Keratinocyte Costimulation and Th2-Cell Immune Deviation

这一建议将检验我们的假设，即表皮角质形成细胞可以促进倾斜的 对引起变态反应性接触性皮炎的半抗原的免疫应答，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对免疫反应做出贡献的情况。这 “免疫偏离”导致IgE抗体应答的发生，而IgE抗体应答的发生与 用半抗原再次攻击时出现即刻类型的过敏症状。我们的假设是基于对转基因生物的研究 (TG)角质形成细胞(KC)在角蛋白14启动子驱动下过度表达CD80或CD86的小鼠。首先，CD80转基因小鼠 产生半抗原特异性的IgE和立即的耳肿胀，以响应致敏和强烈的Th1- 主要的半抗原，如三硝基氯苯和二硝基氟苯。这样的CD80转基因小鼠会发展为慢性 皮炎与皮损中肥大细胞的聚集有关，CD86TG或NTG中没有观察到这种情况 老鼠。其次，CD86TG和非TG小鼠不会产生这样的IgE抗体或对半抗原立即产生反应 敏化。在第一个目标中，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、非甘油三酯小鼠KC表达CD80的生理学研究 发生暴露将被研究，并与体内的IgE反应相关。在目标3中，抗原提呈细胞-T- 将研究淋巴细胞的相互作用，以确定这些Th2-1淋巴细胞是如何出现的。在目标4中，T细胞亚群的作用 在CD80Tg小鼠的半抗原特异性IgE抗体反应中，将通过交叉基因靶向的小鼠(CD4、CD8或 TCR Delta基因敲除小鼠)，以创建双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。这个模型系统 将提供与了解I型过敏反应的发展高度相关的重要信息 对于半抗原、含天然胶乳(NRL)的医疗器械，以及一般的特应性疾病。类似的机制 对牛皮癣等其他皮肤病的分子基础的研究促进了生物学的发展 目前在临床上使用的反应修饰剂。

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.