Fabian Daniel, Gong Nianqiao, Vogt Katrin, Volk Hans-Dieter, Pleyer Uwe, Ritter Thomas
Institute of Medical Immunology, Charité-University Medicine Berlin, Berlin, Germany.
Graefes Arch Clin Exp Ophthalmol. 2007 Oct;245(10):1515-21. doi: 10.1007/s00417-007-0629-y. Epub 2007 Jul 6.
The purpose of this paper is to analyse the effects of local or systemic administration of adenovirus type 5 encoding the inducible costimulator fusion protein (AdICOSIg) on its influence on prolonging corneal allograft survival.
The ICOSIg chimeric molecule was generated by fusing the murine ICOS to a rat FcIgG portion and a recombinant adenovirus (Ad) was made thereof. A major histocompatibility complex (MHC) class I/II mismatched rat corneal transplant model was used. The recipients were randomly assigned to receive ex vivo gene-modified corneas expressing either ICOSIg or a single i.p. injection (1.0 x 10(9) infectious particles) of AdICOSIg two days after transplantation and graft survival was analysed. Moreover, the influence of ICOSIg fusion protein on anti-adenovirus immunity also was investigated.
The ex vivo gene transfer of ICOSIg in cultured corneas resulted in high levels of ICOSIg protein in culture supernatants. However, neither ex vivo nor systemic gene therapy resulted in a significant prolongation of graft survival. Interestingly, the generation of anti-adenovirus antibodies could not be inhibited by systemic ICOSIg fusion protein expression.
Unlike CTLA4Ig, sole ICOSIg gene therapy is not a successful strategy for the prevention of allogeneic graft rejection in corneal transplantation.
本文旨在分析局部或全身给予编码诱导性共刺激融合蛋白（AdICOSIg）的5型腺病毒对延长角膜移植存活时间的影响。
通过将小鼠ICOS与大鼠FcIgG部分融合产生ICOSIg嵌合分子，并据此制备重组腺病毒（Ad）。采用主要组织相容性复合体（MHC）I/II类不匹配的大鼠角膜移植模型。将受体随机分为两组，一组在移植后两天接受表达ICOSIg的体外基因修饰角膜，另一组接受单次腹腔注射（1.0×10⁹感染性颗粒）AdICOSIg，分析移植物存活情况。此外，还研究了ICOSIg融合蛋白对抗腺病毒免疫的影响。
ICOSIg在培养角膜中的体外基因转移导致培养上清液中ICOSIg蛋白水平升高。然而，体外和全身基因治疗均未显著延长移植物存活时间。有趣的是，全身ICOSIg融合蛋白表达不能抑制抗腺病毒抗体的产生。
与CTLA4Ig不同，单纯的ICOSIg基因治疗不是预防角膜移植中同种异体移植物排斥反应的成功策略。
