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

Jing, Weiqing; Chen, Juan; Cai, Yuanhua; Chen, Yingyu; Schroeder, Jocelyn A.; Johnson, Bryon D.; Cui, Weiguo; Shi, Qizhen

doi:10.1182/bloodadvances.2019000650

Cited by 26 publications

(20 citation statements)

References 56 publications

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“…In a subsequent study, they identified an immunodominant CD4 + T-cell epitope recognized by these mice (80). The recent demonstration of expanded CD4 + T-follicular helper cells in spleens of FVIII-deficient mice with an inhibitor response has confirmed the expected essential role of this T-cell subset in providing B-cell help (43). Murine studies have also demonstrated an essential role for activated T cells in the memory B-cell response to FVIII, and the requirement for direct T-cell contact in order to re-stimulate these cells (81).…”

Section: Cd4 + T-cell Response To Fviiimentioning

confidence: 85%

“…T follicular helper cells within germinal centers both select FVIII-specific B cells and drive affinity maturation and class-switching of their B-cell receptors, ultimately generating plasma cells that secrete high-affinity antibodies. Indeed, FVIII-deficient mice showed increased germinal center formation, proliferation of splenic Tfollicular helper cells in vitro, and accumulation of T-follicular CD4 + T cells in the spleen following FVIII immunization (43).…”

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

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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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Section: Cd4 + T-cell Response To Fviiimentioning

confidence: 85%

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

Tolerating Factor VIII: Recent Progress

et al. 2020

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“…Finally, several studies in recent years have highlighted the important involvement of the cells in the marginal zone of the spleen in early FVIII uptake and in the development of inhibitors in mice, including splenic follicular T cells, marginal zone B cells, marginal zone macrophages, and marginal zone metallophilic macrophages (26,45,111,112). Despite this, the mechanisms of interaction between these cells in the induction of immune responses or tolerance to FVIII have yet to be described.…”

Section: Discussionmentioning

confidence: 99%

Escape or Fight: Inhibitors in Hemophilia A

Merlin

Follenzi

2020

Front. Immunol.

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Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.

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“…This observation established that CD4 + T cells play a critical role in maintaining established inhibitor responses, as well as providing initial Teffector help. Subsequent studies of both human blood samples and HA mouse models have further characterized CD4 + Tcell responses to FVIII (10,15,(30)(31)(32)(33)(34)(35). The possible roles of additional leukocyte subsets, and of inflamed endothelium, etc.…”

Section: Discussionmentioning

confidence: 99%

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

Abstract: Key Points Anti-FVIII inhibitory antibody development is TFH-cell dependent. FVIII restimulation can specifically induce FVIII-primed TFH-cell proliferation.

Cited by 26 publications

References 56 publications

Tolerating Factor VIII: Recent Progress

Tolerating Factor VIII: Recent Progress

Escape or Fight: Inhibitors in Hemophilia A

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

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