Targeting HSP70 in autoimmune vitiligo

描述(申请人提供)：在白癜风患者，皮肤色素脱失与CD8+细胞毒性淋巴细胞局部渗入有关，至少部分与黑素细胞分化抗原反应。在黑色素瘤中，可以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打破可以用靶抗原的增加来解释。然而，在白癜风中，涉及HSP70的质量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会大量释放HSP70，并激活树突状细胞，使应激蛋白伴随的抗原的加工和呈递得到增强。HSP70还可以增强T细胞的细胞毒作用，以维持对黑素细胞的持续自身免疫反应。我们假设，消除HSP70在沉淀和维持对黑素细胞的自身免疫反应中的关键作用将阻止白癜风的传播。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潜在适合于治疗进展性疾病的HSP70结合抗体的有效性[1]将确定HSP70在微调DC可及性和处理模式黑素瘤靶抗原TRP1方面的作用，[2]将在我们新建立的自身免疫性白癜风体内小鼠模型中定义HSP70的脱色促进活性，以及[3]HSP70阻断抗体的功能活性和干扰进行性白癜风的能力。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。白癜风患者出现进行性皮肤色素脱失，这是由于表皮基底层形成黑素细胞的色素丧失所致。这给患者留下了毁容的皮肤损伤，使他们在大约55年的生命中受到排斥。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开发一种新的白癜风治疗方法，基于HSP70在皮肤颜色丧失中起关键作用的新概念。 公共卫生相关性：在白癜风患者中，患者通常在皮肤脱色之前经历压力，损害黑素细胞的生理。HSP70是应激黑素细胞和伴随黑素细胞特异性抗原释放的产物，可激活DC，诱导T细胞对黑素细胞的免疫应答。在这里，我们建议探索阻断HSP70激活免疫反应的机制和优点，以阻止我们新建立的自身免疫性白癜风模型的疾病进展。

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.