Spectrum of Autoimmune Gastrointestinal Dysmotility

自身免疫性胃肠动力障碍谱

基本信息

批准号：
7216785
负责人：
VANDA A LENNON
金额：
$ 31.79万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216785
关键词：
Accounting Acetylcholine Active Immunization Adolescent Animal Model Antibodies Antigen Receptors Antigens Autoantibodies Autoimmune Process Autoimmunity Autonomic ganglion Cell-Mediated Cytolysis Cholinergic Receptors Classification Complement Defect Diagnosis Enteric Nervous System Epitopes Fc Receptor Fluorescence Ganglia Genes Green Fluorescent Proteins IgG Receptors IgG(T)Immune response Immunity Immunization Immunoglobulin G Inflammatory Knockout Mice Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Microelectrodes Mus Myxoid cyst Neonatal Neurons Nicotinic Receptors Nuclear Numbers Oryctolagus cuniculus Outcome Pathogenicity Pathology Patients Peptides Personal Satisfaction Principal Investigator Production Recombinants Research Research Proposals Serum Staging Synaptic Transmission T-Lymphocyte Testing Time Tissues Transgenic Mice base cell motility clinically relevant cobra venom factor design fetal gastrointestinal genetic regulatory protein immunopathology improved in utero insight mature animal motility disorder nervous system development programs response synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): The objective of this research proposal is to investigate in animal models the immunopathogenic mechanism(s) accounting for autoimmune gastrointestinal (G.I.) dysmotility. Autoimmunity targeting neurons in ganglia of the enteric nervous system (ENS), and extrinsic autonomic ganglia, is well-documented clinically in association with lung cancer, and may be a cause of several idiopathic forms of G.I. dysmotility, including congenital cases that are not explained by recognized gene defects. The rationale for the research plan is based on the inflammatory pathology found in ganglia, and IgG markers found in serum, of patients with the paraneoplastic entity. Recognized IgG markers are specific for ganglionic nicotinic acetylcholine receptor (AChR) and neuronal nuclear and cytoplasmic antigens. IgG specific for the ganglionic AChR is also found in some patients with idiopathic G.I. dysmotility. This IgG accompanies G.I. dysmotility in rabbits immunized with recombinant fragments or synthetic peptides of the ganglionic AChR a3 subunit, and causes G.I. dysmotility when injected into healthy mice. The Specific Aims are: 1)to elucidate mechanisms responsible for the pathogenicity of AChR-IgG in adult animals, 2) investigate the potential of AChR-IgG to transfer G.I. dysmotility transplacentally, 3) define antigenic determinants of IgG and T cell responses contributing to G.I. dysmotility, and determine if inflammatory ENS ganglionitis will result from immunization strategies designed to activate cytotoxjc (CD8+) T cells specific for peptides derived from neuronal nuclear, cytoplasmic or AChR antigens. Methods include functional tests of G.I. motility, intracellular microelectrode studies of ganglionic synaptic transmission, analyses of cellular and humoral immune responses, production and characterization of monoclonal ganglionic AChR-lgGs, use of cobra venom factor to deplete complement, use of knock-out mice deficient in complement regulatory proteins or Fc receptors required for IgG-dependent cell-mediated cytotoxicity, histological, immunohistochemical and electronmicroscopic analyses of ganglionic tissues, and time lapse fluorescence photomicroscopic recording of ENS development stages in GFP transgenic mice exposed in utero to AChR-IgG. Insights anticipated from these studies will improve the diagnosis and aid classification of idiopathic G.l.dysmotilities, and justify early consideration of immunomodulatory therapies. The proposed research also has high clinical relevance to cancer immunity.

描述（由申请人提供）：该研究建议的目的是在动物模型中调查自身免疫性胃肠道（G.I.）功能障碍的免疫致病机制。肠神经系统神经节（ENS）和外部自主神经节神经元的自身免疫性在临床上与肺癌相关，可能是G.I的几种特发性形式的原因。运动障碍，包括未通过公认基因缺陷解释的先天性病例。研究计划的基本原理基于神经节中发现的炎症病理学，以及在血清中发现的副塑性实体患者的IgG标记。公认的IgG标记是特定于神经节烟碱乙酰胆碱受体（ACHR）和神经元核和细胞质抗原的特异性。在一些特发性G.I的患者中也发现了针对神经节ACHR的IgG。运动障碍。这个IgG伴随着G.I.用神经节ACHR A3亚基的重组片段或合成肽免疫的兔子中的运动障碍，并导致G.I.注射健康小鼠时失调性。具体目的是：1）阐明成年动物中ACHR-IGG致病性的机制，2）研究ACHR-IGG转移G.I.的潜力。运动障碍，3）定义了促成G.I的IgG和T细胞反应的抗原决定因素。动力障碍，并确定炎症性ENS神经节炎是否将是由旨在激活源自神经元核，细胞质或ACHR抗原的肽的细胞毒素（CD8+）T细胞的免疫策略。方法包括G.I.的功能测试。 motility, intracellular microelectrode studies of ganglionic synaptic transmission, analyses of cellular and humoral immune responses, production and characterization of monoclonal ganglionic AChR-lgGs, use of cobra venom factor to deplete complement, use of knock-out mice deficient in complement regulatory proteins or Fc receptors required for IgG-dependent cell-mediated cytotoxicity, histological,神经节组织的免疫组织化学和电子显微镜分析，以及在子宫内暴露于ACHR-IGG的GFP转基因小鼠中ENS发育阶段的ENS发育阶段的时间流逝荧光显微镜记录。从这些研究中预期的见解将改善特发性G.L.多种作用的诊断和帮助分类，并证明早期考虑免疫调节疗法是合理的。拟议的研究还与癌症免疫具有很高的临床相关性。