Delayed-type hypersensitivity response to high doses of adenoviral vectors.
Delayed-type hypersensitivity response to high doses of adenoviral vectors.
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DOI：
10.1089/hum.1997.8.3-323
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发表时间：
1997-02
影响因子：
4.2
通讯作者：
Thomas Russi;E. Hirschowitz;R. Crystal
中科院分区：
文献类型：
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作者：
Thomas Russi;E. Hirschowitz;R. Crystal
本研究评估了当大剂量的腺病毒(Ad)载体注射到先前免疫的动物身上时，迟发性超敏反应(DTH)有助于观察到炎症反应的假说。免疫活性C57BL/6小鼠用10(9)pfu AdCMV免疫小鼠。空载体[带有巨细胞病毒(CMV)启动子但没有转基因的E1-，E3-Ad载体]皮内攻击C57BL/6小鼠的足垫，在用10(9)pfu攻击24小时后出现明显的足垫肿胀，但不是在较低剂量下。足垫组织学显示典型的DTH的单核粒细胞浸润。在C57BL/6背景上对免疫缺陷小鼠Nu/Nu和RAG-2-进行相同剂量的载体评估，在BALB/c背景上对Nu/Nu和严重联合免疫缺陷(SCID)进行评估，结果表明，Nu/Nu和RAG-2-对足垫肿胀有抑制作用。然而，在β2-微球蛋白缺陷(β2-m-)小鼠中，足垫反应保持完整，这表明主要组织相容性复合体(MHC)I类介导的机制在局部炎症区域中几乎没有作用。用表达白细胞介素2基因的重组腺病毒攻击免疫的C57BL/6小鼠后，小鼠的足垫肿胀反应增强。最后，与对照组相比，用环孢菌素预处理可抑制69%的反应，而其他免疫抑制剂(环磷酰胺、甲氨蝶呤和氢化可的松)则没有抑制作用。这些发现为免疫过程的动态相互作用提供了进一步的洞察，当高剂量的Ad载体被注射到靶器官时，最终导致炎症。
The present study evaluates the hypothesis that delayed-type hypersensitivity (DTH) contributes to the inflammatory reaction observed when high-dose adenoviral (Ad) vectors are administered to a previously immunized animal. Immunocompetent C57BL/6 mice immunized intraperitoneally with 10(9) pfu AdCMV.Null [an E1-, E3- Ad vector with a cytomegalovirus (CMV) promoter but no transgene] and challenged intradermally to the footpad with the same vector demonstrated significant footpad swelling 24 hr after challenge with 10(9) pfu, but not with a lower dose. Footpad histology revealed a mononuclear-granulocytic cellular infiltrate typical of that seen in DTH. Evaluation of the same doses of vector in immunodeficient mice nu/nu and RAG-2- on the C57BL/6 background, and nu/nu and severe combined immunodeficiency (SCID) on the BALB/c background demonstrated suppression of footpad swelling. However, the footpad response remained intact in beta 2-microglobulin deficient (beta 2-m-) mice, suggesting minimal or no role of major histocompatibility complex (MHC) class I-mediated mechanisms for the region of localized inflammation. Challenge with an Ad expressing the interleukin-2 cDNA to immunized C57BL/6 mice demonstrated augmented footpad swelling response. Finally, pretreatment with cyclosporin resulted in a 69% inhibition of the response compared to controls, whereas other immunosuppressants (cyclophosphamide, methotrexate, and hydrocortisone) had no inhibitory effect. These findings provide further insight into the dynamic interplay of immune processes ultimately leading to inflammation when high-dose Ad vectors are administered to a target organ.