CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells

Meunier, Sylvain; Menier, Catherine; Marcon, Elodie; Lacroix‐Desmazes, Sébastien; Maillère, Bernard

doi:10.1182/bloodadvances.2017008706

Cited by 28 publications

(37 citation statements)

References 27 publications

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“…The non-HA (healthy control) group also showed gene expression patterns related to leukocyte-mediate immunity, regulation of T-cell activation, hypoxia responses, and regulation of vesicle-mediated transport ( Table 2). This is consistent with nonhemophilic T-cell responses to FVIII characterized initially by the Conti-Fine group (33), as well as more recent analyses that included calculation of FVIII-specific T-cell precursors by the Maillere group (11). FVIII is a large, acute-phase protein (60), and although its role in promoting coagulation via acceleration of FIXa enzymatic activity has been well-characterized, it may also participate in other biological processes and physiological responses, some of which may contribute to its unusually high immunogenicity compared to many other therapeutic proteins.…”

Section: Discussionsupporting

confidence: 87%

Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators

et al. 2020

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Formation of pathological anti-FVIII antibodies, or "inhibitors," is the most serious complication of therapeutic FVIII infusions, affecting up to 1/3 of severe Hemophilia A (HA) patients. Inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development vs. immune tolerance, achieved with or without Immune Tolerance Induction (ITI) therapy, are not well-understood. To address these questions, temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) was carried out for HA subjects with and without a current or historic inhibitor using RNA-Seq. PBMCs were isolated from 40 subjects in the following groups: HA with an inhibitor that resolved either following ITI or spontaneously; HA with a current inhibitor; HA with no inhibitor history and non-HA controls. PBMCs were stimulated with 5 nM FVIII and RNA was isolated 4, 16, 24, and 48 h following stimulation. Time-series differential expression analysis was performed and distinct transcriptional signatures were identified for each group, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. Subjects with a current inhibitor showed differential expression of 56 genes and a clustering analysis identified three major temporal profiles. Interestingly, gene ontology enrichments featured innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A, and COLEC12. NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1β and TNFα, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. RNA-Seq results were validated by RT-qPCR, ELISAs, multiplex cytokine analysis, and flow cytometry. The inflammatory status of HA patients suffering from an ongoing inhibitor includes up-regulated innate immune modulators, which may act as ongoing danger signals that influence the responses to, and eventual outcomes of, ITI therapy.

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Section: Discussionsupporting

confidence: 87%

Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators

et al. 2020

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“…Several intriguing studies have indicated that many healthy individuals possess circulating CD4 + T cells that proliferate and secrete cytokines when stimulated with FVIII in vitro (93)(94)(95). Specificity of this T-cell response was further confirmed by a recent, elegant study in which FVIII-specific Tcell lines, which contained both naïve and memory subsets, were expanded from 16/16 non-HA blood donors (96). The calculated precursor frequency of FVIII-specific T cells was ∼1.7 per million CD4 + T cells.…”

Section: Cd4 + T-cell Response To Fviiimentioning

confidence: 89%

Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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“…The central tolerance process, however, is often imperfect and the escape of reactive cells into the periphery is still possible. FVIII reactive T cells can be found in both healthy donors and hemophilia A patients (12)(13)(14)(15). Therefore, the recognition of self antigens (FVIII, in this case) is possible and can occur in healthy individuals.…”

Section: Self Recognition Central Tolerance and Inhibitor Developmenmentioning

confidence: 99%

Tolerance to FVIII: Role of the Immune Metabolic Enzymes Indoleamine 2,3 Dyoxigenase-1 and Heme Oxygenase-1

et al. 2020

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The occurrence of neutralizing anti-FVIII antibodies is a major complication in the treatment of patients affected by hemophilia A. The immune response to FVIII is a complex, multi-factorial process that has been extensively studied for the past two decades. The reasons why only a proportion of hemophilic patients treated with FVIII concentrates develop a clinically significant immune response is incompletely understood. The "danger theory" has been proposed as a possible explanation to interpret the findings of some observational clinical studies highlighting the possible detrimental impact of inflammatory stimuli at the time of replacement therapy on inhibitor development. The host immune system is often challenged to react to FVIII under steady state or inflammatory conditions (e.g., bleeding, infections) although fine tuning of mechanisms of immune tolerance can control this reactivity and promote longterm unresponsiveness to the therapeutically administered factor. Recent studies have provided evidence that multiple interactions involving central and peripheral mechanisms of tolerance are integrated by the host immune system with the environmental conditions at the time of FVIII exposure and influence the balance between immunity and tolerance to FVIII. Here we review evidences showing the involvement of two key immunoregulatory oxygenase enzymes (IDO1, HO-1) that have been studied in hemophilia patients and pre-clinical models, showing that the ability of the host immune system to induce such regulatory proteins under inflammatory conditions can play important roles in the balance between immunity and tolerance to exogenous FVIII.

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CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells

Abstract: Key Points• Many CD4 T cells specific for FVIII escape thymic selection in healthy donors, revealing a low central tolerance to FVIII.• Some FVIII-specific CD4 T cells are differentiated into memory cells but do not expand.

Cited by 28 publications

References 27 publications

Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators

Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators

Tolerating Factor VIII: Recent Progress

Tolerance to FVIII: Role of the Immune Metabolic Enzymes Indoleamine 2,3 Dyoxigenase-1 and Heme Oxygenase-1

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