DeMatteo R P, Chu G, Ahn M, Chang E, Burke C, Raper S E, Barker C F, Markmann J F
Harrison Department of Surgical Research and Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Transplantation. 1997 Jan 27;63(2):315-9. doi: 10.1097/00007890-199701270-00024.
Adenoviral gene transfer has potential use to attenuate the immunogenicity of hepatic allografts. However, the clinical application of adenoviral gene therapy is currently impeded by the potent host immune response to the virus that limits the duration of its effects. In these studies, we identify the cellular and humoral immune responses to recombinant adenovirus in the liver of mice and define the immunologic barriers to the successful application of this technology to transplantation. The immunobiology of recombinant adenovirus was studied in mouse liver using vectors containing the lacZ and alkaline phosphatase marker genes. The duration of transgene expression was studied in various immunodeficient mice to determine the mechanism of viral clearance. Adoptive transfer of serum to B lymphocyte deficient mice and neutralizing antibody assays were used to define the antiviral humoral response. Hepatic adenoviral transgene expression was prolonged in animals deficient in CD4+ or CD8+ T cells indicating their importance in viral clearance. Unexpectedly, mice lacking B lymphocytes also had delayed elimination of virus suggesting that B cells play a role in the primary immune response. Effective repeat gene transfer was blocked by adenoviral-specific neutralizing antibody. Therefore, a T lymphocyte response results in viral elimination after a primary intravenous inoculation of recombinant adenovirus and a potent humoral response inhibits effective repeat adenoviral gene transfer. The immunogenicity of the vector must be overcome for adenoviral gene therapy to have therapeutic application for hepatic transplantation.
腺病毒基因转移具有减弱肝同种异体移植物免疫原性的潜在用途。然而，腺病毒基因治疗的临床应用目前受到宿主对该病毒的强烈免疫反应的阻碍，这种反应限制了其作用持续时间。在这些研究中，我们确定了小鼠肝脏对重组腺病毒的细胞免疫和体液免疫反应，并明确了将该技术成功应用于移植的免疫障碍。使用含有lacZ和碱性磷酸酶标记基因的载体，在小鼠肝脏中研究重组腺病毒的免疫生物学。在各种免疫缺陷小鼠中研究转基因表达的持续时间，以确定病毒清除机制。将血清过继转移到B淋巴细胞缺陷小鼠并进行中和抗体检测，以确定抗病毒体液反应。在缺乏CD4+或CD8+T细胞的动物中，肝腺病毒转基因表达延长，表明它们在病毒清除中起重要作用。出乎意料的是，缺乏B淋巴细胞的小鼠也有病毒清除延迟的情况，提示B细胞在初次免疫反应中发挥作用。腺病毒特异性中和抗体阻断了有效的重复基因转移。因此，初次静脉接种重组腺病毒后，T淋巴细胞反应导致病毒清除，而强烈的体液反应抑制有效的重复腺病毒基因转移。为使腺病毒基因治疗在肝移植中具有治疗应用价值，必须克服载体的免疫原性。
