title: Immune response against serial infusion of factor VIII antigen through an implantable venous-access device system in haemophilia A mice.
abstract: Haemophilia A is a life long bleeding disorder caused by an inherited deficiency of factor VIII (FVIII). About 30% of haemophilia A patients develop neutralizing antibodies as a consequence of treatment with FVIII concentrates. Immune tolerance protocols for the eradication of inhibitors require daily delivery of intravenous FVIII. We evaluated the immune responses to serial intravenous administration of FVIII in preimmunized haemophilia A mice. We introduced an implantable venous-access device (iVAD) system into haemophilia A mice to facilitate sequential infusion of FVIII. After preimmunization with FVIII, the haemophilia A mice were subjected to serial intravenous administration of FVIII through the iVAD system. In all mice with serial infusion of FVIII, high titers of anti-FVIII inhibitory antibodies developed at 10 exposure days (EDs). However, the anti-FVIII IgG titers were decreased after 150 EDs of sequential low-dose infusion of FVIII [0.05 U g(-1) body weight (BW) five times per week]. Proliferative response to ex vivo FVIII stimulation was significantly suppressed in splenic CD4(+) T cells from mice with serial low-dose FVIII infusion compared with those from mice with high-dose FVIII infusion (0.5 U g(-1) BW five times per week) or preimmunized mice. Moreover, splenic CD4(+) T cells from mice with serial low-dose infusion of FVIII failed to produce interleukin-2 and interferon-γ. These data suggest that serial infusion of FVIII could induce T-cell anergy in haemophilia A mice with inhibitor antibodies.
authors: Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan. madochan@jichi.ac.jp
authors: S
authors: S
authors: Madoiwa
authors: E
authors: E
authors: Kobayashi
authors: Y
authors: Y
authors: Kashiwakura
authors: A
authors: A
authors: Sakata
authors: A
authors: A
authors: Yasumoto
authors: T
authors: T
authors: Ohmori
authors: J
authors: J
authors: Mimuro
authors: Y
authors: Y
authors: Sakata
mesh_terms: D000818:Animals; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood / Q000276:immunology*; D002405:Catheterization, Central Venous; D002408:Catheters, Indwelling; D049109:Cell Proliferation / Q000187:drug effects; D003029:Coagulants / Q000008:administration & dosage / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology*; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects*; D007074:Immunoglobulin G / Q000097:blood; D007262:Infusions, Intravenous; D007518:Isoantibodies / Q000097:blood; D051379:Mice
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D003029:Coagulants; D016207:Cytokines; D007074:Immunoglobulin G; D007518:Isoantibodies; D005169:Factor VIII