Vitiligo in Tyrosinase-specific TCR Transgenic Mice

描述（由申请人提供）：作为本实验室长期以来对识别黑色素瘤患者T细胞识别的抗原的兴趣的结果，我们发现许多这样的抗原在黑色素细胞中表达并与色素产生有关。这一观察结果也很有趣，因为黑素细胞破坏引起的皮肤色素沉着通常伴随着自发或基于免疫治疗的黑色素瘤缓解。此外，在自身免疫性皮肤色素沉着（白癜风）患者的皮肤中发现了针对这些抗原的T细胞。我们最近开发了一种临床前模型，使用转基因小鼠表达人类I类MHC分子和源自小鼠酪氨酸酶（Tyr369）的肽Ag，该肽Ag与人类酪氨酸酶高度同源，并由HLA-A*0201呈递。我们还开发了表达针对酪氨酸酶表位的T细胞受体的转基因小鼠，并观察到，尽管发生了一定程度的自我耐受性，但动物发展为进行性白癜风，显示出区域定位和两侧对称。这些特征与全身性白癜风患者相似。这代表了一种独特的模型，可以检查导致白癜风发展的几个因素，包括免疫效应细胞的性质，它们用来导致黑素细胞破坏的机制，以及导致这些细胞进入皮肤的因素。我们期望这项工作将阐明与理解其他基于皮肤的自身免疫和炎症状况相关的机制。在这个R21应用程序的上下文中，我们的目标是对这个模型的各个方面有一个基本的了解，这将为更全面的基于r01的调查奠定基础。该应用的具体目的是：确定tyr369特异性CD8 T细胞对于新生儿耳部白癜风和成人弥散性白癜风的发展是否必要和充分；研究新生和成年TCR转基因小鼠皮肤细胞浸润与白癜风发生的关系；研究可能导致白癜风发展的皮肤相关归巢机制。

DESCRIPTION (provided by applicant): As an outgrowth of the longstanding interest of this laboratory in identifying antigens recognized on melanoma tumors by T cells from patients with this disease, we have discovered that many such antigens are expressed in melanocytes and concerned with pigment production. This observation is also intriguing because skin depigmentation due to melanocyte destruction often accompanies spontaneous or immunotherapy based remission from melanoma. In addition, T cells directed against some of these antigens have been found in the skin of patients with autoimmune skin depigmentation (vitiligo). We have recently developed a preclinical model using transgenic mice expressing a human class I MHC molecule and a peptide Ag derived from murine tyrosinase (Tyr369) that is highly homologous to its human counterpart and presented by HLA-A*0201. We have also developed transgenic mice that express T cell receptors specific for this tyrosinase epitope, and have observed that, despite the occurrence of some level of self-tolerance, the animals develop a progressive vitiligo that shows both regional localization and bilateral symmetry. These characteristics are similar to those observed in patients with generalized vitiligo. This represents a unique model in which to examine several factor that contribute to the development of vitiligo, including the nature of the immunological effector cells, the mechanisms they use to cause melanocyte destruction, and the factors that cause such cells to enter the skin. It is our expectation that this work will illuminate mechanisms that are relevant to an understanding of other skin-based autoimmune and inflammatory conditions. In the context of this R21 application, our goals are to develop a basic understanding of facets of this model that will set the stage for a more comprehensive R01-based investigation. The specific aims of this application are: To determine whether Tyr369-specific CD8 T cells are both necessary and sufficient for development of ear vitiligo in neonates and disseminated vitiligo in adults; To characterize the cellular infiltration of the skin associated with the development of vitiligo in neonatal and adult TCR transgenic mice; To examine the skin-associated homing mechanisms that may contribute to vitiligo development.