The molecular mechanisms of immunomodulation and tolerance induction to factor VIII

Waters, Braden; Lillicrap, David

doi:10.1111/j.1538-7836.2009.03538.x

Cited by 83 publications

(78 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…42,43 The exact mechanism of the immune-tolerance induction in this hemophilia A dog study is currently unknown. Previous work in murine and nonhuman primate models has shown that sustained AAV-mediated expression of transgenes can induce tolerance, and that this sustained expression is dependent on regulatory T cells.…”

Section: Discussionmentioning

confidence: 97%

Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Finn

Ozelo

Sabatino

et al. 2010

Blood

140

173

View full text Add to dashboard Cite

Inhibitory antibodies to factor VIII (FVIII) are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of patients. Current treatment for inhibitors is based on long-term, daily injections of large amounts of FVIII protein. Liver-directed gene therapy has been used to induce antigen-specific tolerance, but there are no data in hemophilic animals with pre-existing inhibitors. To determine whether sustained endogenous expression of FVIII could eradicate inhibitors, we injected adeno-associated viral vectors encoding canine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs. In 3 dogs, a transient increase in inhibitor titers (up to 7 Bethesda Units [BU]) at 2 weeks was followed by continuous decline to complete disappearance within 4-5 weeks. Subsequently, an increase in cFVIII levels (1.5%-8%), a shortening of clotting times, and a reduction (> 90%) of bleeding episodes were observed. Immune tolerance was confirmed by lack of antibody formation after repeated challenges with cFVIII protein and normal protein half-life. A fourth dog exhibited a strong early anamnestic response (216 BU), with slow decline to 0.8 BU and cFVIII antigen detection by 18 months after vector delivery. These data suggest that liver gene therapy has the potential to eradicate inhibitors and could improve the outcomes of hemophilia A patients. (Blood. 2010;116(26): 5842-5848) IntroductionThe development of neutralizing antibodies to replacement protein is a major complication of protein and enzyme replacement therapies for several genetic diseases. Hemophilia A is an X-linked bleeding disorder characterized by deficiency in the activity of factor VIII (FVIII), a key component of the coagulation cascade. The disease occurs in approximately 1 in 10 000 live births worldwide, and Ͼ 40% of these patients have severe disease, with FVIII activity Ͻ 1% of normal. 1 Infusion of plasma-derived or recombinant FVIII is the standard treatment. Alloantibodies (inhibitors) that neutralize the protein-replacement therapy develop in 20% to 30% of young patients with severe and moderate hemophilia A, resulting in high morbidity and mortality, 2,3 and this is a growing problem for adults as well. 4,5 Risk factors for inhibitor formation include both genetic and environmental factors. Underlying mutations in the FVIII gene, such as large gene deletions, nonsense mutations, and the most common mutation in severe hemophilia A patients, the inversion of intron 22, are all associated with inhibitor formation; however, it is not possible to predict with certainty which patients will develop inhibitors. For this reason, preventive strategies are not currently feasible. [6][7][8] Patients with high titers of inhibitors, defined as Ͼ 5 Bethesda units (BU), cannot usually be treated with FVIII replacement, necessitating the use of products that bypass the procoagulant effect of FVIII and are extremely expensive. 1 Thus, strategies for the eradication of inhibitors are of fundamental clinical relevance.Currently, the only pro...

show abstract

Section: Discussionmentioning

confidence: 97%

Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Finn

Ozelo

Sabatino

et al. 2010

Blood

140

173

View full text Add to dashboard Cite

show abstract

“…These new approaches have been tested in haemophilia A models and involve B cell and T cell immune modulation or FVIII antigen presentation (recently reviewed in Waters & Lillicrap, 2009). Although there would be many challenges to overcome in translating to the clinic, the development of tolerance induction strategies based on immune modulation appears to be an attainable perspective.…”

Section: Discussionmentioning

confidence: 99%

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

2010

View full text Add to dashboard Cite

SummaryImmune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors in severe haemophilia A patients. Thirty years experience has shown high success rates (60-80%) with heterogeneous dose regimens and has led to the identification of clinical features that define the patients' prognostic profile. Children with recently diagnosed inhibitors are the best candidates for ITI and adequate management may further contribute to improve the shortand long-term ITI outcome. In these patients inhibitor eradication represents a cost-effective option because it enables the restoration of FVIII prophylaxis and consequently prevents arthropathy development. Adults with long-standing inhibitors often show bad predictors of ITI outcome, however, ITI may be considered as a suitable and costeffective approach in cases with frequent bleeds that are not satisfactorily controlled by by-passing treatment and/or when orthopaedic surgery is needed. Optimal ITI regimens should be established in these different settings and randomized trials are addressing these issues. This article reviews the available literature evidence and clinical implications with current recommendations on ITI management, and highlights the issues still unsolved.

show abstract

“…Possible mechanisms by which tolerance is induced by ITI include inhibition of B-cell memory and induction of T-cell anergy, anti-idiotypic antibodies, or suppressor T cells. 29 Overall, ITI is successful in ;70% of patients with hemophilia A and 30% of those with hemophilia B. 30 When successful, patients can return to using factor concentrates for the routine prevention and treatment of bleeding.…”

Section: Immune Tolerance Inductionmentioning

confidence: 99%

Toward optimal therapy for inhibitors in hemophilia

Kempton

Meeks

2014

Blood

134

156

View full text Add to dashboard Cite

Treatment of patients with hemophilia A and B has undergone significant advances during the past 2 decades. However, despite these advances, the development of antibodies that inhibit the function of infused clotting factor remains a major challenge and is considered the most significant complication of hemophilia treatment. This chapter reviews current tools available for the care of patients with inhibitors and highlights areas where progress is imminent or strongly needed. For management of bleeding, bypassing agents remain the mainstay of therapy. Recombinant factor VIIa and activated prothrombin complex concentrates are similarly effective in populations of patients with hemophilia and inhibitors; however, individuals may show a better response to one agent over another. Recent studies have shown that prophylaxis with bypassing agents can reduce bleeding episodes by ∼50%-80%. The prophylactic use of bypassing agents is an important tool to reduce morbidity in patients before they undergo immune tolerance induction (ITI) and in those with persistent high titer inhibitors, but cost and lack of convenience remain barriers. Because of the significant burden that inhibitors add to the individual patient and the health care system, inhibitor eradication should be pursued in as many patients as possible. ITI is an effective tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a return to a normal factor VIII response in ∼60% of patients. However, for the group of patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed.

show abstract

The molecular mechanisms of immunomodulation and tolerance induction to factor VIII

Cited by 83 publications

References 76 publications

Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

Toward optimal therapy for inhibitors in hemophilia

Contact Info

Product

Resources

About