Complement activation by recombinant adenoviruses
Complement activation by recombinant adenoviruses
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DOI：
10.1038/sj.gt.3301611
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发表时间：
2001-12-01
期刊：
影响因子：
5.1
通讯作者：
Burger, R
中科院分区：
文献类型：
--
作者：
Cichon, G;Boeckh-Herwig, S;Burger, R
重组腺病毒是目前基因治疗中最重要的载体系统。腺病毒经常引起人类上呼吸道感染，抗腺病毒抗体存在于35-70%的人群中。因此，在大多数接受腺病毒基因治疗的潜在患者中，病毒颗粒与血液的接触会导致抗原-抗体复合体的形成。这些复合体有能力通过激活补体系统来诱导炎症反应。我们已经测定了健康个体在用重组和野生型腺病毒攻击后，在分离的柠檬酸盐血浆中产生的C3a(最活跃的补体成分)水平，其数量与腺病毒基因治疗期间患者预期的病毒血液水平相对应。所有含抗腺病毒抗体的血浆样本都显示出大量的C3a产生，呈剂量依赖关系。病毒血浆水平约为7.5x10(9)粒子/毫升(据计算，这是过去临床试验期间达到的最高血液水平)，导致平均释放约3000 ng/mlC3a(基线水平和140 ng/ml)。分析抗腺病毒抗体的性质表明，不仅具有中和性的抗体(抗Ad5)，而且非中和性的抗腺病毒抗体也能够激活补体。这项研究表明，局部小剂量应用重组腺病毒时，补体激活可以被忽略，但在全身大剂量应用病毒后，补体激活值得注意。在针对系统性病毒应用的临床方案中，应定期包括监测和控制补体系统的措施。
Recombinant adenoviruses are currently the most important vector system in gene therapy. Adenoviruses frequently cause upper respiratory tract infections in humans and anti-adenoviral antibodies are found in 35-70% of the population. Therefore in the majority of potential patients receiving adenoviral gene therapy, the contact of virus particles and blood will lead to the formation of antigen-antibody complexes. These complexes have the ability to induce inflammatory reactions via an activation of the complement system. We have determined the level of C3a (the most reactive complement component) generated in isolated citrate plasma of healthy individuals after challenge with recombinant and wild-type adenoviruses in amounts corresponding to virus blood levels to be expected in patients during adenoviral gene therapy. All plasma samples containing anti-adenoviral antibodies showed a substantial, dose-dependent generation of C3a. A virus plasma level of about 7.5 x 10(9) particles/ml (which was calculated to be the highest blood level reached during clinical trials in the past) induced an average release of about 3000 ng/ml C3a (baseline levels < 140 ng/ml). Analyzing the nature of anti-adenoviral antibodies showed, that not only antibodies with neutralizing properties (anti-Ad5), but also non-neutralizing anti-adenoviral antibodies are capable of complement activation. This study suggests that complement activation can be ignored in local low-dose applications of recombinant adenoviruses, but warrants attention after systemic application of large viral quantities. In clinical protocols aiming at systemic virus application, measures for monitoring and controlling the complement system should be included on a regular basis.