ANIMAL MODELS OF HYPERTHYROIDISM

甲亢动物模型

• 批准号: 7516680
• 负责人: Sandra M McLachlan
• 金额: $ 36.21万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516680
• 关键词: Address; Adenoviruses; Animal Model; Antibodies; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; Breeding; Cell Maturation; Cells; Chemicals; Chimeric Proteins; Complex; Constitution; Dendritic Cells; Disease; Disease model; Dose; Engineering; Etiology; Eye diseases; Gene Dosage; Genes; Goals; Gonadotropin Receptors; Graves' Disease; Human; Hyperthyroidism; Hypothyroidism; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Inflammation; Iodide Peroxidase; Knockout Mice; Lead; Link; Lymphocytic Infiltrate; MHC Class II Genes; Mediating; Messenger RNA; Molecular; Monoclonal Antibodies; Mouse Strains; Mus; Organ; Outcome Study; Pathogenesis; Peripheral; Postpartum Period; Process; Proteins; Public Health; Recombinants; Role; Self Tolerance; Signal Transduction; Structure; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Thymus Gland; Thyroglobulin; Thyroid Gland; Thyroid stimulating immunoglobulins; Thyroiditis; Thyrotropin Receptor; Transgenic Mice; Transgenic Organisms; disulfide bond; insight; mouse model; novel; prevent; promoter; response; single molecule; transgene expression

DESCRIPTION (provided by applicant): Graves' disease, a common disorder, has an unusual etiology: the immune system targets one molecule, the thyrotropin receptor (TSHR), autoantibodies mediate disease, and the target organ is stimulated not destroyed. The TSHR is unusual because it undergoes intramolecular cleavage into an A-subunit linked by disulfide bonds to a transmembrane B-subunit. Shed A-subunits drive immunity leading to thyroid stimulating antibodies and hyperthyroidism. Immunization using an adenovirus (Ad) engineered to express the A-subunit is an effective approach to induce thyroid stimulating antibodies and hyperthyroidism in mice. Our goal is to use this Graves' disease model to provide insight into the following important issues: 1. Tolerance to the TSHR. We generated transgenic mice with the human TSHR A-subunit targeted to the thyroid. These mice are unresponsive, or "tolerant", to A-subunit-Ad immunization. Tolerance is a complex process that may involve the Autoimmune Regulator (Aire) protein and/or regulatory T cells (Treg). The role of Aire can be studied in Aire knockout mice; Treg can be depleted by pretreatment with specific antibodies. To investigate tolerance to the TSHR, we will cross our A-subunit transgenics to Aire deficient mice and study the outcome of A-subunit-Ad immunization in untreated or Treg depleted mice. 2. TSHR-associated thyroid inflammation: A-subunit-Ad immunization of some A-subunit transgenics depleted of Treg induces thyroid lymphocytic infiltrates, hypothyroidism and murine thyroglobulin and thyroid peroxidase antibodies. Mice without infiltrates lack these antibodies. Moreover, TSHR autoantibody and T cell epitopes are highly restricted. We will further characterize immune responses to the TSHR and other thyroid autoantigens in mice with thyroid infiltrates. These studies will provide insight into the relationship between thyroiditis, auto antibodies and TSHR T cell epitopes in mice and possibly also into the pathogenesis of human thyroid autoimmunity. 3. Induced tolerance to prevent or treat experimental Graves' disease. Dendritic cells (DC) are potent antigen-presenting cells. In the "mature" state, DC initiate immunity but immature DC induce antigen-specific tolerance. We will target the TSHR A-subunit to these cells using antibodies to a DC-specific marker (DEC205) and test the abilityof these antibody:A-subunit complexes to blunt responses to A-subunit-Ad immunization. These studies will demonstrate the feasibility of antigen-specific immune tolerance and, if successful, could be adapted for use in humans to more intractable aspects of Graves' disease, namely ophthalmopathy and dermopathy. PUBLIC HEALTH RELEVANCE: Graves' hyperthyroidism, a common disease in humans, is caused by an abnormal immune response to a "self" protein in the thyroid gland called the thyrotropin receptor. We will use a mouse model of Graves' disease to provide insight into the factors involved in the breakdown in "self tolerance" to self proteins that lead to the abnormal autoimmune response to the thyrotropin receptor. Moreover, we will test the efficacy of an approach to block autoimmune responses to the thyrotropin receptor in order to prevent or treat Graves' disease, initially in mice and ultimately in humans.

描述（由申请人提供）：Graves疾病，一种常见的疾病，具有异常的病因：免疫系统靶向一个分子，甲状腺激素受体（TSHR），自身抗体介导疾病，靶器官刺激未破坏。 TSHR是不寻常的，因为它经历了分子内裂解，将二硫键连接到跨膜b-subunit的A-亚基。脱落的A-亚基驱动免疫力，导致甲状腺刺激抗体和甲状腺功能亢进症。使用设计以表达A-亚基的腺病毒（AD）的免疫是诱导甲状腺刺激抗体和甲状腺功能亢进症的有效方法。我们的目标是使用这种Graves疾病模型来洞悉以下重要问题：1。对TSHR的耐受性。我们用针对甲状腺的人类TSHR A-亚基产生了转基因小鼠。这些小鼠对A-Subunit-AD免疫无反应或“耐受性”。公差是一个复杂的过程，可能涉及自身免疫调节剂（AIR）蛋白和/或调节性T细胞（Treg）。可以在Aire淘汰小鼠中研究AIR的作用。 Treg可以通过特定抗体预处理来耗尽。为了研究对TSHR的耐受性，我们将使我们的A-亚基转基因转移到AIRE不足的小鼠上，并研究未处理或Treg耗尽小鼠中A-亚基AD免疫的结果。 2。与TSHR相关的甲状腺炎症：某些A-亚基AD-AD AD免疫对TREG的A-subunit-AD炎症诱导甲状腺淋巴细胞浸润，甲状腺功能减退症和鼠甲状腺甲状腺素和甲状腺甲状腺素蛋白和甲状腺甲状腺多生酶抗体。没有浸润的小鼠缺乏这些抗体。此外，TSHR自身抗体和T细胞表位受到高度限制。我们将进一步表征甲状腺浸润的小鼠中对TSHR和其他甲状腺自身抗原的免疫反应。这些研究将洞悉小鼠甲状腺炎，自身抗体和TSHR T细胞表位之间的关系，并可能介绍人类甲状腺自身免疫的发病机理。 3。诱导的耐受性，以预防或治疗实验性坟墓疾病。树突状细胞（DC）是有效的抗原呈递细胞。在“成熟”状态下，DC启动免疫力，但未成熟的DC诱导抗原特异性耐受性。我们将使用对DC特异性标记物（DEC205）的抗体将TSHR A-subunit靶向这些细胞，并测试这些抗体的能力：A-Subunit络合物对A-Subunit-AD AD免疫的反应。这些研究将证明抗原特异性免疫耐受性的可行性，如果成功的话，可以适应人类用于更棘手的坟墓疾病，即眼科和皮肤病。公共卫生相关性：Graves的甲状腺功能亢进症是人类的一种常见疾病，是由对甲状腺腺体中“自我”蛋白质的异常免疫反应引起的，称为甲状腺激素受体。我们将使用Graves疾病的小鼠模型来洞悉对自蛋白的“自耐力”中所涉及的因素，从而导致对甲状腺激素受体的异常自身免疫反应。此外，我们将测试一种方法，以阻止对甲状腺素受体的自身免疫反应的疗效，以防止或治疗坟墓疾病，最初是在小鼠中，最终在人类中。