TSLP in Th2 Immunity and Allergic Airway Inflammation

TSLP 在 Th2 免疫和过敏性气道炎症中的作用

• 批准号: 8884060
• 负责人: BAOHUA ZHOU
• 金额: $ 39万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884060
• 关键词: Adjuvant; Aerosols; Affect; Age; Allergens; Allergic Disease; Allergic rhinitis; Antigens; Asthma; Atopic Dermatitis; Attenuated; Bacterial Model; Blood; Breathing; CD4 Positive T Lymphocytes; Cells; Controlled Clinical Trials; Double-Blind Method; Dust; Environment; Funding; Genes; Glycolipids; Health; House Dust; House Dust Mite Allergens; Household; Human; Hypersensitivity; Immunity; Individual; Infant; Laboratories; Learning; Life; Ligands; Literature; Lung; Measures; Mediating; Modeling; Mouse Strains; Mucous Membrane; Mus; Neonatal; Pathogenesis; Patients; Peptide Hydrolases; Placebo Control; Play; Population; Prevalence; Production; Pyroglyphidae; Regulation; Regulatory T-Lymphocyte; Role; Serum; Severity of illness; Single Nucleotide Polymorphism; Skin; Societies; Source; Sputum; Sterility; Susceptibility Gene; Testing; Therapeutic; Time; airway hyperresponsiveness; allergic airway inflammation; asthmatic; asthmatic patient; cytokine; design; eosinophil; genome wide association study; high risk; human TSLP protein; insight; microbial; neutralizing antibody; ovalbumin-alum; prevent; public health relevance; response; therapeutic target

 DESCRIPTION (provided by applicant): Thymic stromal lymphopoietin (TSLP) is an important factor involved in the pathogenesis of asthma and allergy. Mucosal tolerance is induced early in life and is an important mechanism of protection from allergic diseases such as asthma. Our preliminary results demonstrate that neonatal CD4+ T cells are tolerogenic and, even when immunized with OVA+Alum, preferentially differentiate into inducible regulatory T cells (iTregs) rather than T helper 2 (Th2) cells. We find that infants (age range 6-18 months) with atopic dermatitis (AD) have elevated serum TSLP (200 - 300 pg/ml), a concentration sufficient to suppress iTreg differentiation. Failed to establish airway tolerance against a particular aerosol antigen, the individuals may become sensitized at a later time in the presence of natural adjuvants such as microbial products in the environment. Recent studies show that majority household dust extracts contain bacterial-derived glycolipids capable of activating human and mice NKT cells and thus act as natural adjuvants to promote Th2 sensitization against aerosol allergens. We surprisingly find that this glycolipid-induced Th2 sensitization requires TSLP, and the mechanism underlying this requirement is unknown. Taken together, we hypothesize that skin-derived TSLP in young infants disrupts the establishment of tolerance in airway mucosa, rendering them more susceptible to be sensitized against environmental antigens in the presence of natural adjuvant-induced TSLP, the two-step mechanism underlying the "atopic march". Thus, we will test our hypothesis in two Specific Aims. 1) Define the role of skin-derived TSLP in the regulation of airway tolerance. 2) Define the role of TSLP in NKT cell activation-mediated Th2 polarization in airway mucosa. The information learned from these studies will provide a greater understanding of the role of TSLP in asthma pathogenesis, and insights in targeting TSLP to prevent "atopic march".

 描述(申请人提供)：胸腺间质淋巴生成素(TSLP)是哮喘和过敏发病机制中的一个重要因素。粘膜耐受是在生命早期诱导的，是预防哮喘等过敏性疾病的重要机制。我们的初步结果表明，新生儿的CD4+T细胞是耐受性的，即使用OVA+Alum免疫，也会优先分化为可诱导的调节性T细胞(ITregs)，而不是辅助性T细胞2(Th2)。我们发现，患有特应性皮炎(AD)的婴儿(年龄范围6-18个月)血清TSLP(200-300pg/ml)升高，该浓度足以抑制iTreg分化。如果不能建立对特定气雾剂抗原的呼吸道耐受性，个体可能会在以后环境中存在天然佐剂(如微生物产品)时变得敏感。最近的研究表明，大多数家庭粉尘提取物含有细菌衍生的糖脂，能够激活人和小鼠的NKT细胞，从而作为天然佐剂促进Th2对气溶胶变应原的敏化。我们惊讶地发现，糖脂诱导的Th2敏化需要TSLP，而这一要求背后的机制尚不清楚。综上所述，我们假设婴幼儿皮肤来源的TSLP破坏了呼吸道粘膜耐受性的建立，使他们更容易在天然佐剂诱导的TSLP存在的情况下对环境抗原敏感，这是“特应性进行曲”背后的两步机制。因此，我们将在两个具体目标上检验我们的假设。1)明确皮源性TSLP在调节呼吸道耐受中的作用。2)明确TSLP在NKT细胞激活介导的气道黏膜Th2极化中的作用。从这些研究中获得的信息将使我们更好地了解TSLP在哮喘发病机制中的作用，并提供针对TSLP的见解，以防止“特应性进行曲”。