Achdout Hagit, Lustig Shlomo, Israely Tomer, Erez Noam, Politi Boaz, Tamir Hadas, Israeli Ofir, Waner Trevor, Melamed Sharon, Paran Nir
Department of Infectious Diseases, Israel Institute for Biological Research (IIBR), Ness-Ziona, Israel.
Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research (IIBR), Ness-Ziona, Israel.
Vaccine. 2017 Jul 24;35(33):4245-4254. doi: 10.1016/j.vaccine.2017.06.014. Epub 2017 Jun 20.
Eczema vaccinatum is a severe and occasionally lethal complication of smallpox vaccine, characterized by systemic viral dissemination, distant from the initial inoculation site of the vaccine. A major risk factor for eczema vaccinatum is a background of atopic dermatitis, a chronic, common allergic, relapsing disorder, manifested by dry and inflamed skin, itchy rash, Th2 biased immune response and hypersensitivity to various antigens. Unlike the severe manifestations of eczema vaccinatum in humans, current models present only mild symptoms that limits examination of potential therapeutics for eczema vaccinatum. The atopic dermatitis and eczema vaccinatum models we present here, are the first to simulate the severity of the diseases in humans. Indeed, dermatitic mice display persistent severe dermatitis, characterized by dry and inflamed skin with barrier dysfunction, epidermal hyperplasia and significant elevation of serum IgE. By exposing atopic dermatitis mice to ectromelia virus, we generated eczema vaccinatum that mimic the human disease better than known eczema vaccinatum models. Similarly to humans, eczematous mice displayed enlarged and disseminated skin lesions, which correlated with elevated viral load. Cidofovir and antiviral antibodies conferred protection even when treatment started at a late eczematous stage. Moreover, we are the first to demonstrate that despite a severe background of atopic dermatitis, modified vaccinia Ankara virus (MVA) vaccination protects against lethal ectromelia virus exposure. We finally show that protection by MVA vaccination is dependent on CD4 T cells and is associated with significant activation of CD8 cytotoxic T cells and induction of humoral immunity.
牛痘性湿疹是天花疫苗的一种严重且偶尔致命的并发症，其特征为病毒在全身扩散，远离疫苗的初始接种部位。牛痘性湿疹的一个主要风险因素是特应性皮炎背景，这是一种慢性、常见的过敏性复发性疾病，表现为皮肤干燥、发炎、瘙痒性皮疹、偏向Th2的免疫反应以及对各种抗原的超敏反应。与人类牛痘性湿疹的严重表现不同，目前的模型仅呈现轻微症状，这限制了对牛痘性湿疹潜在治疗方法的研究。我们在此展示的特应性皮炎和牛痘性湿疹模型是首个模拟人类疾病严重程度的模型。事实上，患皮炎的小鼠表现出持续性严重皮炎，其特征为皮肤干燥、发炎且屏障功能障碍、表皮增生以及血清IgE显著升高。通过将特应性皮炎小鼠暴露于埃可病毒，我们生成了比已知牛痘性湿疹模型更能模拟人类疾病的牛痘性湿疹。与人类相似，患湿疹的小鼠出现扩大和扩散的皮肤病变，这与病毒载量升高相关。即使在湿疹晚期开始治疗，西多福韦和抗病毒抗体也能提供保护。此外，我们首次证明，尽管存在严重的特应性皮炎背景，但安卡拉痘苗病毒（MVA）疫苗接种可预防致命的埃可病毒暴露。我们最终表明，MVA疫苗接种提供的保护依赖于CD4 T细胞，并且与CD8细胞毒性T细胞的显著激活以及体液免疫的诱导相关。
