectively.…”

Section: Immunologic Assaysmentioning

confidence: 99%

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Zhang

Rossi

Yoon

et al. 2016

Cellular Immunology

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a b s t r a c tThe immune response of hemophilia A patients to administered FVIII is a major complication that obviates this very therapy. We have recently described the use of synthetic, biodegradable nanoparticles carrying rapamycin and FVIII peptide antigens, to induce antigen-specific tolerance. Herein we test the tolerogenicity of nanoparticles that contains full length FVIII protein in hemophilia A mice, focusing on anti-FVIII humoral immune response. As expected, recipients of tolerogenic nanoparticles remained unresponsive to FVIII despite multiple challenges for up to 6 months. Furthermore, therapeutic treatments in FVIII-immunized mice with pre-existing anti-FVIII antibodies resulted in diminished antibody titers, albeit efficacy required longer therapy with the tolerogenic nanoparticles. Interestingly, durable FVIII-specific tolerance was also achieved in animals co-administered with FVIII admixed with nanoparticles encapsulating rapamycin alone. These results suggest that nanoparticles carrying rapamycin and FVIII can be employed to induce specific tolerance to prevent and even reverse inhibitor formation.Published by Elsevier Inc.

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Section: Immunologic Assaysmentioning

confidence: 99%

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Zhang

Rossi

Yoon

et al. 2016

Cellular Immunology

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“…In a direct comparison of the immunogenicity of equal doses of adjuvant-free ovalbumin and human fVIII in fVIII Ϫ/Ϫ mice, anti-fVIII antibody titers were ϳ 100-fold higher than antiovalbumin titers. 4 Model monomeric protein immunogens such as ovalbumin or lysozyme typically are given with adjuvants with a dose Ͼ 50-fold higher than the adjuvant-free doses of ϳ 10 g/kg or less that are required to produce fVIII inhibitors in patients with hemophilia A and fVIII Ϫ/Ϫ mice. In addition, although the concentration of fVIII in plasma is lower than all the other coagulation factors, it is the most commonly targeted coagulation factor in autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

A major determinant of the immunogenicity of factor VIII in a murine model is independent of its procoagulant function

Meeks

Cox

Healey

et al. 2012

Blood

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“…Enzyme-linked immunosorbent assay and Bethesda assays for measuring anti-FVIII IgG titer and for the FVIII inhibitor titer, respectively, were performed as previously described. 13,14 …”

Section: Immunologic Assaysmentioning

confidence: 99%

Effect of B-cell depletion using anti-CD20 therapy on inhibitory antibody formation to human FVIII in hemophilia A mice

Zhang

Skupsky

Scott

2011

Blood

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We herein tested the effect of B-cell depletion on tolerance induction to factor VIII (FVIII) in a mouse model of hemophilia A. Two subclasses of anti–mouse CD20 monoclonal antibodies with differential depletion effects were used. Thus, IgG1 anti-CD20 selectively depleted follicular B cells and spared marginal zone B cells, whereas IgG2a anti-CD20 efficiently depleted both. In FVIII primed mice, a single dose of either IgG1 or IgG2a anti-CD20 pretreatment prevented the increase in inhibitor formation in the majority of treated mice by subsequent daily, high-dose FVIII intravenous injection as a model for immune tolerance induction. However, the IgG1, but not the IgG2a, anti-CD20 pretreatment led to a significant increase of regulatory T cells in the spleen. Importantly, 3 months after the partial B-cell depletion with IgG1 anti-CD20, the FVIII-specific hyporesponsive state remained. We suggest a tolerogenic role of the remaining marginal zone B cells as a potential mechanism for anti-CD20 therapy.

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A role for thrombin in the initiation of the immune response to therapeutic factor VIII

Cited by 43 publications

References 44 publications

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

A major determinant of the immunogenicity of factor VIII in a murine model is independent of its procoagulant function

Effect of B-cell depletion using anti-CD20 therapy on inhibitory antibody formation to human FVIII in hemophilia A mice

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