Abstract Number: PB0178
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: The development of immune responses to therapeutic factor VIII (fVIII) implies fVIII internalization by antigen presenting cells. The study of the endocytosis of fVIII complexed to anti-fVIII IgG by dendritic cells (DCs) in vitro has yielded contradictory results with either increased, decreased or unchanged uptake. The differences could be due to the murine/human origin of the IgG and DCs, or to the nature of the anti-fVIII IgG: subclass and epitope specificity.
Aims: To understand how the nature of fVIII-IgG immune complexes (fVIII-IC) might influence fVIII uptake by DCs.
Methods: Four human monoclonal inhibitory anti-A2, anti-A3, anti-C1 and anti-C2 IgG were produced as IgG1κ or IgG4κ. Binding and inhibition of fVIII was validated by ELISA and Bethesda assay. Endocytosis of fVIII alone or complexed with single or pooled IgG was studied in vitro using human monocyte-derived DCs (MODCs) and blood DCs (bDCs).
Results: Binding to fVIII was not affected by the change in IgG subclass. The inhibitory activity was greater for IgG1κ than IgG4κ. Both MODCs and bDCs expressed surface FcgRIIA. With the exception of the anti-A2 IgG1κ, all single and pooled fVIII-IC reduced fVIII endocytosis by MODCs and bDCs, irrespective of the IgG subclass. The maturation profile of MODCs was not affected by the incubation of the cells with fVIII alone or fVIII-IC.
Conclusions: Changes in subclass did not drastically alter the recognition of fVIII by the monoclonal anti-fVIII IgG. Most anti-fVIII IgG blocked fVIII uptake by DCs, with the exception of the anti-A2 IgG1κ. Co-incubation of DCs with fVIII-IC did not impact their maturation status. Future work will determine whether fVIII-IC alter fVIII uptake under pro-inflammatory conditions, and the potential consequences on DC maturation and on the polarization of CD4+ T-cell responses. At term, our findings will foster the rational design of fVIII-IC with tolerogenic properties for the treatment of inhibitor-positive patients.
To cite this abstract in AMA style:
Bou Jaoudeh M, Mimoun A, Daventure V, Delignat S, Lacroix-Desmazes S. Endocytosis of Factor VIII by Human Dendritic Cells in the Presence of Anti-Factor VIII Antibodies from Patients with Hemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/endocytosis-of-factor-viii-by-human-dendritic-cells-in-the-presence-of-anti-factor-viii-antibodies-from-patients-with-hemophilia-a/. Accessed March 21, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/endocytosis-of-factor-viii-by-human-dendritic-cells-in-the-presence-of-anti-factor-viii-antibodies-from-patients-with-hemophilia-a/