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病是一种常见疾病，具有不寻常的病因学：免疫系统靶向一种分子，促甲状腺激素受体（TSHR），自身抗体介导疾病，靶器官被刺激而不是被破坏。TSHR是不寻常的，因为它经历分子内切割成通过二硫键连接到跨膜B亚基的A亚基。脱落的A亚单位驱动免疫，导致甲状腺刺激抗体和甲状腺功能亢进。利用腺病毒（Ad）基因工程表达的A亚单位免疫小鼠是一种有效的方法，诱导甲状腺刺激抗体和甲状腺功能亢进症。我们的目标是使用这个Graves病模型来提供对以下重要问题的洞察：1。耐受TSHR。我们用靶向甲状腺的人TSHR A亚基产生转基因小鼠。这些小鼠对A-亚基-Ad免疫无应答或“耐受”。耐受性是一个复杂的过程，可能涉及自身免疫调节（Aire）蛋白和/或调节性T细胞（Treg）。可以在Aire敲除小鼠中研究Aire的作用; Treg可以通过用特异性抗体预处理来耗尽。为了研究对TSHR的耐受性，我们将我们的A-亚基转基因小鼠与Aire缺陷小鼠杂交，并研究A-亚基-Ad免疫在未治疗或Treg缺失小鼠中的结果。2. TSHR相关的甲状腺炎症：A-亚基-Ad免疫的一些A-亚基转基因耗尽的Treg诱导甲状腺淋巴细胞浸润，甲状腺功能减退症和鼠甲状腺球蛋白和甲状腺过氧化物酶抗体。没有浸润的小鼠缺乏这些抗体。此外，TSHR自身抗体和T细胞表位高度受限。我们将进一步表征甲状腺浸润小鼠对TSHR和其他甲状腺自身抗原的免疫反应。这些研究将提供深入了解甲状腺炎，自身抗体和TSHR T细胞表位在小鼠和人类甲状腺自身免疫的发病机制之间的关系。3.诱导耐受性以预防或治疗实验性Graves病。树突状细胞（DC）是一种有效的抗原提呈细胞。在“成熟”状态下，DC启动免疫，但未成熟DC诱导抗原特异性耐受。我们将使用针对DC特异性标记物（DEC 205）的抗体将TSHR A亚基靶向这些细胞，并测试这些抗体：A亚基复合物钝化A亚基-Ad免疫应答的能力。这些研究将证明抗原特异性免疫耐受的可行性，并且如果成功，可以适用于人类，以治疗格雷夫斯病的更难治的方面，即眼病和皮肤病。公共卫生关系：格雷夫斯甲状腺功能亢进症是人类的一种常见疾病，是由对甲状腺中一种称为促甲状腺激素受体的“自身”蛋白质的异常免疫反应引起的。我们将使用一个小鼠模型的格雷夫斯病，以提供深入了解的因素，在“自我耐受性”的崩溃，导致异常的自身免疫反应促甲状腺激素受体的自身蛋白质。此外，我们将测试阻断促甲状腺激素受体的自身免疫反应的方法的有效性，以预防或治疗Graves病，最初在小鼠中，最终在人类中。