Tolerating Factor VIII: Novel Strategies to Prevent and Reverse Anti-FVIII Inhibitors

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Background

Hemophilia A (HA) is a bleeding disorder caused by mutations in the gene encoding blood coagulation factor VIII (FVIII). Bleeding is prevented by regular intravenous infusions of recombinant or plasma-derived FVIII protein. Unfortunately, up to one third of HA patients develop neutralizing anti-FVIII antibodies, clinically referred to as “inhibitors”, within their first 10-20 exposures. Inhibitors can also develop as a rare but severe autoimmune response to self-FVIII. Interestingly, low levels of FVIII-specific CD4+ T cells circulate in many non-hemophilic individuals, indicating escape from thymic deletion. Tolerogenic mechanisms preventing their expansion in the periphery are not yet understood. Clinical management of inhibitor patients entails intensive FVIII therapy referred to as “Immune Tolerance Induction” (ITI), in which titres subside over time in 70-80% patients who have access to this extraordinarily expensive and clinically demanding therapy.

The mechanisms of inhibitor development, and of tolerization through ITI, remain poorly understood. Importantly, the “danger” signals that lower the threshold for this adverse immune response have not been identified, and the molecular basis for the unusual immunogenicity of this therapeutic protein requires further elucidation. The strongest known risk factor for inhibitor development is the nature of the HA-causing mutation, with null mutations carrying higher risk. Racial disparities in clinical outcomes suggest that additional genetic elements contribute to increased risk of developing HA. However, some monozygotic twins have exhibited discordant inhibitor profiles, clearly indicating that environmental factors also play a significant role in the pathogenesis of this disease. HLA-restricted CD4+ T-cell responses to FVIII have been characterized, but there is no evidence for strong dominance of specific HLA alleles or haplotypes in influencing inhibitor risk. Novel approaches to induce tolerance, many at the preclinical stage, include: (i) oral or transplacental delivery of FVIII; (ii) manipulation of cellular populations or co-stimulation; (iii) generation of FVIII-specific T-regulatory cells; (iv) transient administration of corticosteroids, rapamycin or nanoparticles; (v) gene therapy to express FVIII in “immunoprivileged sites”, and (vi) the engineering of FVIII to make it less immunogenic, e.g. by incorporating an Fc or other moiety. All of these strategies have the goal of preventing or reversing inhibitor development.

Immune responses to therapeutic proteins such as FVIII provide scientists with an opportunity to carry out mechanistic studies in which the antigen is well defined. Accordingly, it is hoped that progress in “inhibitor” research will benefit the hemophilia community while providing insights into additional human immune disorders.

In this Research Topic, we welcome the submission of Review, Mini-Review, Original Research, Protocol, Method, Clinical Trial and Perspective articles that address, but are not limited to, the following topics:

1. Mechanisms of central and/or peripheral tolerance to FVIII.
2. Mechanisms of FVIII immunogenicity.
3. Clinical immune tolerance induction protocols for hemophilia A patients: correlates and mechanisms of successful and unsuccessful attempts to tolerize inhibitor patients.
4. Novel (pre-clinical) approaches to induce tolerance to FVIII, including cellular therapies, co-stimulatory agonists/antagonists, oral tolerance, gene therapy, and novel targets or approaches.
5. Clinical perspectives on novel approaches to induce tolerance to FVIII.


The article processing charges (APCs) for some articles in this collection were partly financed by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Maryland, USA (HJF), with funds which were originally granted by Grifols S.A, Barcelona, Spain (Grifols). Neither HJF nor Grifols influenced the content of any article in this collection.

Keywords: tolerance, hemophilia, cellular therapies, anti-drug antibodies

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