ArticleBlood advances2019
Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 32 citations in OpenAlex.
- B cell-activating factor modulates the factor VIII immune response in hemophilia A.The Journal of clinical investigation · 2021Trial
- Differential expression of miR-128 in memory T cells of patients with severe hemophilia A with and without inhibitors.Research and practice in thrombosis and haemostasis · 2026Article
- The T follicular helper/T follicular helper regulatory pathway in FVIII immune responses in mice.Blood · 2025Article
- CXCR5 engineered human and murine Tregs for targeted suppression in secondary and tertiary lymphoid organs.Frontiers in immunology · 2025Article
- Transplanted gene-modified placental cells boost FVIII activity in pediatric sheep without eliciting immunity, toxicity, or adverse events.Frontiers in immunology · 2025Article
- Chemokine CXCL13 facilitates anti-FVIII inhibitory antibody development in hemophilia A patients and murine models.International immunopharmacology · 2024Article
- Marginal Zone B Cells Represent a Conserved Initiating Player in the Immune Response to Factor VIII in Hemophilia A Mice.Thrombosis and haemostasis · 2024Article
- The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A.Frontiers in immunology · 2024Article
- Vagal innervation limits brain injury by inhibiting gut-selective integrin-mediated intestinal immunocyte migration in intracerebral hemorrhage.Theranostics · 2024Article
- Factor IX administration in the skin primes inhibitor formation and sensitizes hemophilia B mice to systemic factor IX administration.Research and practice in thrombosis and haemostasis · 2023Article
- Article
- Suppression of anti-drug antibody formation against coagulation factor VIII by oral delivery of anti-CD3 monoclonal antibody in hemophilia A mice.Cellular immunology · 2023Article
- Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs.The Journal of clinical investigation · 2022Article
- Risk factors for inhibitors in hemophilia A based on RNA-seq and DNA methylation.Research and practice in thrombosis and haemostasis · 2022Article
- Immunogenicity of Current and New Therapies for Hemophilia A.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Article
- Association of Platelet Desialylation and Circulating Follicular Helper T Cells in Patients With Thrombocytopenia.Frontiers in immunology · 2022Article
- Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway.Frontiers in immunology · 2022Article
- Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications.Frontiers in immunology · 2022Review
- Recent advances in lentiviral vectors for gene therapy.Science China. Life sciences · 2021Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The development of neutralizing anti-FVIII antibodies (inhibitors) is a major complication of FVIII protein replacement therapy in patients with hemophilia A (HA). Although multiple lines of evidence indicate that the immune response against FVIII is CD4 T-cell-dependent and many FVIII-derived CD4 epitopes have already been discovered, the role of T follicular helper (TFH) cells in FVIII inhibitor development is unknown. TFH cells, a newly identified subset of CD4 T cells, are characterized by expression of the B-cell follicle-homing receptor CXCR5 and PD-1. In this study, we show for the first time that IV FVIII immunization induces activation and accumulation and/or expansion of PD-1+CXCR5+ TFH cells in the spleen of FVIII-deficient (FVIIInull) mice. FVIII inhibitor-producing mice showed increased germinal center (GC) formation and increased GC TFH cells in response to FVIII immunization. Emergence of TFH cells correlated with titers of anti-FVIII inhibitors. Rechallenge with FVIII antigen elicited recall responses of TFH cells. In vitro FVIII restimulation resulted in antigen-specific proliferation of splenic CD4+ T cells from FVIII-primed FVIIInull mice, and the proliferating cells expressed the TFH hallmark transcription factor BCL6. CXCR5+/+ TFH-cell-specific deletion impaired anti-FVIII inhibitor production, confirming the essential role of CXCR5+/+ TFH cells for the generation of FVIII-neutralizing antibodies. Together, our results demonstrate that the induction of activated TFH cells in FVIIInull mice is critical for FVIII inhibitor development, suggesting that inhibition of FVIII-specific TFH-cell activation may be a promising strategy for preventing anti-FVIII inhibitor formation in patients with HA.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.