Antigen specific therapy for bullous pemphigoid

大疱性类天疱疮的抗原特异性治疗

• 批准号: 7470245
• 负责人: Francoise A Van den Bergh
• 金额: $ 22.73万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470245
• 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; Condition; Coupled; Cytoplasm; Defect; Dermal; Development; Disease; Disease model; Down-Regulation; Endoribonucleases; 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; Molecular Models; Monitor; Morbidity - disease rate; Mus; Numbers; Outcome; Pancreatic ribonuclease; Patients; Plasma; Plasma Proteins; Population; Positioning Attribute; Preparation; Production; Property; Protein Biosynthesis; Protein Isoforms; Proteins; Public Health; Range; Reaction; Reagent; Replacement Therapy; 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; gene replacement; 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）是一种自身免疫性水疱性皮肤病。这种情况的特点是对表皮细胞表面蛋白 BP180（也称为 XVII 胶原蛋白）产生潜在危及生命的体液免疫反应。整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定靶向治疗的迫切需要。 R21 应用的目标是探索和开发一种以抗原特异性方式消除自身反应性 B 细胞的疗法。我们对于这项探索性/开发性研究资助 (R21) 申请的假设是，BP180 特异性抗原毒素能够通过结合并选择性杀死 BP180 特异性 B 细胞，从而大大减少抗 BP180 抗体的产生。该融合蛋白的细胞毒性部分是人血管生成素，这是一种血浆 RNase，在被递送到靶细胞的细胞质中之前是无毒的。第一个目标将集中于生成和表征检验我们的假设所需的血管生成素-抗原融合和控制蛋白。将进行生化和免疫学分析，以确保血管生成素的酶活性和 BP180 部分的抗原特性没有改变。第二个目标是测试抗原毒素在体外和体内的功效。我们的体外方法包括监测 BP180 特异性 B 细胞杂交瘤（人和小鼠）以及 BP 患者外周血细胞的细胞死亡。非特异性免疫细胞将用作阴性对照。该抗原毒素的功效和安全性的体内测试将使用小鼠模型进行，该模型可在 BP 中重现抗 BP180 免疫反应。治疗效果将通过跟踪抗 BP180 抗体滴度并监测小鼠体内 BP180 特异性 B 细胞群来量化。先天性和适应性免疫系统的其他细胞的命运将被跟随。这项研究代表了血管生成素抗原在体内系统中的首次测试。这项研究与公共卫生的相关性：如果我们的假设得到证实，该项目的研究结果很可能会导致针对 BP 和其他 B 细胞驱动的自身免疫性疾病患者的特定疗法的开发。预期结果是与这些临床病症相关的发病率和死亡率显着降低。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反应是一个严重的陷阱。