Madoiwa S, Yamauchi T, Kobayashi E, Hakamata Y, Dokai M, Makino N, Kashiwakura Y, Ishiwata A, Ohmori T, Mimuro J, Sakata Y
Research Division of Cell and Molecular Medicine, Centre for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
J Thromb Haemost. 2009 May;7(5):811-24. doi: 10.1111/j.1538-7836.2009.03314.x. Epub 2009 Feb 12.
Hemophilia A is a congenital bleeding disorder caused by a deficiency of coagulation factor VIII. Approximately 30% of hemophilia A patients develop inhibitors against FVIII following replacement therapy. We have reported that neonatal exposure of FVIII antigen can induce antigen-specific immune tolerance by interferon-gamma (IFN-gamma)-dependent T-cell anergy in hemophilia A mice.
The thymus plays crucial roles in self-tolerance, with negative selection of self-reactive effector T cells and positive selection of self-reactive regulatory T cells. We investigated the possibility of the induction of antigen-specific immune tolerance by intrathymic injection of FVIII in hemophilia A mice.
Hemophilia A mice were injected with recombinant FVIII into the thymus under real-time high-resolution image guidance.
Anti-FVIII inhibitory antibody titers in mice challenged with intravenous administration of FVIII were significantly lower in mice (n = 22) that had received thymic FVIII injection than in mice (n = 18) without thymic injection (9.4 +/- 2.3 vs. 122.5 +/- 27.6 BU mL(-1), respectively, P = 0.00078). The CD4(+) T cells from thymic-injected mice could not proliferate or produce interleukin (IL)-2, IL-12 and IFN-gamma in response to FVIII. The CD4(+)CD25(+) T cells generated from thymic-treated mice but not from naïve mice efficiently suppressed the in vitro proliferative response of CD4(+) T cells and blocked the in vivo development of anti-FVIII antibodies in the adoptive transfer.
These data suggest that intrathymic administration of FVIII could result in immune tolerance by induction of FVIII-specific regulatory T cells.
摘要 背景：甲型血友病是一种由凝血因子VIII缺乏引起的先天性出血性疾病。约30%的甲型血友病患者在替代治疗后会产生针对FVIII的抑制物。我们曾报道，在甲型血友病小鼠中，新生期暴露于FVIII抗原可通过干扰素-γ（IFN-γ）依赖的T细胞无能诱导抗原特异性免疫耐受。
胸腺在自身耐受中起关键作用，可对自身反应性效应T细胞进行阴性选择，并对自身反应性调节性T细胞进行阳性选择。我们研究了在甲型血友病小鼠中通过胸腺内注射FVIII诱导抗原特异性免疫耐受的可能性。
在实时高分辨率图像引导下，向甲型血友病小鼠的胸腺内注射重组FVIII。
静脉注射FVIII激发的小鼠中，接受胸腺内FVIII注射的小鼠（n = 22）的抗FVIII抑制性抗体滴度显著低于未接受胸腺内注射的小鼠（n = 18）（分别为9.4±2.3与122.5±27.6 BU mL(-1)，P = 0.00078）。胸腺内注射小鼠的CD4(+) T细胞在接触FVIII后不能增殖或产生白细胞介素（IL）-2、IL-12和IFN-γ。胸腺处理小鼠而非未处理小鼠产生的CD4(+)CD25(+) T细胞能有效抑制CD4(+) T细胞的体外增殖反应，并在过继转移中阻断抗FVIII抗体的体内产生。
这些数据表明，胸腺内注射FVIII可通过诱导FVIII特异性调节性T细胞导致免疫耐受。
