自身免疫性甲状腺疾病的发病机制和治疗-猫眼课题宝

自身免疫性甲状腺疾病的发病机制和治疗

批准号：

7670775

负责人：

LESLIE J DE GROOT

金额：

$9.16万

依托单位：

UNIVERSITY OF RHODE ISLAND

依托单位国家：

美国

项目类别：

财政年份：

1980

资助国家：

美国

项目状态：

已结题

起止时间：

1980-07-01 至 2010-12-31

来源：

https://reporter.nih.gov/project-details/7670775

关键词：

2p21 2q33 AIDS therapy Accounting Acute Adjuvant Adrenal gland hypofunction Affect Affinity Aftercare Algorithms Alleles Allergic rhinitis Allogenic Amino Acid Sequence Amino Acids Animal Model Animals Antibodies Antibody Formation Antigen Mimicry Antigen Presentation Antigen-Presenting Cells Antigens Antithyroid Agents Apoptosis Arginine Attention Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Autologous B-Lymphocytes Bibliography Binding Binding Proteins Biological Assay Blocking Antibodies Blood Circulation Blood Vessels Blood specimen CD3 Antigens CD8-Positive T-Lymphocytes CTLA4 gene Candidate Disease Gene Cardiac Caring Caucasians Caucasoid Race Cell Adhesion Molecules Cell Line Cell surface Cells Cellular Immunity Charge Childhood Chromosomes Chromosomes, Human, Pair 6 Class Cleaved cell Clinical Codon Nucleotides Collaborations Complex Computers Condition Crystallization Cytoplasm DNA Data Depth Development Diffuse Disease Diseases in Twins Elevation Engraftment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Epithelial Cells Epitopes Ethanol Excision Exposure to Eye diseases Failure Family Female Floor Functional disorder Future Gene Pool General Population Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Predisposition to Disease Genome Genomics Genotype Goals Goiter Grant Graves&apos Disease HLA Antigens Hand Haplotypes Hashimoto Disease Hematoxylin and Eosin Staining Method Hereditary Disease High Prevalence Histocompatibility Antigens Class II Human Hyperactive behavior Hyperthyroidism Hypoparathyroidism Hypothyroidism Immune Immune response Immunity Immunization Immunodominant Epitopes Immunoglobulin Variable Region In Vitro Incidence Individual Inflammation Inflammatory Inherited Injection of therapeutic agent Insulin-Dependent Diabetes Mellitus Interferon Type II Interferon-alpha Interferons Interleukin-1 Interleukin-10 Interleukin-2 Interleukin-4 Interleukin-5 Interleukin-6 Interleukins Introns Iodide Peroxidase Iodides Japanese Population Knock-out Laboratories Laboratory Finding Lead Learning Length Life Ligands Link Linkage Disequilibrium Liver diseases Localized Lod Score Lymphocyte Lymphocyte Count Lymphocyte antigen Lymphokines MHC Class II Genes MabCampath Measures Mediating Medical Messenger RNA Methods Modeling Multiple Sclerosis Mus Mutate Myasthenia Myasthenia Gravis Names Numbers Operative Surgical Procedures Organ Other Finding Outcome Pathogenesis Patients Peptide Fragments Peptides Peripheral Peripheral Blood Mononuclear Cell Personal Satisfaction Persons Pharmacotherapy Phase Phenotype Pituitary Gland Play Polishes Polymorphic Microsatellite Marker Population Population Study Porosity Positioning Attribute Postpartum Period Predisposition Pregnancy Premature Ovarian Failure Principal Investigator Process Production Proliferating Promoter Regions Protein Glycosylation Proteins Proteolysis Publications Publishing R peptide Radiation Radioactive Range Reaction Recovery Relative (related person)Replacement Therapy Reporting Research Risk Role SCID Mice SHFM1 gene SLC26A3 gene Sampling Screening procedure Serum Side Signal Transduction Sinus Sorting - Cell Movement Specific qualifier value Specificity Stress Structure Surface Surface Antigens Surveys Susceptibility Gene System Systemic Lupus Erythematosus T-Cell Activation T-Cell Proliferation T-Lymphocyte T-Lymphocyte Epitopes TNF gene TNFRSF5 gene Testing Therapeutic Therapeutic Intervention Thymus Gland Thyroglobulin Thyroid Diseases Thyroid Gland Thyroid Hormones Thyroid Nodule Thyroid stimulating immunoglobulins Thyroiditis Thyrotoxicosis Thyrotropin Receptor Tissues To specify Transcriptional Activation Transplantation Tumor Necrosis Factor-alpha Up-Regulation Variant Virus Walkers Week Woman Work Writing anakinra antigen binding arginyllysine autoimmune thyroid disease base cell injury clinical phenotype cross reactivity cytokine design fetal genetic linkage analysis human TNF protein human leukocyte antigen gene humanized monoclonal antibodies immunoreactivity in vitro Assay in vivo indexing infancy insight intercellular cell adhesion molecule interest interleukin-2 (59-72)mRNA Stability macrophage male member men migration mouse model multicatalytic endopeptidase complex novel therapeutics pathogen prevent programs promoter receptor response sodium-iodide symporter theories thyroid associated ophthalmopathies thyroid xenograft vitamin D 1-alpha hydroxylase

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中文摘要

翻译

描述（由申请人提供）：Graves病是一种由自身免疫引起的常见甲状腺疾病，可产生严重并发症，包括心脏问题和眼病。环境因素起一定作用，但疾病的发展在很大程度上受遗传因素的制约，包括特定HLA II类基因的遗传，以及特定版本的CTLA-4基因。我们之前已经研究了II类MHC基因在Graves病中的作用，通过它们在抗原呈递细胞上的TSH受体衍生的T细胞表位呈递到T细胞，在免疫发展中。我们已经证明，某些TSH受体表位，经常刺激来自Graves病患者的T细胞，以中等亲和力结合HLA-DRbetal*0301。我们将研究TSH受体表位、HLA蛋白和T细胞的相互作用，以更好地了解疾病的发展和可能抑制免疫过程的方法。TSH受体表位与Graves患者中常见的所有DR和DQ蛋白的结合将被详细描述，并与患者的基因型和来自相同基因型患者的T细胞的反应性有关。利用计算机算法、亲和性研究和T细胞反应，以及从DR蛋白洗脱表位测序中获得的信息，我们将建立重要的或免疫优势的TSH受体T细胞表位。有了这些信息，我们将尝试推导突变的TSH受体序列，抑制患者T细胞对TSH受体表位的反应。我们还将使用结合在DR或DQ分子或四聚体中的TSH受体表位，在体外从患者血液样本中去除反应性T细胞，以确定是否可以找到降低免疫反应性的方法。在tsh - r免疫小鼠的Graves病模型中，我们将开发可能抑制疾病进程的表位，包括眼病的发展。这样的表位将来可能会同样用于患者。我们的研究将与a . Godkin博士合作完成，他将在计算机算法中分析TSH-R表位。Phelps博士将分析我们从DR3分子中洗脱出来的TSH-R表位，W. Kwok博士将提供DR3四聚体，M. Ludgate博士将研究Graves病模型。

英文摘要

DESCRIPTION (provided by applicant): Graves' disease is a common disease of the thyroid caused by autoimmunity and can produce serious complications including cardiac problems and eye disease. Environmental factors play some role, but development of disease is strongly conditioned by genetic factors including inheritance of specific HLA Class II genes, and a specific version of the CTLA-4 gene. We have previously investigated the role of Class II MHC genes in Graves' disease through their presentation of T cell epitopes derived from the TSH receptor on antigen presenting cells, to T cells, in the development of immunity. We have shown that certain TSH receptor epitopes, which frequently stimulate T cells from patients with Graves' disease, bind with moderate affinity to HLA-DRbetal*0301. We will study the interaction of TSH receptor epitopes, HLA proteins, and T cells to better understand the development of disease and methods for possible inhibition of the immune process. Binding of TSH receptor epitopes to all of the DR and DQ proteins commonly found in our Graves' patients will be detailed and related to the genotype of the patient and reactivity of T cells from patients with the same genotype. Using computer algorithms, affinity studies, and T cell responses, as well as information gained from sequencing eluted epitopes from DR protein, we will establish the important or immunodominant TSH receptor T cell epitopes. With this information in hand, we will attempt to derive mutated TSH receptor sequences which inhibit the response of patients' T cells to TSH receptor epitopes. We will also use TSH receptor epitopes bound in DR or DQ molecules, or in tetramers, to remove reactive T cells from patient blood samples in vitro to determine whether a method can be found to reduce immunoreactivity. In a model of Graves' disease in TSH-R-immunized mice, we will develop epitopes that may inhibit the disease process, including the development of ophthalmopathy. Such epitopes might similarly be used in patients in the future. Our studies will be done in collaboration with Dr. A. Godkin, who will analyze TSH-R epitopes in a computer algorithm, Dr. R .G. Phelps, who will analyze TSH-R epitopes which we elute from DR3 molecules, Dr. W. Kwok, who will provide DR3 tetramers, and with Dr. M. Ludgate on the model of Graves' disease.

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