Mariarosaria Miranda, Eelke Brandsma, Lotte Robben, Helena Van Dender, Floris P J van Alphen, Karin Fijnvandraat, Maartje van den Biggelaar, Sebastien Lacroix-Desmazes, Robin van Bruggen, Jan Voorberg
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引用次数: 0
Abstract
Background: The main complication in hemophilia A treatment is the development of inhibitory antibodies against factor VIII (FVIII). Immune tolerance induction, the gold standard for eradicating anti-FVIII antibodies, is efficient in only 60-80% of cases. This underscores the need for more efficient induction of tolerance in hemophilia A patients with FVIII inhibitors.
Objectives: In this study we explored whether red blood cells (RBCs) can be utilized as antigen delivery system to modulate the immune response against FVIII.
Methods: Two promiscuously HLA-DR presented peptides derived from the A2 and C1 domains of FVIII were fused to the TAT-cell penetrating peptide and incubated with RBCs.
Results: Biotinylated TAT-A2 and TAT-C1 peptides were found to interact with RBCs as shown by flow cytometry and imaging flow cytometry. Moreover, macrophages efficiently phagocytosed TAT-FVIII peptide-treated RBCs. Using mass spectrometry based immunopeptidomics we established that TAT-FVIII peptides were presented on MHC class II of macrophages that phagocytosed TAT-peptide pulsed RBCs. Specifically, the TAT-A2 peptide exhibited efficient processing and presentation on HLA-DR molecules. Importantly, incubation of TAT-C1 peptide treated RBCs loaded macrophages with a FVIII-specific T cell hybridoma led to a significant increase in IL-2 production, suggesting functional presentation of TAT-C1 derived peptides by macrophages.
Conclusions: Our findings indicate that RBCs can serve as effective vehicle for the delivery of FVIII derived peptides to antigen presenting cells. The successful display of T cell epitopes on APC using ex vivo loaded RBC may be potentially utilized to modulate pathogenic immune responses such as observed in a subset of patients with hemophilia A.
期刊介绍:
The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community.
Types of Publications:
The journal publishes a variety of content, including:
Original research reports
State-of-the-art reviews
Brief reports
Case reports
Invited commentaries on publications in the Journal
Forum articles
Correspondence
Announcements
Scope of Contributions:
Editors invite contributions from both fundamental and clinical domains. These include:
Basic manuscripts on blood coagulation and fibrinolysis
Studies on proteins and reactions related to thrombosis and haemostasis
Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms
Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases
Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.