Maecker H T, Hansen G, Walter D M, DeKruyff R H, Levy S, Umetsu D T
Division of Oncology, Department of Medicine, and the Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University Medical Center, Stanford, CA 94305, USA.
J Immunol. 2001 Jan 15;166(2):959-65. doi: 10.4049/jimmunol.166.2.959.
Vaccination with naked DNA encoding a specific allergen has been shown previously to prevent, but not reverse, the development of allergen-induced airway hyperresponsiveness (AHR). To enhance the effectiveness of DNA vaccine therapies and make possible the treatment of established AHR, we developed a DNA vaccination plasmid containing OVA cDNA fused to IL-18 cDNA. Vaccination of naive mice either with this fusion DNA construct or with an OVA cDNA-containing plasmid protected the mice from the subsequent induction of AHR. Protection from AHR correlated with increased IFN-gamma production and reduced OVA-specific IgE production. The protection appeared to be mediated by IFN-gamma and CD8(+) cells because treatment of mice with neutralizing anti-IFN-gamma mAb or with depleting anti-CD8 mAb abolished the protective effect. Moreover, vaccination of mice with preexisting AHR with the OVA-IL-18 fusion DNA, but not with the OVA cDNA plasmid, reversed established AHR, reduced allergen-specific IL-4, and increased allergen-specific IFN-gamma production. Thus, combining IL-18 cDNA with OVA cDNA resulted in a vaccine construct that protected against the development of AHR, and that was unique among cDNA constructs in its capacity to reverse established AHR.
先前已证明，用编码特定变应原的裸DNA进行疫苗接种可预防变应原诱导的气道高反应性（AHR）的发生，但不能逆转其发展。为提高DNA疫苗疗法的有效性并使已确立的AHR的治疗成为可能，我们构建了一种DNA疫苗接种质粒，其中OVA cDNA与IL-18 cDNA融合。用这种融合DNA构建体或含OVA cDNA的质粒对未接触过抗原的小鼠进行疫苗接种，可保护小鼠免受随后诱导的AHR。对AHR的保护作用与IFN-γ产生增加和OVA特异性IgE产生减少相关。这种保护作用似乎由IFN-γ和CD8(+)细胞介导，因为用中和性抗IFN-γ单克隆抗体或耗竭性抗CD8单克隆抗体处理小鼠可消除保护作用。此外，用OVA-IL-18融合DNA而非OVA cDNA质粒对已患有AHR的小鼠进行疫苗接种，可逆转已确立的AHR，降低变应原特异性IL-4水平，并增加变应原特异性IFN-γ的产生。因此，将IL-18 cDNA与OVA cDNA结合可产生一种疫苗构建体，该构建体可预防AHR的发生，并且在逆转已确立的AHR的能力方面在cDNA构建体中是独特的。
