Tiarks C, Humphreys R E, Anderson J, Mole J, Pechet L
Scand J Immunol. 1992 Nov;36(5):653-60. doi: 10.1111/j.1365-3083.1992.tb03125.x.
The study of the immunobiology of FVIII inhibitors may lead to new therapies for this potentially severe complication of haemophilia A and to new principles for the use of therapeutic proteins. In order to characterize the idiotype-anti-idiotype networks regulating FVIII inhibitors, we developed rabbit anti-idiotypic sera to 7 murine inhibitors and found at least 12 independent FVIII loci to which inhibitors could be raised. Rabbit antisera to the FVIII peptide, Ser1687-Thr1695, characterized one functional site to which about 46% of patients' inhibitor sera reacted. The multiplicity of inhibitor-recognized epitopes in FVIII makes it impractical, at the present time, to develop clinically useful specific anti-idiotypic therapies for FVIII inhibitors. Alternatively, one might induce genomic mutations in recombinant FVIII molecules to decrease immunogenicity of epitopes recognized by T helper cells. Methods to design such altered therapeutic proteins are presented, based on changing the longitudinal hydrophobic strip-of-helix which is in or near many T-cell-presented epitopes.
对凝血因子VIII抑制剂免疫生物学的研究可能会为甲型血友病这种潜在的严重并发症带来新的治疗方法，并为治疗性蛋白质的使用提供新的原则。为了表征调节凝血因子VIII抑制剂的独特型-抗独特型网络，我们制备了针对7种鼠源抑制剂的兔抗独特型血清，并发现至少有12个独立的凝血因子VIII基因座可引发抑制剂产生。针对凝血因子VIII肽段Ser1687 - Thr1695的兔抗血清鉴定出一个功能位点，约46%的患者抑制剂血清可与之反应。凝血因子VIII中抑制剂识别表位的多样性使得目前开发针对凝血因子VIII抑制剂的临床有用的特异性抗独特型疗法不切实际。或者，可以诱导重组凝血因子VIII分子发生基因组突变，以降低T辅助细胞识别的表位的免疫原性。基于改变许多T细胞呈递表位内部或附近的纵向疏水螺旋条带，本文介绍了设计此类改变的治疗性蛋白质的方法。
