Investigating Immunoglobulin CSR as a Novel Therapeutic Target for SLE

研究免疫球蛋白 CSR 作为 SLE 的新治疗靶点

基本信息

批准号：
9034544
负责人：
CAROLINE McPhee LEETH
金额：
$ 8.05万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-16 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9034544
关键词：
Activated B-Lymphocyte Adverse effects Affect Animal Model Antibodies Antigen-Antibody Complex Apoptotic Attenuated Autoantibodies Autoimmune Diseases B-Cell Leukemia B-Lymphocytes Cells Cessation of life Clinical effectiveness Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Alteration Data Development Disease Disease Progression Enzyme Activation Event FDA approved Future Gene Duplication Genes Genetic Genetic screening method Germinal Center B-Lymphocyte Goals Health Human Immune Tolerance Immune response Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulins Immunosuppression Intervention Investigation Laboratories Lead Life Lymphocyte Activation Mediating Modification Monitor Monoclonal Antibodies Mus Mutation Nephritis Organ Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Process Production Research Role Structure of germinal center of lymph node Symptoms Systemic Lupus Erythematosus TLR7 gene Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Tissues Toxic effect United States Y Chromosome activation-induced cytidine deaminase attenuation base belimumab design ds-DNA genome wide association study homologous recombination improved inhibitor/antagonist leukemia/lymphoma member mouse model new therapeutic target novel novel therapeutics prevent promoter repaired research study response small molecule small molecule inhibitor success systemic autoimmune disease targeted treatment therapeutic target translational study

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease characterized by a loss of immune tolerance which results in the production of autoantibodies and immune complexes, and culminating in potentially fatal organ damage. Autoreactive B lymphocytes are at the center of this aberrant immune response, producing copious amounts of pathogenic autoantibodies. The first FDA drug in decades approved for the treatment of SLE directly targets and depletes B lymphocytes, making this approach appealing and warranting further exploration. B lymphocytes undergo the unique processes of class switch recombination (CSR) and somatic hypermutation, during which permanent DNA changes occur. These changes are due to double-stranded DNA breaks that are initiated by the molecule, AID, and subsequently repaired through homologous recombination. Using these genetic modifications, B lymphocytes are able to change the class of antibody they produce to more effectively respond to pathogenic invasion. In SLE, B lymphocytes actively undergo AID-initiated CSR to produce pathogenic autoantibodies. Our laboratory recently observed that AID is upregulated in the BXSB.Yaa mouse, which is arguably the most relevant animal model for human SLE. Most pathogenic antibodies produced in these mice originate from B-lymphocytes having undergone CSR. Since CSR is unique to B lymphocytes, therapeutic targeting of this process would provide a directed approach to eliminating only activated B lymphocytes producing pathogenic antibodies. The objective of this project is to investigate novel research strategies of therapeutic intervention in the BXSB.Yaa SLE mouse model that could be used in future translational studies aimed at improved therapeutic approaches for SLE patients. We hypothesize that AID-mediated CSR plays an important role in the pathogenesis of SLE, and that this process can be targeted for therapeutic intervention. To test our hypothesis, we propose two aims. Aim 1: Test if genetic deletion of Aicda (the gene encoding AID) abrogates the pathogenesis of SLE-like disease in the BXSB.Yaa mouse. We anticipate that SLE progression will be attenuated in these mice validating the targeting of this pathway for therapeutic intervention. Aim 2: Test whether administrations of novel therapeutic agents that prevent the repair of AID-induced DNA damage inhibit SLE-like disease progression in BXSB.Yaa mice. One therapeutic option is blocking the repair of AID-induced DNA breaks, which has been shown to result in B lymphocyte death. Mice will be treated with the small molecule inhibitors of DNA break repair, DIDS and C- 1523-1a, and monitored for disease progression. These compounds are members of a class of drugs currently being tested as a potential therapeutic for leukemia and lymphoma. The results of this study are expected to provide conclusive evidence that CSR plays a critical role in the pathogenesis of SLE and serves as a potential target for therapeutic intervention. Success of this approach in SLE would be novel for autoimmune disease therapy and would present future avenues for therapeutic exploration.

描述（由应用程序提供）：全身性红斑狼疮（SLE）是一种严重的全身性自身免疫性疾病，其特征是免疫耐受性丧失，导致自身抗体和免疫复合物的产生，并导致潜在致命的器官损害最终导致。自动反应性B淋巴细胞位于这种异常免疫响应的中心，产生大量的致病自身抗体。几十年来，FDA药物的第一个药物已批准用于治疗SLE的直接靶向和耗尽B淋巴细胞，从而使这种方法出现并警告进一步探索。 B淋巴细胞在类开关重组（CSR）和体细胞超松受的独特过程中，在此期间发生永久性DNA变化。这些变化是由于分子，AID引发的双链DNA断裂，随后通过同源重组修复。使用这些遗传修饰，B淋巴细胞能够更改其产生的抗体类别，以更有效地应对致病性侵袭。在SLE中，B淋巴细胞积极接受辅助发射的CSR，以产生致病性自身抗体。我们的实验室最近观察到，在BXSB.yaa小鼠中进行了更新，这可以说是人类SLE的最相关的动物模型。这些小鼠中产生的大多数致病性抗体源自具有CSR的B淋巴细胞。由于CSR是B淋巴细胞独有的，因此该过程的治疗靶向将提供一种有针对性的方法来消除仅产生致病性抗体的活化的B淋巴细胞。该项目的目的是研究BXSB.YAA SLE小鼠模型中理论干预的新研究策略，该模型可用于未来的翻译研究，旨在改善SLE患者的治疗方法。我们假设AID介导的CSR在SLE的发病机理中起重要作用，并且该过程可以作为治疗干预的目标。为了检验我们的假设，我们提出了两个目标。目标1：测试AICDA的遗传缺失（基因编码AID）是否可以废除BXSB.YAA小鼠中SLE样疾病的发病机理。我们预计，这些小鼠将减弱SLE进展，以验证该途径用于治疗干预措施。 AIM 2：测试新型治疗剂是否可以防止辅助诱导的DNA损伤抑制BXSB.YAA小鼠的SLE样疾病进展。一种治疗选择是阻止辅助诱导的DNA断裂的修复，这已证明会导致B淋巴细胞死亡。小鼠将用DNA断裂修复，DIDS和C-1523-1A的小分子抑制剂治疗，并监测疾病进展。这些化合物是目前正在对白血病和淋巴瘤的潜在疗法进行测试的一类药物的成员。预计这项研究的结果将提供确定的证据，表明企业社会责任在SLE的发病机理中起着至关重要的作用，并作为治疗干预的潜在目标。这种方法在SLE中的成功将是自身免疫性疾病疗法的新颖，并将展示未来的疗法探索途径。