Harnessing the anti-inflammatory activity of extracellular sialylation of IgG.

利用 IgG 细胞外唾液酸化的抗炎活性。

基本信息

批准号：
10589050
负责人：
Robert McCullough Anthony
金额：
$ 54.97万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-16 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589050
关键词：
Affinity Amino Acid Sequence Anti-Inflammatory Agents Antibodies Antibody Therapy Antigen-Antibody Complex Attenuated Autoantibodies Autoimmune Autoimmune Diseases B-Lymphocytes Binding Biological Biological Assay Biology Biophysics Blood Platelets CD209 gene Cell Lineage Clinical Clinical Trials Communicable Diseases Data Deposition Development Disease Dissection Dose Engineering Enzymes Exhibits Fc-Gamma Receptor II Galactose Goals Hepatocyte Hospitals Hypersensitivity IgG Receptors IgG1 IgG2 IgG3 IgG4 Immune response Immunocompromised Host Immunoglobulin G Immunology In Situ In Vitro Individual Inflammation Inflammatory Institution Intravenous Immunoglobulins Kidney Knowledge Malignant Neoplasms Mediating Mission Modeling Molecular Mus Nephritis Outcome Pathogenicity Pathway interactions Patients Plasma Policies Polysaccharides Preparation Property Public Health Recombinant Immune Globulin Regulation Replacement Therapy Research Rheumatoid Arthritis Role Sialic Acids Site Systemic Lupus Erythematosus Testing Therapeutic Therapeutic Uses Thrombocytopenia Transplantation United States National Institutes of Health Wegener&apos s Granulomatosis attenuation autoimmune arthritis autoimmune inflammation autoreactivity design experimental study extracellular glycosylated IgG glycosylation glycosyltransferase improved in vivo innovation insight mouse model nephrotoxicity novel receptor binding sialylation success sugar nucleotide

项目摘要

Project Summary/Abstract. Despite the tremendous clinical success of immunotheraputics, little is known regarding IgG2-4 biology relative to IgG1. Our long-term goal is to understand how glycosylation of antibodies regulates, and is regulated, by immune responses. The overall objective of this application is to examine the regulation of extracellular sialylation of IgG, and understand how IgG sialylation exerts anti-inflammatory activity. Studies over the last decade have illuminated the importance of IgG1 glycosylation, little is known about the contribution of glycosylation to other IgG subclasses or the regulation of IgG sialylation. We recently demonstrated sialylation of IgG during inflammation occurs extracellularly in situ following administration of soluble glycosyltransferases, termed B4ST6Fc. Our central hypothesis is that extracellular sialylation by B4ST6Fc conveys type II FcγR binding and anti-inflammatory activity selectively to IgG1 and IgG3. Our hypothesis is informed by preliminary data shown here in the Approach subsection of the Research Strategy section. Extracellular sialylation in situ of pathogenic mouse IgG in the kidneys or paws during autoantibody-induced disease attenuates two distinct models of autoimmune disease. Further, we show sialylation of IgG1 and IgG3 results in anti-inflammatory activity in vivo, and DC-SIGN binding in vitro. The rationale that underlies the proposed research is understanding the contribution of Fc glycosylation to all IgG subclasses 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 specific aims using a combination of biophysical experiments, and in vitro and in vivo functional assays. 1) Define the regulation of extracellular IgG sialylation during autoimmune disease. Hypothesis: B4ST6Fc reduces SLE nephritis by sialylation of pathogenic IgG1 and IgG3 with the aid of nucleotide-sugar substrates released by deposited platelets. 2) Identify the molecular determinants of sialylated IgG anti-inflammatory activity. Hypothesis: a specific amino acid sequence that is unique to IgG1 and IgG3 and absent from IgG2 and IgG4, in combination with N297 sialylation, results in DC-SIGN binding ability and anti-inflammatory activity.

项目摘要/摘要。尽管免疫治疗在临床上取得了巨大成功，但人们对于 IgG2-4 的生物学相关性知之甚少。我们的长期目标是了解抗体的糖基化如何调节以及如何被调节。该应用的总体目标是检查细胞外的调节。 IgG 的唾液酸化，并了解 IgG 唾液酸化如何发挥抗炎活性。十年来阐明了 IgG1 糖基化的重要性，但人们对 IgG1 糖基化的贡献知之甚少其他 IgG 亚类的糖基化或 IgG 唾液酸化的调节我们最近证明了唾液酸化。施用可溶性糖基转移酶后，炎症期间 IgG 的产生在细胞外原位发生，我们的中心假设是 B4ST6Fc 的细胞外唾液酸化可传递 II 型 FcγR 结合。以及针对 IgG1 和 IgG3 的选择性抗炎活性我们的假设是基于初步数据。此处显示在“研究策略”部分的“方法”小节中。在自身抗体诱发的疾病期间，肾脏或爪子中的致病性小鼠 IgG 可减弱两种不同的此外，我们还显示了 IgG1 和 IgG3 的唾液酸化在抗炎中的作用。体内活性和体外 DC-SIGN 结合拟议研究的基本原理是理解。 Fc 糖基化对所有 IgG 亚类的贡献将为 IgG 生物学提供新的见解，并可能导致我们将测试我们的中心假设，从而实现基于抗体的创新疗法的开发。本申请的目的是通过结合生物物理学来追求以下特定目标实验以及体外和体内功能测定。 1) 定义自身免疫性疾病期间细胞外 IgG 唾液酸化的调节假设：B4ST6Fc。在核苷酸-糖底物的帮助下，通过致病性 IgG1 和 IgG3 的唾液酸化来减少 SLE 肾炎由沉积的血小板释放。 2) 确定唾液酸化 IgG 抗炎活性的分子决定因素：具体假设。 IgG1 和 IgG3 特有且 IgG2 和 IgG4 不存在的氨基酸序列，与 N297 组合唾液酸化，导致 DC-SIGN 结合能力和抗炎活性。