Antigen specific therapy for bullous pemphigoid

大疱性类天疱疮的抗原特异性治疗

• 批准号: 7686174
• 负责人: Francoise A Van den Bergh
• 金额: $ 18.94万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686174
• 关键词: Adhesions; Adverse effects; Amino Acids; Animal Model; Antibodies; Antigens; Apoptosis; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Baculoviruses; Binding; Biochemical; Blood; Blood Cells; Blood specimen; Bulla; Bullous Pemphigoid; Cell Adhesion Molecules; Cell Death; Cell Line; Cell Surface Proteins; Cell-Matrix Junction; Cells; Chimeric Proteins; Clinical; Collagen Type XVII; Coupled; Cytoplasm; Defect; Dermal; Development; Disease; Disease model; Down-Regulation; Ensure; Epithelial; Epitopes; Functional disorder; Generations; Goals; Grant; Host Defense Mechanism; Human; Hybridomas; Immune; Immune response; Immune system; Immunodominant Epitopes; Immunologics; Immunosuppressive Agents; Impairment; In Vitro; Investigation; Knowledge; Lead; Life; Mediating; Methodology; Modeling; Molecular Genetics; Monitor; Morbidity - disease rate; Mus; Outcome; Pancreatic ribonuclease; Patients; Plasma; Plasma Proteins; Population; Positioning Attribute; Preparation; Production; Property; Protein Biosynthesis; Protein Isoforms; Proteins; Public Health; Reaction; Reagent; Research; Research Project Grants; Ribonucleases; Safety; Skin; Specificity; Stretching; System; T-Lymphocyte; Testing; Time; Toxin; Transfer RNA; Transgenes; Transgenic Animals; angiogenin; autoreactive B cell; base; cytotoxic; desmoglein III; effective therapy; efficacy testing; gene replacement therapy; improved; in vivo; killings; member; mortality; mutant; novel; skin disorder; tool; treatment effect

DESCRIPTION (provided by applicant): Bullous Pemphigoid (BP) is an autoimmune blistering skin disease. This condition is characterized by potentially life-threatening humoral immune reactions to an epidermal cell surface protein, BP180 (also known as collagen XVII). Global immunosuppressive treatments are generally used to control such antibody-mediated disorders; however, serious side effects underscore the critical need for specific targeted therapy. The goal of this R21 application is to explore and develop a therapy that would deplete autoreactive B-cells in an antigen-specific manner. Our hypothesis for this exploratory/developmental research grant (R21) application is that a BP180-specific antigen-toxin is capable of greatly reducing the production of anti-BP180 antibodies by binding to, and selectively killing, BP180-specific B-cells. The cytotoxic moiety of this fusion protein is human angiogenin, a plasma RNase that is non-toxic until it is delivered into the cytoplasm of the target cell. The first aim will focus on generating and characterizing the angiogenin-antigen fusion and control proteins necessary to test our hypothesis. Biochemical and immunological analyses will be carried out to ensure that the enzymatic activity of angiogenin and the antigenic properties of the BP180 moiety have not been altered. The second aim is directed toward testing the efficacy of the antigen-toxin in vitro and in vivo. Our in vitro approaches involve monitoring cell death in BP180-specific B-cell hybridomas (both human and murine), as well as on BP patients' peripheral blood cells. Non-specific immune cells will be used as negative control. In vivo testing of the efficacy and safety of this antigen-toxin will be carried out using a murine model that reproduces the anti-BP180 immune response in BP. The effects of the treatments will be quantified by following anti-BP180 antibody titers and monitoring BP180-specific B-cell populations in the mice. The fate of other cells of the innate and adaptive immune systems will be followed. This study represents the first test of an angiogenin-antigen in an in vivo system. RELEVANCE of this research to public health: If our hypothesis is confirmed, the findings from this project could well lead to the development of specific therapies for patients with BP and other B-cell driven autoimmune disorders. The expected outcome is a significant reduction in the morbidity and mortality associated with these clinical conditions. We envision that antigen-specific immuno-modulation could also be employed to improve the outcomes of certain types of gene replacement therapy, in which a humoral immune response to the transgene product is a serious pitfall.

描述（由申请人提供）：大疱性类天疱疮（BP）是一种自身免疫性起泡皮肤病。这种疾病的特征是对表皮细胞表面蛋白BP 180（也称为胶原蛋白XVII）的潜在危及生命的体液免疫反应。总体免疫抑制治疗通常用于控制此类抗体介导的疾病;然而，严重的副作用强调了对特异性靶向治疗的迫切需求。这项R21申请的目标是探索和开发一种以抗原特异性方式消耗自身反应性B细胞的疗法。我们对这项探索性/发展性研究资助（R21）申请的假设是，BP 180特异性抗原毒素能够通过结合并选择性杀死BP 180特异性B细胞，大大减少抗BP 180抗体的产生。该融合蛋白的细胞毒性部分是人血管生成素，其是一种血浆RNA酶，在被递送到靶细胞的细胞质中之前是无毒的。第一个目标将集中在生成和表征血管生成素-抗原融合和控制蛋白质，以测试我们的假设。将进行生物化学和免疫学分析，以确保血管生成素的酶活性和BP 180部分的抗原特性未发生改变。第二个目的是在体外和体内测试抗原毒素的功效。我们的体外方法包括监测BP 180特异性B细胞杂交瘤（人和鼠）以及BP患者外周血细胞中的细胞死亡。非特异性免疫细胞将用作阴性对照。将使用在BP中再现抗BP 180免疫应答的鼠模型进行该抗原-毒素的功效和安全性的体内测试。将通过以下抗BP 180抗体滴度和监测小鼠中BP 180特异性B细胞群来定量治疗的效果。先天性和适应性免疫系统的其他细胞的命运将被跟踪。这项研究代表了血管生成素抗原在体内系统中的第一次测试。这项研究与公共卫生的相关性：如果我们的假设得到证实，该项目的发现很可能会导致BP和其他B细胞驱动的自身免疫性疾病患者的特异性疗法的发展。预期结果是与这些临床病症相关的发病率和死亡率显著降低。我们设想，抗原特异性免疫调节也可用于改善某些类型的基因替代疗法的结果，其中对转基因产物的体液免疫应答是一个严重的陷阱。