Keratinocyte Costimulation and Th2-Cell Immune Deviation

角质形成细胞共刺激和 Th2 细胞免疫偏差

• 批准号: 7033086
• 负责人: ANTHONY A GASPARI
• 金额: $ 32.23万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-18 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033086
• 关键词: T lymphocyte; allergens; antibody; cellular immunity; contact dermatitis; gene expression; genetically modified animals; haptens; immune response; immunoglobulin E; keratin; keratinocyte; laboratory mouse; rubber; skin hypersensitivity

EXCEED THE SPACE PROVIDED, This proposal will test our hypothesis that epidermal keratinocytes can contribute to the development of a skewed immune response to haptens that cause allergic contact dermatitis, promoting the emergence of Th2-1ymphocytes under circumstances when this type of Th-lymphocyte subset would not normally contribute to an immune response. This "immune deviation" leads to the development of IgE antibody response, which is associated with the development of immediate-type allergic symptoms upon rechallenge with the hapten. Our hypothesis is based on studies of transgenic (Tg) mice whose keratinocytes (KC) over-express CD80 or CD86 driven by a keratin 14 promoter. First, CD80 Tg mice develop hapten-specific IgE and immediate ear swelling in response to sensitization and challenge with strong Thl- dominant haptens such as trinitrochlorobenzene and dinitrofluorobenzene. Such CD80 Tg mice develop chronic dermatitis associated with an accumulation of mast cells in the skin lesions, which is not observed inCD86 Tg or NTg mice. Second, CD86 Tg and non-Tg mice do not develop such IgE antibodies or immediate responses to hapten sensitization. In aim one, the fine characteristics of the IgE antibody response will be studied (kinetics of IgE response, fine quantitation of low levels of lgE, passive transfer of cutaneous anaphylaxis, and studies of contact dermatitis in mast cell deficient mice). In aim two, the physiology of CD80 expression by KC from normal, non-Tg mice in response to happen exposure will be studied and correlated with IgE responses in vivo. In aim 3, antigen presenting cell-T- lymphocyte interactions will be studied to define how these Th2-1ymphocytes emerge. In aim 4, the role of T-cell subsets in hapten-specific IgE antibody response by CD80 Tg mice will be defined by crossing gene targeted mice (CD4, CD8 or TCR delta knock-out mice) to create double Tg mice. These studies are highly relevant to human allergic skin disease because human KC can express CD80-1ike molecules that are upregulated during contact dermatitis. This model system will provide important information that is highly relevant to the understanding of development of type I allergic responses to haptens, natural rubber latex (NRL)-containing medical devices, and atopic diseases in general. Similar mechanistic studies of the molecular basis of other skin diseases such as psoriasis have led to the development of biological response modifiers that are now in clinical use.

超越空间 假如， 该提案将检验我们的假设，即表皮角质形成细胞可能有助于倾斜的发展 对引起过敏性接触性皮炎的半抗原的免疫反应，促进 Th2-1 淋巴细胞的出现 这种类型的 Th 淋巴细胞亚群通常不会参与免疫反应。这 “免疫偏差”导致 IgE 抗体反应的发展，这与 再次使用半抗原后会出现立即型过敏症状。我们的假设是基于转基因研究 (Tg) 角质形成细胞 (KC) 过度表达由角蛋白 14 启动子驱动的 CD80 或 CD86 的小鼠。一、CD80 Tg小鼠 响应于强Thl-的致敏和挑战，产生半抗原特异性IgE并立即发生耳部肿胀 主要半抗原如三硝基氯苯和二硝基氟苯。这种CD80 Tg小鼠发展为慢性 与皮损中肥大细胞积聚相关的皮炎，在 CD86 Tg 或 NTg 中未观察到 老鼠。其次，CD86 Tg 和非 Tg 小鼠不会产生此类 IgE 抗体或对半抗原的立即反应 敏化。在目标一中，将研究 IgE 抗体反应的精细特征（IgE 反应的动力学、 低水平 lgE 的精细定量、皮肤过敏反应的被动转移以及肥大接触性皮炎的研究 细胞缺陷小鼠）。在目标二中，正常非 Tg 小鼠的 KC 表达 CD80 的生理学反应 将研究发生的暴露并与体内 IgE 反应相关联。在目标 3 中，抗原呈递细胞-T- 将研究淋巴细胞相互作用，以确定这些 Th2-1 淋巴细胞如何出现。在目标 4 中，T 细胞亚群的作用 CD80 Tg 小鼠的半抗原特异性 IgE 抗体反应将通过交叉基因靶向小鼠（CD4、CD8 或 TCR delta 敲除小鼠）创建双 Tg 小鼠。这些研究与人类过敏性皮肤病高度相关 因为人类 KC 可以表达在接触性皮炎期间上调的 CD80-1 样分子。本模型系统 将提供与了解 I 型过敏反应的发展高度相关的重要信息 半抗原、含有天然橡胶乳胶 (NRL) 的医疗器械以及一般特应性疾病。类似的机制 对牛皮癣等其他皮肤病的分子基础的研究导致了生物学的发展 现已投入临床使用的反应调节剂。