Catalytic Immunity and Autoimmune Mechanisms

催化免疫和自身免疫机制

• 批准号: 6731218
• 负责人: ALFONSO TRAMONTANO
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731218
• 关键词: abzyme; active immunization; antibody neutralization test; antigen antibody reaction; autoantibody; autoimmunity; biotechnology; catalyst; covalent bond; immunologic substance development /preparation; immunoregulation; laboratory mouse; monoclonal antibody; peptide chemical synthesis; phage display; serine proteinases; tumor necrosis factor alpha; vaccine development

DESCRIPTION (provided by applicant): Antibodies and their fragments that specifically break down proteins and peptides are found in an autoimmune context, in multiple myeloma and in certain experimental immune responses elicited against viral polypeptides. Studies support the premise that antibodies with catalytic activity are inherent to the immune repertoire, but may be excluded from dominant responses in the healthy immune subject. Two approaches are described that could lead to production of efficient serine protease-like catalytic antibodies. A new method of immunization is proposed to specifically elicit antibodies that utilize covalent reactivity in antigen binding. Antibodies induced in the covalent immunization procedure will be characterized for hydrolytic activity against defined peptide analogs. Differences in the covalent immunization responses in normal and autoimmune mice will be investigated to reveal possible mechanisms of its regulation. Alternatively, covalent binding will be used to select recombinant antibodies represented on phage display libraries. The recombinant clones or hybridomas from immunized mice will be screened for expression of monoclonal antibodies with covalent binding and efficient peptidase activities. The primary sequence, specificity and kinetic efficiency of defined clones will be studied to identify molecular and functional attributes of the efficient catalysts. These methods will be applied to develop specific proteolytic antibodies against the cytokine TNF-alpha. Potential involvement of catalytic antibodies that cleave TNF-alpha in regulating immune responses and cytotoxicity will be examined. Antibodies that efficiently degrade self or foreign antigens could provide a direct mechanism for neutralization and thus significantly enhance the immune system's capacity to mount protective responses against cancer, chronic inflammation or infectious agents. These efforts could lead to useful applications as therapeutics or for enhanced vaccine design.

描述（由申请人提供）： 抗体及其片段 在自身免疫细胞中发现特异性分解蛋白质和肽 在多发性骨髓瘤和某些实验性免疫反应中 诱导对抗病毒多肽。研究支持这样的前提： 具有催化活性的抗体是免疫库所固有的，但是 可能被排除在健康免疫受试者的显性反应之外。二 描述了可能导致高效丝氨酸生产的方法 蛋白酶样催化抗体。提出了一种新的免疫方法 特异性引发利用抗原共价反应性的抗体 绑定。共价免疫程序中诱导的抗体将是 具有针对特定肽类似物的水解活性。 正常和自身免疫的共价免疫反应的差异 将研究小鼠以揭示其调节的可能机制。 或者，共价结合将用于选择重组抗体 出现在噬菌体展示库上。重组克隆或杂交瘤 将筛选免疫小鼠的单克隆抗体表达 具有共价结合和有效的肽酶活性。初级序列， 将研究确定克隆的特异性和动力学效率 识别高效催化剂的分子和功能属性。这些 方法将用于开发针对特定蛋白水解抗体 细胞因子TNF-α。切割的催化抗体的潜在参与 将检查 TNF-α 调节免疫反应和细胞毒性的作用。 有效降解自身或外源抗原的抗体可以提供 直接中和机制，从而显着增强免疫 系统针对癌症、慢性病发起保护性反应的能力 炎症或感染因子。这些努力可能会带来有益的成果 作为治疗或增强疫苗设计的应用。

项目成果

Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy.

• DOI: 10.1681/asn.2008050555
• 发表时间: 2009-05
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: T. Shcheglova;S. Makker;A. Tramontano

Aldehyde modification of peptide immunogen enhances protein-reactive antibody response to toxic shock syndrome toxin-1.

肽免疫原的醛修饰增强了对中毒性休克综合征毒素 1 的蛋白质反应性抗体反应。

• DOI: 10.1002/psc.821
• 发表时间: 2006
• 期刊: Journal of peptide science : an official publication of the European Peptide Society
• 作者: Bavoso,Alfonso;Ostuni,Angela;DeVendel,Jolanda;Pollaro,Francesco;Armentano,Francesca;Knight,Thomas;Makker,Sudesh;Tramontano,Alfonso
• 通讯作者: Tramontano,Alfonso