Tolerating adenoviral vectors

Abstract

Early pre-clinical and clinical studies that assessed adenoviral vectors for gene therapy were encouraging, but a T-cell-mediated immune response against both the virus and virally transduced cells was often observed, limiting the effectiveness of re-administered vector. Improved adenoviral vectors have now been developed but immunity remains an issue. Thus, the recent description of a new approach to this problem by modulating the immune response against the adenovirus itself is of particular interest. The strategy of Zhang et al. 1 Zhang H-G. et al. Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand-producing antigen presenting cells. Nat. Biotechnol. 1998; 16: 1045-1049 Crossref PubMed Scopus (79) Google Scholar was to induce T-cell tolerance to the adenovirus by expression of Fas ligand. Fas ligand induces apoptosis, and its expression on activated lymphocytes and cells within immunoprivileged sites has implicated it in the induction of tolerance. In particular, the elevated expression of Fas ligand on antigen-presenting cells (APCs) can lead to the apoptosis of the T cells with which they interact during antigen presentation, inducing an antigen-specific, clonal deletion of T cells. In this study, APCs transduced with an adenovirus expressing Fas ligand were administered to mice; animals were subsequently challenged with an adenovirus vector expressing the marker gene lacZ. Expression of lacZ rapidly declined in control animals but remained constant in those animals that were pre-treated with Fas ligand-transduced APCs. Further analysis showed that an adenovirus-specific T-cell tolerance was induced in these animals. Although the clinical application of this methodology would require the generation of APCs that are specific for each individual to be treated, for certain conditions this might be a feasible approach.