| Project/Area Number |
15591021
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | JICFII MEDICAL SCHOOL |
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Principal Investigator |
MADOIWA Seiji Jichi Medical School, Department of Medicine, Assistant Professor, 医学部, 講師 (70296119)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Fiji Jichi Medical School, Department of Medicine, Professor, 医学部, 教授 (00245044)
SAKATA Yoichi Jichi Medical School, Department of Medicine, Professor, 医学部, 教授 (40129028)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Factor VIII / Hemophilia A / Immune tolerance / Neonate / knockout mice / ウイルスベクター |
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| Research Abstract |
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.
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