Targeting HSP70 in autoimmune vitiligo

靶向 HSP70 治疗自身免疫性白癜风

• 批准号: 7893134
• 负责人: I. Caroline Le Poole
• 金额: $ 32.74万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893134
• 关键词: Antibodies; Antigen Presentation Pathway; Antigen Targeting; Antigens; Atypical lymphocyte; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; Blocking Antibodies; CD8B1 gene; Cancer Vaccines; Cells; Clinical Trials; Dendritic Cells; Development; Differentiation Antigens; Disease Progression; Epidermis; Event; Fab Immunoglobulins; Figs - dietary; Generations; Genes; Granzyme; Heat shock proteins; Heat-Shock Proteins 70; Immune; Immune response; Immunologic Monitoring; In Vitro; Injury; Laboratories; Lead; Left; Life; Mechanics; Modality; Modeling; Molecular Chaperones; Monitor; Mus; Pathway interactions; Patients; Phenols; Physiology; Pigments; Play; Principal Investigator; Process; Progressive Disease; Property; Protein Binding; Recruitment Activity; Research; Role; Skin; Stratum Basale; Stress; T-Cell Activation; T-Lymphocyte; Testing; Translating; Trauma; UV Radiation Exposure; Vitiligo; abstracting; base; cell mediated immune response; cytotoxic; cytotoxicity; efficacy testing; experience; extracellular; immune activation; in vivo; killings; lymph nodes; melanocyte; melanoma; mouse model; novel; novel therapeutics; perforin; programs; public health relevance; response; skin color; skin lesion; stress protein; stressor; therapeutic target

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.

描述（由申请人提供）：在白癜风中，皮肤色素脱失与至少部分与黑素细胞分化抗原反应的CD8+细胞毒性淋巴细胞的局部浸润有关。在黑色素瘤中，观察到类似的 T 细胞介导的针对黑色素细胞分化抗原的免疫反应，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 的定性差异似乎对于打破对黑素细胞分化抗原的耐受性至关重要。 HSP70 在压力下由白癜风黑素细胞大量释放，并会激活树突状细胞，从而增强应激蛋白陪伴下的抗原的加工和呈递。 HSP70 还增强 T 细胞的细胞毒性，以维持对黑素细胞持续的自身免疫反应。我们假设，消除 HSP70 作为促进和维持黑素细胞自身免疫反应的关键因素，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 在模型可及性和处理的微调中的作用将鉴定 DC 的黑素体靶抗原 TRP1，[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 的脱色增强活性，以及​​ [3]将测试 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病理学。白癜风患者由于表皮基底层色素形成黑素细胞的丧失而出现皮肤进行性色素脱失。这给患者留下了毁容性的皮肤损伤，使他们在大约 55 年的生命中受到排斥。对于这种毁灭性的病症，目前几乎没有有效的治疗方法。我们当前项目申请中提出的研究将基于 HSP70 在肤色丧失中发挥关键作用的新概念，支持开发一种新的白癜风治疗方式。 公众健康相关性：在白癜风中，患者通常会在色素脱失之前经历皮肤压力，从而损害黑素细胞的生理机能。 HSP70 从受应激的黑素细胞和陪伴黑素细胞特异性抗原中释放出来，可以激活 DC 并引发渐进性 T 细胞介导的针对黑素细胞的免疫反应。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。