Study of FcR Genes: Macrophages and Lymphocytes

FcR基因研究：巨噬细胞和淋巴细胞

• 批准号: 8265241
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 47.06万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2013-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265241
• 关键词: Active immunity; Address; Affinity; Alleles; Animal Model; Antibodies; Antibody Specificity; Antigen-Antibody Complex; Autoimmune Diseases; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Cells; Dendritic Cells; Disease; Effector Cell; Engineering; Evaluation; Fc Receptor; Generations; Genes; Human; Immune; Immunoglobulin G; Individual; Inflammation; Inflammatory; Inflammatory Response; Knock-in Mouse; Knockout Mice; Libraries; Lupus; Lymphocyte; Lymphoid Cell; Maintenance; Mediating; Modeling; Modification; Mouse Strains; Mus; Myeloid Cells; Natural Killer Cells; Outcome; Passive Immunity; Pattern; Phenotype; Plasma Cells; Polysaccharides; Population; Property; Proteins; Receptor Signaling; Regulation; Rheumatoid Arthritis; Role; Signal Transduction; Specificity; System; Therapeutic; Therapeutic antibodies; Thrombocytopenia; Transgenes; Transgenic Organisms; Yeasts; antibody-dependent cell cytotoxicity; autoreactive B cell; base; cell type; cytotoxic; cytotoxicity; defined contribution; embryonic stem cell; human disease; immunopathology; in vivo; macrophage; mast cell; mutant; neoplastic; neutrophil; peripheral tolerance; receptor; receptor function; response; tumor

DESCRIPTION (provided by applicant): Fc receptors for IgG (Fc?R) are essential for mediating the effector properties of IgGs in vivo, as well as regulating the afferent response through the engagement of immune complexes with B cells and dendritic cells. Perturbations in expression and signaling of these receptors can contribute to the loss of tolerance and immunopathology observed in autoimmune diseases such as lupus and rheumatoid arthritis. While previous studies utilizing gene disruptions have revealed the overall function of these receptors, a detailed analysis of the contribution of individual cellular populations with their specific FcR expression and binding properties is, as yet, lacking. 1) We will address the functional contribution of specific receptors on discrete lymphoid and myeloid cells using conditionally floxed alleles of murine Fc?Rs B6 ES cells. RIIB deletion in B cell subsets and dendritic cells will determine their respective contributions to the regulation by immune complexes of autoreactive B cells in the periphery. The contribution of macrophage/neutrophils, mast cells and NK cells to IgG mediated cytotoxicity and immune complex triggered inflammation will be characterized in strains conditionally deleted for Fc?Rs on these effector cells. 2) Extrapolation of these results to the human system will be addressed by the generation of fully humanized FcR mouse lines, in which all endogenous murine FcR expression is ablated and human FcR expression is obtained in a cellular pattern appropriate for the human FcRs. These lines will be characterized in models of human IgG mediated cytotoxicity and immune complex inflammation for specific IgG subclasses and modified human Fcs. RELEVANCE TO HUMAN DISEASE: The studies outlined in this proposal will provide a rational basis for the re-engineering of therapeutic IgG antibodies for the treatment of neoplastic and inflammatory diseases and for their evaluation in vivo in an animal model that recapitulates the human system.

描述（由申请人提供）：IgG的FC受体（FC？r）对于介导体内IgG的效应特性以及通过通过与B细胞和树突状细胞接合来调节传入的反应至关重要。这些受体的表达和信号传导的扰动可以导致在狼疮和类风湿关节炎等自身免疫性疾病中观察到的耐受性和免疫病理学的丧失。尽管以前利用基因破坏的研究揭示了这些受体的总体功能，但尚未缺乏对单个细胞群体及其特定FCR表达和结合特性的贡献的详细分析。 1）我们将使用有条件的鼠FC？RS B6 ES细胞的等位基因来解决特定受体对离散淋巴样和髓样细胞的功能贡献。 B细胞亚群和树突状细胞中的RIIB缺失将确定它们对周围自身反应性B细胞免疫复合物对调节的贡献。巨噬细胞/嗜中性粒细胞，肥大细胞和NK细胞对IgG介导的细胞毒性和免疫复合物触发炎症的贡献将以有条件删除的菌株在这些效应细胞上有条件删除。 2）将这些结果推断到人类系统将通过完全人性化的FCR小鼠系的产生来解决，其中所有内源性鼠FCR表达都是烧蚀的，并以适合人类FCR的细胞模式获得了人类FCR表达。这些线将在人IgG介导的细胞毒性和免疫复合炎症的模型中进行表征，以针对特定的IgG亚类和改良的人FC。与人类疾病的相关性：该提案中概述的研究将为重新设计用于治疗肿瘤和炎症性疾病的治疗性IgG抗体的理性基础，并在体内对人类系统的动物模型进行评估。

项目成果

Biochemical nature and cellular distribution of the paired immunoglobulin-like receptors, PIR-A and PIR-B.

• DOI: 10.1084/jem.189.2.309
• 发表时间: 1999-01-18
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Kubagawa, H;Chen, C C;Ho, L H;Shimada, T S;Gartland, L;Mashburn, C;Uehara, T;Ravetch, J V;Cooper, M D
• 通讯作者: Cooper, M D

Inhibitory Fcγ receptor is required for the maintenance of tolerance through distinct mechanisms.

抑制性 Fcγ 受体是通过不同机制维持耐受性所必需的

• DOI: 10.4049/jimmunol.1302934
• 发表时间: 2014-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Li F;Smith P;Ravetch JV
• 通讯作者: Ravetch JV

Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade.

• DOI: 10.1126/science.8066448
• 发表时间: 1994-08
• 期刊: Science
• 影响因子: 56.9
• 作者: Diana L Sylvestre;Jeffrey V. Ravetch

IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity.

• DOI: 10.1126/science.aai8128
• 发表时间: 2017-01-27
• 期刊: Science (New York, N.Y.)
• 作者: Wang TT;Sewatanon J;Memoli MJ;Wrammert J;Bournazos S;Bhaumik SK;Pinsky BA;Chokephaibulkit K;Onlamoon N;Pattanapanyasat K;Taubenberger JK;Ahmed R;Ravetch JV
• 通讯作者: Ravetch JV