Targeting HSP70 in autoimmune vitiligo

描述（由申请人提供）：在白癜风中，皮肤色素沉着与CD8+细胞毒性淋巴细胞的局灶性浸润有关，至少部分与黑素细胞分化抗原有关。在黑色素瘤中，观察到类似的针对黑素细胞分化抗原的T细胞介导的免疫反应，其中对自身抗原的耐受性的破坏可以通过目标抗原的丰度增加来解释。然而，在白癜风中，涉及HSP70的质的差异似乎是打破对黑素细胞分化抗原耐受性的关键。白癜风黑素细胞在应激状态下大量释放HSP70，并激活树突状细胞，导致应激蛋白伴随抗原的加工和呈递增强。HSP70也增强T细胞的细胞毒性，使对黑素细胞的自身免疫反应持续存在。我们假设，消除HSP70作为促进和维持对黑素细胞的自身免疫反应的关键角色，将阻止白癜风的扩散。我们建议进一步证明HSP70在白癜风中的关键作用，并根据以下具体目标测试可能适合治疗进展性疾病的HSP70结合抗体的功效[1]HSP70在DC微调模型黑素体靶抗原TRP1的可及性和加工中的作用b[2] HSP70的增强活性将在我们新建立的自身免疫性白癜风小鼠体内模型中定义。和[3]HSP70阻断抗体将测试其功能活性和对进行性白癜风的干扰能力。摘要：Le Poole博士实验室的研究重点是自身免疫性白癜风的病因病理学。白癜风患者表现为皮肤进行性脱色，这是由于表皮基底层形成黑色素细胞的色素丧失所致。这使得患者的皮肤损伤毁容，使他们在大约55年的生命中被排斥。对于这种毁灭性的疾病，几乎没有有效的治疗方法。我们目前的项目申请中提出的研究将基于HSP70在皮肤颜色丧失中起关键作用的新概念，支持白癜风治疗新模式的发展。

DESCRIPTION (provided by applicant): In vitiligo, skin depigmentation is associated with focal infiltrates of CD8+ cytotoxic lymphocytes reactive, at least in part, with melanocyte differentiation antigens. In melanoma, a similar T cell mediated immune response targeting melanocyte differentiation antigens is observed where breaking of tolerance to self antigens can be explained by the increasing abundance of target antigens. In vitiligo however, a qualitative difference involving HSP70 appears to be crucial for breaking of tolerance to melanocyte differentiation antigens. HSP70 is abundantly released by vitiligo melanocytes under stress and will activate dendritic cells, leading to enhanced processing and presentation of antigens chaperoned by the stress protein. HSP70 also enhances T cell cytotoxicity to perpetuate an ongoing autoimmune response to melanocytes. We hypothesize that eliminating HSP70 as a key player in precipitating and perpetuating the autoimmune response to melanocytes will halt the spread of vitiligo. We propose to further demonstrate a crucial role for HSP70 in vitiligo and to test the efficacy of HSP70-binding antibodies potentially suitable for treatment of progressive disease according to the following specific aims [1] The role of HSP70 in fine tuning accessibility and processing of model melanosomal target antigen TRP1 by DC will be identified, [2] The depigmentation enhancing activity of HSP70 will be defined in our newly established in vivo mouse model of autoimmune vitiligo, and [3] HSP70 blocking antibodies will be tested for functional activity and the ability to interfere with progressive vitiligo. Lay abstract: Research in the laboratory of Dr. Le Poole is focused on the etiopathology of autoimmune vitiligo. Patients with vitiligo present with progressive depigmentation of the skin due to the loss of pigment forming melanocytes from the basal layer of the epidermis. This leaves patients with disfiguring skin lesions, ostracizing them for approximately 55 years of their life. There are few treatments of limited efficacy available for this devastating condition. The research proposed in our current project application will serve to support the development of a novel treatment modality for vitiligo, based on the novel concept that HSP70 plays a crucial role in the loss of skin color. PUBLIC HEALTH RELEVANCE: In vitiligo, patients generally experience stress to the skin preceding depigmentation, compromising melanocyte physiology. HSP70, released from stressed melanocytes and chaperoning melanocyte specific antigens, can activate DC and elicit a progressive T cell mediated immune response to melanocytes. Here we propose to explore the mechanism and the merit of blocking HSP70 from activating an immune response in order to halt disease progression in our newly established model of autoimmune vitiligo.