Modulation of the Immune Response to Cutaneous Immunization by S. aureus

金黄色葡萄球菌对皮肤免疫的免疫反应的调节

• 批准号: 8887211
• 负责人: RAIF SALIM GEHA
• 金额: $ 60.22万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8887211
• 关键词: Allergic; Allergic inflammation; Antibody Response; Antigens; Area; Atopic Dermatitis; Biological Models; Biology; Blocking Antibodies; CD4 Positive T Lymphocytes; Cells; Clinical Trials; Collection; Cutaneous; Data; Eczema; Epithelial; Fluzone; Human; IgE; Immune; Immune response; Immunity; Immunization; Incidence; Inflammation; Influenza; Influenza vaccination; Injury; Interleukin-13; Interleukin-4; Intramuscular; Mechanics; Mouse Strains; Mus; Patients; Predisposition; Preparation; Reagent; Research; Role; Route; Serum; Severities; Severity of illness; Site; Skin; Skin Abnormalities; Source; Staphylococcal Enterotoxin B; Staphylococcus aureus; T cell response; TSLP gene; Testing; Transgenic Mice; Vaccination; Vaccinia virus; Viral; Virus Diseases; Work; Yellow Fever Vaccine; cytokine; experience; human TSLP protein; influenza virus vaccine; influenzavirus; keratinocyte; migration; mouse model; response; subcutaneous

Skin colonization by S. aureus is common in atopic dermatitis (AD) and is associated with increased disease severity. Both allergic skin inflammation and S. aureus skin colonization influence the immune response to cutaneously introduced antigen. Thus, AD patients are susceptible to cutaneously acquired viral infections, and the incidence of eczema heperticum correlates with disease severity and serum IgE level. Through the ADRN, we have shown that inoculation of vaccinia virus (VV) at the site of allergic skin inflammation results in increased viral spread compared and skews the immune response of mice to VV towards Th2 and Th17. Moreover, AD patients have a reduction in the T cell response to transcutaneous (TC) vaccination, with Yellow Fever vaccine that correlates with IgE levels, and in the antibody response to TC vaccination with Fluzone that correlates with S. aureus skin colonization. We have shown that epicutaneous (EC) sensitization by application of antigen to mouse skin after tape stripping, a surrogate for scratching, results in allergic skin inflammation with many features of AD, and a systemic Th2 response. Our preliminary data shows that co-application of staphylococcal enterotoxin B (SEB) aggravates the allergic skin inflammation and Th2 response to antigen induced by EC sensitization Mechanical skin injury by tape stripping during EC sensitization caused keratinocytes to release the epithelial cytokines TSLP, IL-25 and IL-33, induced rapid expression of IL-4 and IL-13 by innate immune skin cells and resulted in IL-4/IL-13-dependent polarization of skin DCs to promote a Th2- immune response by naïve CD4+ cells. We will test the overall hypothesis that that S. aureus skin colonization in the setting of AD-like Th2 allergic skin inflammation results in an altered immune response to cutaneous antigen exposure using TC immunization to influenza virus as a representative model system. We will first test the hypothesis that TC immunization in mice elicits immune responses comparable to, or stronger, than those elicited by IM immunization to influenza. We will then test the hypothesis that S. aureus skin colonization and AD-like allergic skin inflammation, individually and/or in synergy, alter the immune response to influenza TC immunization. We will then investigate the mechanisms by which the immune response to TC vaccination is altered by examining the migration function and polarization of skin DCs, determining the role of epithelial cytokines, and of Th2 cytokines and their sources in the skin, in the Th2 polarization of the immune response to TC vaccination. The proposed studies synergize with the studies in this U19 on TC vaccination of AD patients with a human influenza vaccine (Fluzone), and the clinical trials with blocking antibodies to IL-4Rα and TSLP in AD.

皮肤定殖S.金黄色葡萄球菌在特应性皮炎（AD）中很常见， 疾病严重程度。过敏性皮肤炎症和S.金黄色葡萄球菌皮肤定植影响免疫 对引入的抗原的应答。因此，AD患者易受非获得性病毒感染。 感染，和湿疹的发病率与疾病的严重程度和血清IgE水平。 通过ADRN，我们已经表明，在过敏性皮肤部位接种牛痘病毒（VV） 炎症导致病毒传播增加，并使小鼠对VV的免疫反应发生偏移， 向Th 2和Th 17方向发展。此外，AD患者对经皮（TC） 疫苗接种，黄热病疫苗与IgE水平相关，以及对TC的抗体反应 流感疫苗接种与S.金黄色皮肤定植。 我们已经表明，通过将抗原应用于胶带后的小鼠皮肤， 剥脱，一种抓挠的替代品，导致具有AD许多特征的过敏性皮肤炎症， Th 2反应。我们的初步数据表明，葡萄球菌肠毒素B（SE B） 阐明EC致敏机制诱导的过敏性皮肤炎症和Th 2对抗原的应答 EC致敏过程中胶带剥离引起的皮肤损伤引起角质形成细胞释放上皮细胞因子 TSLP、IL-25和IL-33通过先天免疫皮肤细胞诱导IL-4和IL-13的快速表达， 皮肤DC的IL-4/IL-13依赖性极化促进幼稚CD 4+细胞的Th 2免疫应答。 我们将检验S.在AD样背景下的金黄色葡萄球菌皮肤定植 Th 2过敏性皮肤炎症导致对皮肤抗原暴露的免疫应答改变 使用流感病毒的TC免疫作为代表性模型系统。我们将首先检验假设 TC免疫小鼠引起的免疫应答与IM引起的免疫应答相当或更强， 流感免疫。然后我们将检验S.金黄色葡萄球菌皮肤定植和AD样过敏 皮肤炎症单独和/或协同改变对流感TC免疫的免疫应答。我们 然后，将研究对TC疫苗接种的免疫反应改变的机制， 皮肤DC的迁移功能和极化，决定上皮细胞因子和Th 2的作用 细胞因子及其在皮肤中的来源，在对TC疫苗接种的免疫应答的Th 2极化中。 拟定的研究与U19中关于AD患者TC疫苗接种的研究具有协同作用， 人流感疫苗（Fluzone），以及针对IL-4 R α和TSLP的阻断抗体在AD中的临床试验。