Vitiligo in Tyrosinase-specific TCR Transgenic Mice

酪氨酸酶特异性 TCR 转基因小鼠中的白癜风

• 批准号: 6864875
• 负责人: VICTOR H ENGELHARD
• 金额: $ 22.85万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864875
• 关键词: SCID mouse; T cell receptor; autoimmune disorder; cell migration; cytotoxic T lymphocyte; disease /disorder model; genetically modified animals; laboratory mouse; mature animal; melanocyte; melanoma; monophenol monooxygenase; newborn animals; pathologic process; tumor antigens; vitiligo

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.

描述（由申请人提供）：作为本实验室长期以来对鉴定黑色素瘤肿瘤上被黑色素瘤患者的 T 细胞识别的抗原感兴趣的结果，我们发现许多此类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，因为黑色素细胞破坏导致的皮肤色素脱失通常伴随着黑色素瘤的自发缓解或基于免疫治疗的缓解。此外，在患有自身免疫性皮肤色素脱失（白癜风）的患者皮肤中发现了针对其中一些抗原的 T 细胞。我们最近开发了一种临床前模型，使用表达人类 I 类 MHC 分子和源自鼠酪氨酸酶 (Tyr369) 的肽 Ag 的转基因小鼠，该肽与人类对应物高度同源，由 HLA-A*0201 呈递。我们还开发了表达针对该酪氨酸酶表位的 T 细胞受体的转基因小鼠，并观察到，尽管存在一定程度的自我耐受，但动物仍会出现进行性白癜风，并显示出局部定位和双侧对称性。这些特征与在全身性白癜风患者中观察到的特征相似。这代表了一个独特的模型，可以在其中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、它们引起黑素细胞破坏的机制以及导致这些细胞进入皮肤的因素。我们期望这项工作能够阐明与理解其他皮肤自身免疫和炎症性疾病相关的机制。在此 R21 应用程序的背景下，我们的目标是对该模型的各个方面有一个基本的了解，这将为基于 R01 的更全面的调查奠定基础。本申请的具体目的是： 确定 Tyr369 特异性 CD8 T 细胞对于新生儿耳部白癜风和成人播散性白癜风的发展是否是必要和充分的；表征与新生和成年 TCR 转基因小鼠白癜风发展相关的皮肤细胞浸润；研究可能导致白癜风发展的皮肤相关归巢机制。