Targeting HSP70 in autoimmune vitiligo

描述（申请人提供）：白癜风患者皮肤色素脱失与局部CD8+细胞毒性淋巴细胞浸润有关，这些淋巴细胞至少部分与黑素细胞分化抗原反应。在黑色素瘤中，观察到靶向黑素细胞分化抗原的类似T细胞介导的免疫应答，其中对自身抗原的耐受性的破坏可以通过靶抗原丰度的增加来解释。然而，在白癜风中，涉及HSP70的质的差异似乎是破坏对黑素细胞分化抗原的耐受性的关键。白癜风黑素细胞在应激下大量释放HSP 70，并将激活树突状细胞，从而增强应激蛋白陪伴的抗原的加工和呈递。HSP 70还增强T细胞的细胞毒性，以使对黑素细胞的持续自身免疫应答永久化。我们假设，消除HSP70作为一个关键的球员，沉淀和持久的自身免疫反应，黑素细胞将停止白癜风的蔓延。我们建议进一步证明HSP 70在白癜风中的关键作用，并根据以下具体目的测试可能适用于治疗进行性疾病的HSP 70结合抗体的功效[1]将鉴定HSP 70在DC精细调节模型黑素体靶抗原TRP 1的可及性和加工中的作用，[2]将在我们新建立的自身免疫性白癜风体内小鼠模型中确定HSP 70的脱色增强活性，[3]将测试HSP 70阻断抗体的功能活性和干扰进行性白癜风的能力。Lay摘要：Le Poole博士实验室的研究主要集中在自身免疫性白癜风的病因学上。白癜风患者由于表皮基底层形成黑素细胞的色素丧失而呈现皮肤进行性色素脱失。这使得患者皮肤损伤，排斥他们约55年的生活。对于这种毁灭性的疾病，几乎没有疗效有限的治疗方法。在我们目前的项目申请中提出的研究将有助于支持开发一种新的白癜风治疗方法，该方法基于HSP 70在皮肤颜色丧失中起关键作用的新概念。 公共卫生相关性：白癜风患者在色素脱失之前通常会对皮肤产生压力，损害黑素细胞的生理功能。应激黑素细胞释放的HSP70和黑素细胞特异性抗原可激活DC并引发T细胞介导的针对黑素细胞的免疫应答。在这里，我们建议探讨机制和优点，阻止热休克蛋白70激活免疫反应，以阻止疾病的进展，在我们新建立的模型，自身免疫性白癜风。

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.