Induction of Immune Tolerance by Neonatal Intravenous Injection of Human Factor VIII in Murine Hemophilia A

点击翻译按钮获取中文摘要

Inhibitory antibody formation is the most serious complication of factor VIII replacement therapy in patients with hemophilia A. Factor VIII-deficient mice served as a model of severe hemophilia A to characterize the immune response to human factor VIII and to study new approaches for induction of immune tolerance. Neither anti-factor VIII inhibitory antibodies nor anti-factor VIII IgGs were observed in 13 of 14 adult mice that received 0.05 unit/g body weight of human factor VIII intravenously within 24 hours after birth, as well as repeated injections as adults. In contrast, high factor VIII antibody titers (>50 Bethesda units/mL) were found in 7 of 13 mice injected on day 3 post-partum and in all adult mice that had not been treated neonatally. One out of 9 mice and 3 of 17 mice developed high-titer anti-factor VIII inhibitory antibody, when they were initially treated with 2-fold (0.1 unit/g body weight) and 10-fold higher doses (0.5 unit/g body weight) factor VIII on day 0 respectively. A human factor VIII specific T cell proliferative response was absent in splenocytes obtained from neonatally treated mice. However, the tolerant mice immunized with tetanus toxoid developed high anti-tetanus toxoid antibody, demonstrating that tolerance is factor VIII specific. The splenocytes failed to proliferate or produce interferon-γ in response to factor VIII stimulation, yet still secreted significant amounts of interleukin-2 and were restored proliferation by the addition of exogenous interferon-γ or the interleukin-12, suggesting that the lack of inhibitor to factor VIII is due to interferon-γ dependent anergy. These studies indicate that exposure on day 0 to physiological levels of factor VIII antigen might be important for induction of immune tolerance. This immune tolerance model may provide a basis for new approaches regarding prevention of factor VIII inhibitors during replacement therapy.