Examining IgG4 sialylation as a gain of function post-translation modification in IgG4-related diseases

检查 IgG4 唾液酸化作为 IgG4 相关疾病中翻译后修饰的功能获得

基本信息

批准号：
10202454
负责人：
Robert McCullough Anthony
金额：
$ 82.3万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10202454
关键词：
Anti-Inflammatory Agents Antibodies Antibody Therapy Autoantigens Autoimmune B-Lymphocytes Binding Biological Biological Assay Biology Biophysics Blocking Antibodies CD4 Positive T Lymphocytes Cell-Mediated Cytolysis Cells Clinical Communicable Diseases Complement 1q Complement-Dependent Cytotoxicity Complex Data Development Disease Dose Effector Cell Family Galectin 3 Goals Human Hypersensitivity IgG1 IgG2 IgG3 IgG4 Immune checkpoint inhibitor Immunoglobulin G Immunology Immunotherapeutic agent In Vitro Inflammation Inflammatory Intravenous Immunoglobulins Knowledge Laminin Lead Lesion MS4A1 gene Malignant Neoplasms Mediating Mission Modification Mus Pathology Patients Phagocytosis Plasma Cells Polysaccharides Public Health Recombinant Immune Globulin Regulation Research Resolution Role Signal Transduction Testing Therapeutic Uses Therapeutic antibodies Translations Transplantation United States National Institutes of Health anti-CD20 antibody-dependent cell cytotoxicity autoinflammatory cytotoxic defined contribution design experimental study gain of function glycosylation immunoregulation in vivo innovation insight neoplasm immunotherapy programmed cell death protein 1 receptor receptor binding sialylation standard of care success translational impact

项目摘要

Project Summary/Abstract. IgG4-related diseases (IgG4-RDs) are a family of related autoinflammatory diseases characterized by fibrotic lesions comprised of CD4+ T cells and IgG4+ plasma cells, and markedly elevated oligoclonal IgG4. However, whether IgG4 antibodies contribute to IgG4-RD pathology remains unclear. Despite the tremendous clinical success of immunotheraputics, little is known regarding IgG4 biology relative to IgG1. Our long-term goals are to understand the role and regulation of glycosylation to antibody biology, to ultimately modulate antibody effector functions in vitro and in vivo. The overall objective of this application is to comprehensively dissect cytotoxic activity of sialylated IgG4. Our central hypothesis is autoantigen-specific IgG4 in IgG4-RD is sialylated, and contributes to the pathology Of IgG4-RD. Our approach combines characterizing IgG from the sera of IgG4-RD and healthy patients, while examining precisely glycoengineered IgG4 in receptor binding and effector function assays. Our hypothesis is informed by preliminary data shown here in the Approach subsection of the Research Strategy section. The rationale that underlies the proposed research is understanding how IgG4 mediate cytotoxic effector function will enable new insights into IgG biology, and may lead to development of innovative antibody-based therapies. We will test our central hypothesis and, thereby, attain the objective of this application by pursuing the following three specific aims using a combination of biophysical experiments, and in vitro and in vivo functional assays. 1) Define the glycosylation and FcγRs-binding profiles of total and autoantigen-specific IgG in IgG4-RD. Hypothesis: Sialylation enables FcγR binding by IgG4. 2) Examine the effector functions of sialylated IgG4 in vitro. Hypothesis: Sialylated IgG4 mediates effector cell-specific pro-inflammatory effector functions. 3) Determine the in vivo effector functions of sialylated IgG4. Hypothesis: Sialylated IgG4 exerts pro- inflammatory effector functions in vivo. This proposal is expected to have broad clinical implications, ranging from diseases where elevated IgG4 titers are associated in the pathology or resolution, as well as to design of immunotherapeutics, and represents a substantive departure from the status quo by underscoring the cytotoxic capacity of IgG4.

项目摘要/摘要。 IgG4相关疾病（IgG4-RD）是一类以纤维化为特征的相关自身炎症性疾病病变由 CD4+ T 细胞和 IgG4+ 浆细胞组成，并且寡克隆 IgG4 显着升高。尽管有大量的临床研究，但 IgG4 抗体是否会导致 IgG4-RD 病理学仍不清楚。尽管免疫治疗取得了成功，但关于 IgG4 相对于 IgG1 的生物学知之甚少，我们的长期目标是。了解糖基化对抗体生物学的作用和调节，最终调节抗体效应子该应用的总体目标是全面剖析细胞毒性。我们的中心假设是 IgG4-RD 中的自身抗原特异性 IgG4 是唾液酸化的，并且我们的方法结合了 IgG4-RD 血清中 IgG 的表征。和健康患者，同时检查精确的糖工程化 IgG4 的受体结合和效应器功能化验。我们的假设是根据研究策略“方法”小节中显示的初步数据得出的拟议研究的基本原理是了解 IgG4 如何介导细胞毒性效应器。功能将为 IgG 生物学带来新的见解，并可能导致基于抗体的创新开发我们将测试我们的中心假设，从而通过追求来实现该应用的目标。结合生物物理实验以及体外和体内功能，遵循三个具体目标化验。 1) 定义 IgG4-RD 中总和自身抗原特异性 IgG 的糖基化和 FcγRs 结合谱。假设：唾液酸化使 FcγR 能够与 IgG4 结合。 2) 体外检查唾液酸化 IgG4 的效应器功能假设：唾液酸化 IgG4 介导效应器。细胞特异性促炎效应功能。 3) 确定唾液酸化 IgG4 的体内效应器功能假设：唾液酸化 IgG4 发挥亲-作用。炎症效应器在体内发挥作用。该提议预计将具有广泛的临床意义，包括 IgG4 滴度升高的疾病与病理学或解决方案以及免疫治疗的设计相关，并代表通过强调 IgG4 的细胞毒性能力，与现状有了实质性的不同。