期刊
HAEMATOLOGICA
卷 93, 期 1, 页码 83-89出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.11535
关键词
hemophilia; factor VIII; inhibitors; dendritic cells; T-cell clone; CD91/LRP
类别
资金
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Universite Pierre et Marie Curie
- Indo-French Center for Promotion of Advanced Research (CEFIPRA)
- Agence Nationale de la Recherche [ANR-05-MRAR-030, ANR-07-JCJC-0100-01]
- Fondation de la Recherche Medicale
- LFB (Les Ulis, France)
- Agence Nationale de la Recherche (ANR) [ANR-07-JCJC-0100] Funding Source: Agence Nationale de la Recherche (ANR)
Background The development of factor VIII (FVIII) inhibitors remains the major hurdle in the clinical management of patients with hemophilia A. FVIII uptake by professional antigen-presenting cells (APC) is the first step involved in initiation of immune responses to FVIII. Studies on FVIII catabolism have highlighted the role played by CD91/LRP as a potential target for increasing FVIII half-life in patients and prolonging treatment efficiency. We investigated the involvement of CD91 in FVIII endocytosis by human dendritic cells (DC), a model of professional APC. Design and Methods Immature DC were generated from circulating monocytes from healthy donors. Surface expression of CD91 was assessed by flow cytometry. Uptake of fluoroscein isothiocyanate-conjugated ligands by immature DC was studied in the presence of various blocking agents. Results CD91 was expressed on approximately 20% of DC and mediated the internalization of its model ligand, alpha 2-macroglobulin. DC internalized FVIII and activated a human FVIII-specific T-cell clone in a dose-dependent manner. FVIII uptake by DC and subsequent T-cell activation were not inhibited by receptor-associated protein. Conclusions Our results indicate that CD91 and other members of the LDL receptor family are not strongly implicated in FVIII internalization by monocyte-derived DC, and suggest the involvement of alternative divalent ion-dependent endocytic receptors.
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