Autoimmune vitiligo and tolerance in the immune response to a melanoma antigen

描述（由申请人提供）：先前的工作已经表明，患者来源的T淋巴细胞在黑素瘤上识别的许多Ag来源于黑素细胞（MDP）中表达的分化蛋白。在自身免疫性白癜风患者的皮肤中也发现了针对MDP衍生的Ag的T细胞，并且白癜风通常伴随自发的或基于免疫疗法的黑色素瘤消退。因此，对MDP的自身耐受性是不完全的，调节它的机制与自身免疫性白癜风的发展和有效的黑色素瘤免疫有关。我们已经开发了动物和细胞试剂来分析自身耐受性和自身免疫性的模型MDP来自鼠酪氨酸酶（Tyr 369），是高度同源的，其人类对应。使用最近开发的Tyr 369特异性TCR转基因小鼠，我们已经确定对该Ag的自身耐受性是基于外周而不是中心缺失。然而，该过程的定位和提呈Tyr 369的细胞的性质与当前任何其他模型中的不同。尽管发生了自我耐受，动物也发展新生儿色素脱失，显示区域定位和双边对称性，然后在成年人进行性离域过程。这种模式显示出与人类自身免疫性白癜风的相似性，并且在其他实验模型中没有先例。本申请的主要目标是使用这种独特的模型来研究控制对这种内源性黑素细胞Ag的自身耐受性和自身免疫性的发展的细胞和分子。驱动所有方面工作的主要假设是，该模型中的自身免疫和自身耐受性由T细胞活化的质量和/或T细胞进入表皮和毛囊的控制的变化决定。我们的目标是：1）鉴定提呈Tyr 369的APC，并鉴定缺失性自身耐受和自身免疫性白癜风的原因; 2）在FH TCR转基因小鼠中区分促进局限性新生/表皮型白癜风和播散性/毛囊型成人型白癜风发展的皮肤相关因子; 3）确定在将IL-2支持的Tyr 369特异性T细胞过继转移到亚致死剂量照射的受者中后，使平衡从耐受性向白癜风倾斜的机制。所获得的知识将提供深入了解控制白癜风发展的因素，并将其与其他皮肤自身免疫性疾病区分开来。

DESCRIPTION (provided by applicant): Previous work has shown that many Ags recognized on melanomas by patient-derived T lymphocytes are derived from differentiation proteins expressed in melanocytes (MDP). T cells directed against MDP-derived Ags have also been found in the skin of patients with autoimmune vitiligo, and vitiligo often accompanies spontaneous or immunotherapy based melanoma regression. Thus, self-tolerance to MDP is incomplete, and the mechanisms that regulate it are relevant to both autoimmune vitiligo development and effective melanoma immunity. We have developed animal and cellular reagents to analyze self-tolerance and autoimmunity to a model MDP derived from murine tyrosinase (Tyr369) that is highly homologous to its human counterpart. Using recently developed Tyr369-specific TCR transgenic mice we have established that self- tolerance to this Ag is based on peripheral, not central, deletion. However, the localization of this process and the nature of the cells presenting Tyr369 are different from those in any other current model. Despite the occurrence of self-tolerance, the animals also develop neonatal depigmentation that shows both regional localization and bilateral symmetry, followed by a progressive delocalized process in adults. This pattern shows similarities to autoimmune vitiligo in humans, and is without precedent in other experimental models. The primary goal of this application is to use this unique model to investigate the cells and molecules that control the development of self-tolerance and autoimmunity to this endogenous melanocyte Ag. The primary hypothesis driving all aspects of the work is that autoimmunity and self-tolerance in this model are determined by changes in the quality of T cell activation and/or control of T cell access to the epidermis and hair follicle. Our aims are: 1) To identify the APC that present Tyr369 and are responsible for deletional self-tolerance and autoimmune vitiligo; 2) To distinguish the skin-associated factors that promote development of localized neonatal/epidermal vitiligo and disseminated/hair follicle adult vitiligo in FH TCR transgenic mice; 3) To identify the mechanisms that tip the balance from tolerance to vitiligo after adoptive transfer of IL-2 supported Tyr369 specific T cells into sublethally irradiated recipients. The knowledge gained will provide insight into factors that control the development of vitiligo, and that distinguish it from other autoimmune diseases of the skin.