Zhang H G, Liu D, Heike Y, Yang P, Wang Z, Wang X, Curiel D T, Zhou T, Mountz J D
The University of Alabama at Birmingham, Department of Medicine, 35294, USA.
Nat Biotechnol. 1998 Nov;16(11):1045-9. doi: 10.1038/3488.
A major problem associated with adenovirus gene therapy is the T cell-mediated immune response, which is elicited by inoculation of the adenovirus vector and leads to rapid clearance of the virus and loss of transgene expression. In this study, the immune response to adenovirus was prevented by induction of specific T-cell tolerance by pretreatment with adenovirus-infected antigen-presenting cells (APC) that express Fas ligand. Compared with control-treated mice, the tolerized mice showed prolonged expression of lacZ upon administration of AdCMVlacZ 1 week after tolerance induction. In contrast to the control mice, the tolerized mice did not display proliferation of CD3+ T cells in the spleen in response to AdCMVlacZ. Tolerance induction also was indicated by the lower production of interferon-gamma and interleukin-2 by peripheral T cells isolated from AdCMVlacZ-challenged tolerized mice than by AdCMVlacZ-challenged control-treated mice. The T-cell tolerance was specific for the adenovirus as the T-cell responses to irrelative murine cytomegalovirus remained unimpaired. Our results indicate that adenovirus-specific T-cell tolerance can be induced by APCs that coexpress Fas ligand and adenovirus antigens. We propose that this new strategy can be used to induce tolerance to adenovirus vector gene therapy with resultant prolonged expression of the transgene.
腺病毒基因治疗的一个主要问题是T细胞介导的免疫反应，这种反应由腺病毒载体接种引发，导致病毒快速清除和转基因表达丧失。在本研究中，通过用表达Fas配体的腺病毒感染的抗原呈递细胞（APC）进行预处理来诱导特异性T细胞耐受，从而预防对腺病毒的免疫反应。与对照处理的小鼠相比，耐受诱导的小鼠在耐受诱导1周后给予AdCMVlacZ时，lacZ表达延长。与对照小鼠不同，耐受诱导的小鼠在对AdCMVlacZ的反应中脾脏中CD3 + T细胞未出现增殖。从AdCMVlacZ攻击的耐受诱导小鼠中分离的外周T细胞产生的干扰素-γ和白细胞介素-2低于AdCMVlacZ攻击的对照处理小鼠，这也表明了耐受诱导。T细胞耐受对腺病毒具有特异性，因为对无关的鼠巨细胞病毒的T细胞反应未受损害。我们的结果表明，共表达Fas配体和腺病毒抗原的APC可以诱导腺病毒特异性T细胞耐受。我们提出，这种新策略可用于诱导对腺病毒载体基因治疗的耐受，从而使转基因表达延长。
