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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：
10394191
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/10394191
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 Galactose Goals Hepatocyte Hospitals Hypersensitivity IgG1 IgG2 IgG3 IgG4 Immune response Immunocompromised Host Immunoglobulin G Immunology In Situ In Vitro Individual Inflammation Inflammatory Institution Intravenous Immunoglobulins Kidney Knowledge Lead 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 anti-IgG attenuation autoimmune arthritis autoimmune inflammation autoreactivity design experimental study extracellular glycosylation glycosyltransferase improved in vivo innovation insight mouse model nephrotoxicity novel receptor 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.

项目概要/摘要。尽管免疫治疗在临床上取得了巨大的成功，但关于IgG 2 - 4生物学相关性知之甚少。 IgG1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，免疫反应。本申请的总体目标是检查细胞外蛋白的调节。 IgG的唾液酸化，并了解IgG唾液酸化如何发挥抗炎活性。过去几年的研究尽管近十年来人们已经阐明了IgG 1糖基化的重要性，但对IgG 1糖基化的贡献却知之甚少。糖基化至其他IgG亚类或调节IgG唾液酸化。我们最近证明了唾液酸化炎症期间IgG的释放在施用可溶性糖基转移酶后在细胞外原位发生，称为B4ST6Fc。我们的中心假设是B4ST 6Fc的细胞外唾液酸化传递II型Fc γ R结合和对IgG 1和IgG 3选择性的抗炎活性。我们的假设是根据初步数据得出的在研究策略部分的方法小节中显示。细胞外原位唾液酸化在自身抗体诱导的疾病期间，肾脏或爪中的致病性小鼠IgG减弱了两种不同的自身免疫性疾病的模型。此外，我们发现IgG1和IgG3的唾液酸化导致抗炎作用。体内活性和体外DC-SIGN结合。所提出的研究的基本原理是理解 Fc糖基化对所有IgG亚类的贡献将使人们对IgG生物学有新的认识，创新抗体疗法的发展。我们将测试我们的中心假设，从而获得本申请的目的是通过使用生物物理学和生物化学的组合来实现以下具体目的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 通过核苷酸-糖底物对致病性IgG1和IgG3进行唾液酸化，减轻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。假设：具体 IgG1和IgG3所特有且IgG2和IgG4中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。