Keratinocyte Costimulation and Th2-Cell Immune Deviation

这项建议将测试我们的假设，表皮角质形成细胞可以有助于发展的歪斜， 对引起过敏性接触性皮炎的半抗原的免疫应答，促进Th 2 - 1淋巴细胞的出现， 当这种类型的Th-淋巴细胞亚群通常不会有助于免疫应答时的情况。这 “免疫偏离”导致IgE抗体反应的发展，这与以下疾病的发展有关： 在用半抗原再激发后的速发型过敏症状。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CD 80或CD 86的小鼠。首先，CD 80 Tg小鼠 产生半抗原特异性IgE和响应于致敏和强Thl激发的立即耳肿胀， 主要半抗原如三硝基氯苯和二硝基氟苯。这种CD 80 Tg小鼠发生慢性 与皮肤病变中肥大细胞积聚相关的皮炎，在CD 86 Tg或NTg中未观察到 小鼠第二，CD 86 Tg和非Tg小鼠不产生这种IgE抗体或对半抗原的立即反应。 致敏在目标一中，将研究IgE抗体应答的精细特征（IgE应答的动力学， 低水平IgE的精细定量、皮肤过敏反应的被动转移和肥大细胞接触性皮炎的研究 细胞缺陷小鼠）。在第二个目标中，来自正常非Tg小鼠的KC响应于 将研究发生的暴露并与体内IgE反应相关。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Th 2 - 1淋巴细胞是如何出现的。在目标4中，T细胞亚群的作用 在CD 80 Tg小鼠的半抗原特异性IgE抗体应答中，将通过交叉基因靶向小鼠（CD 4、CD 8或 TCR δ敲除小鼠）以产生双Tg小鼠。这些研究与人类过敏性皮肤病高度相关 因为人KC可以表达在接触性皮炎期间上调的CD 80样分子。该模型系统 将提供与理解I型变态反应的发展高度相关的重要信息 半抗原、含天然橡胶胶乳（NRL）的医疗器械和一般的特应性疾病。相似机制 对其它皮肤病如银屑病的分子基础的研究已经导致了生物学的发展 现在临床上使用的反应调节剂。

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.