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。

• 批准号: 10096946
• 负责人: Robert McCullough Anthony
• 金额: $ 56.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10096946
• 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' 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

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。 尽管免疫疗法取得了巨大的临床成功，但对于IgG2-4生物学相对，知之甚少 到IgG1。我们的长期目标是了解抗体的糖基化如何调节，并通过 免疫反应。该应用的总体目的是检查细胞外的调节 IgG的溶解度，并了解IgG溶解度如何发挥抗炎活性。对最后的研究 十年阐明了IgG1糖基化的重要性，对 糖基化对其他IgG亚类或IgG溶解的调节。我们最近证明 炎症过程中的IgG发生在固体糖基转移酶时，在原位发生了细胞外发生的。 称为B4ST6FC。我们的中心假设是，B4ST6FC的细胞外溶解传达II型FcγR结合 和IgG1和IgG3选择性的抗炎活性。我们的假设通过初步数据告知 此处显示在研究策略部分的方法小节中。原位细胞外苷 自身抗体诱导的疾病期间，儿童或爪子中的致病小鼠IgG减弱了两个不同的 自身免疫性疾病的模型。此外，我们显示了IgG1和IgG3的溶解度导致抗炎 体内活性和DC-SIGN结合体外。拟议研究的基础是理解的基本原理 FC糖基化对所有IgG亚类的贡献将使IgG生物学有新的见解，并可能领导 开发基于创新抗体的疗法。我们将检验我们的中心假设，从而获得 通过使用生物物理的组合来追求以下特定目标来实现此应用的目的 实验，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溶解度的调节。假设：B4ST6FC 借助于核刺刺激底物，通过致病性IgG1和IgG3溶解来降低SLE肾炎 由沉积的血小板释放。 2）确定垂直IgG抗炎活性的分子鉴定。假设：特定的 IgG1和IgG3独有的氨基酸序列，IgG2和IgG4不存在，与N297结合 鉴别，导致DC符号结合能力和抗炎活性。