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

描述(申请人提供)：以前的工作已经表明，许多由患者来源的T淋巴细胞在黑色素瘤上识别的AGS来自于黑素细胞(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来源的AGS的T细胞，白癜风通常伴随着基于自发或免疫治疗的黑色素瘤消退。因此，自身对MDP的耐受性是不完全的，调节它的机制与自身免疫性白癜风的发生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对来自小鼠酪氨酸酶(Tyr369)的模型MDP的自身耐受性和自身免疫，该模型与人类酪氨酸酶(Tyr369)高度同源。使用最近开发的Tyr369特异性TCR转基因小鼠，我们已经确定对这种抗原的自我耐受是基于外周而不是中心缺失。然而，这一过程的局部化和呈现Tyr369的细胞的性质与任何其他当前模型中的不同。尽管出现了自我耐受，但这些动物也会出现新生儿色素脱失，表现出区域性和两侧对称性，随后在成年动物中会出现一个渐进的离局化过程。这种模式与人类自身免疫性白癜风有相似之处，在其他实验模型中是没有先例的。这项应用的主要目标是利用这一独特的模型来研究控制对这种内源性黑素细胞抗原的自我耐受和自身免疫发展的细胞和分子。推动所有方面工作的主要假设是，在这个模型中，自身免疫和自我耐受是由T细胞激活质量的变化和/或T细胞进入表皮和毛囊的控制决定的。我们的目标是：1)鉴定表达Tyr369并与缺失性自身耐受和自身免疫性白癜风有关的APC；2)在FH TCR转基因小鼠中区分促进局限性新生儿/表皮白癜风和播散性/毛囊成人白癜风发生的皮肤相关因素；3)确定过继转移IL-2支持的Tyr369特异性T细胞进入亚致死剂量照射受体后，使平衡从耐受转向白癜风的机制。所获得的知识将提供对控制白癜风发展的因素的洞察，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.