Mechanisms of autoimmune thyroid disease and the role of interferon-alpha

自身免疫性甲状腺疾病的机制和干扰素-α的作用

• 批准号: 8880197
• 负责人: Jennifer Sophie Mammen
• 金额: $ 17.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880197
• 关键词: Adjuvant Therapy; Adverse effects; Affect; Aftercare; Antibodies; Atrial Fibrillation; Atypical lymphocyte; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; Biological Assay; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cells; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Cohort Analysis; Collaborations; Competence; Contrast Media; Cytotoxic T-Lymphocytes; Data; Data Set; Development; Diagnostic; Disease; Disease Progression; Disease model; Drug Exposure; Endocrinology; Environment; Environmental Exposure; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Exposure to; FDA approved; Faculty; Female; Flow Cytometry; Functional disorder; Funding; Future; Gene Expression; Goals; Growth; Health; Heart failure; Hepatitis C; Hypothyroidism; Immune; Immune system; Immunity; Immunologics; Immunology; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Interferon-alpha; Interferons; International; Iodide Peroxidase; Knowledge; Laboratory Procedures; Laboratory Research; Left; Literature; Logistic Regressions; Lymphocyte; Lymphocyte Function; Major Histocompatibility Complex; Measures; Mediating; Mentors; Mentorship; Messenger RNA; Methods; Microarray Analysis; Modeling; Molecular; Monitor; Multivariate Analysis; Onset of illness; Organ; Outcome; Pathologic; Pathway interactions; Patient Self-Report; Patients; Phase III Clinical Trials; Play; Population; Prevalence; Primary Cell Cultures; Process; Progressive Disease; Public Health; Publishing; Regression Analysis; Regulatory Pathway; Reporting; Research; Research Technics; Resources; Risk; Risk Factors; Role; Sampling; Serum; Stroke; Surveys; System; T-Cell Activation; T-Lymphocyte; TSH receptor antibody; Techniques; Testing; Thyroglobulin antibody; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroiditis; Thyrotoxicosis; Tissues; Western Blotting; Woman; Work; autoimmune thyroid disease; cancer immunotherapy; cancer therapy; career; chemokine; clinically significant; cohort; cytotoxicity; disorder risk; disorder subtype; high risk; improved; in vitro Assay; innovation; melanoma; member; novel; organ growth; patient oriented research; peripheral tolerance; prognostic tool; research study; sex; statistics; targeted treatment; therapy development; translational approach

DESCRIPTION (provided by applicant):As a faculty member of the Johns Hopkins Endocrinology Division with a background in laboratory research and a commitment to public health, my scientific and clinical focus is on using innovative translational approaches to understand the molecular mechanisms and role of environmental factors in the development of organ specific autoimmunity, using thyroid disease a model system. Autoimmune thyroid disease affects millions of people and is thought to be the leading autoimmune disease. In the NHANESIII survey, 4.7% of the US population self-reported thyroid disease, 5.9% had abnormal thyroid function tests, and 15.6% of euthyroid white women have thyroid antibodies indicating possible susceptibility.1 The NHANESIII study also found that one third of those being treated for thyroid disease were not euthyroid. This means that errors in therapy leave millions of people at risk for the long-term consequences of thyroid dysfunction, which can include heart failure, atrial fibrillation, and stroke. During the award period, I will build on my strong foundaion in research to acquire the additional expertise I need in immunology and clinical research techniques to develop a career focused on using thyroid disease as a powerful model to understand the mechanisms of organ-specific autoimmunity. The long term goals of this work are to improve diagnostic and prognostic tools, and support the development of strategies to abort disease progression before there is irreversible tissue destruction. This proposal will test our hypothesis that autoimmune disease requires both the activation/proliferation of self-reactive lymphocytes and an altered target tissue microenvironment that promotes ongoing inflammation. Our approach takes advantage of the unique disease model of pharmacologically triggered thyroid disease to examine the onset of disease prospectively in clinical populations exposed to immunomodulatory agents, with parallel mechanistic experiments with primary thyroid cells in vitro. Thyroid dysfunction is a frequent and potentially severe side effect of broad-spectrum immunomodulatory therapies such as interferon alpha (IFN�). Novel therapies that act specifically on T-cell regulatory pathways appear to have lower rates of thyroid disease. The first of these to be approved by the FDA, Ipilimumab, is now actively being used in the treatment of melanoma, a disease for which IFN� is also a standard therapy. In our analyses of thyroid disorders in 1233 initially euthyroid subjects treated for up to one year with IFN� for hepatitis C in the ACHIEVE study,6 interferon-induced thyroid disease (IITD) occurred in 16.7% of patients, with similar results found in the analysis of a second cohort.7 In contrast, phase 3 trials of Ipilimumab report thyroid dysfunction rates of 2-4%.8,9 Biphasic thyroiditis proved to be the most common, and most frequent clinically significant form of IITD in our published analyses.6,7 Although prior authors have proposed that biphasic thyroiditis is not an immune- mediated process,21 we found that it was strongly predicted by female sex, supporting the hypothesis that autoimmunity plays a dominant role in IITD. Therefore, Aim 1 will test the hypothesis that IITD-induced destructive thyroiditis is autoimmune in the IFN�-treated cohorts of ACHIEVE by asking which subtypes of IITD are predicted by the presence of pre-treatment anti-thyroid autoantibodies, markers for latent autoimmunity. Post-treatment antibody levels will be measured to investigate the extent to which latent disease is induced by exposure and to ask whether antibody-negative patients who develop IITD also develop evidence of autoimmunity. Aim 2 proceeds to test the proposed mechanism directly, first by confirming across individuals that pro-inflammatory changes, such as the increased major histocompatibility complex 1 expression seen in our preliminary data, occur in IFN�-exposed thyrocytes. We will then test whether the altered microenvironment is sufficient to enhance the activation of CD8+ cytotoxic T cells in vitro. Through a collaboration with international leaders in cancer immunotherapy in the Melanoma Group here at Johns Hopkins, Aim 3 will test the hypothesis in a clinical setting, by asking whether Ipilimumab is able to increase the incidence of latent anti-thyroid autoimmunity without triggering thyroid destruction in a prospectively analyzed cohort of melanoma patients undergoing therapy. I have phenomenal institutional resources available to gain expertise in immunology, statistics and clinical trials as well as grow my technical competence with important laboratory procedures including microarray and analysis of large data sets, flow cytometry techniques, and a variety of assays of lymphocyte function. I have an outstanding mentorship team to guide my development and assist me in all aspects of the research and my professional growth. My mentors, Dr. Paul Ladenson and Dr. Antony Rosen, both world leaders in their fields of thyroidology and autoimmunity respectively, provide me with tremendous intellectual and financial resources. The proposal includes developing in vitro assay systems, clinical cohorts and depth of knowledge that will support my successful transition to independent, RO1 funded, patient-oriented research.

描述（由申请人提供）：作为Kins内分泌学的教职员工，具有实验性研究的背景和对公共卫生的研究，我的科学和临床重点是使用创新的翻译方法来了解环境因素在环境因素中的分子机械性能在使用甲状腺疾病的特定自身免疫性的发展是一种模型系统。还发现，甲状腺疾病的甲状腺中的第三个不是甲状腺，这意味着在治疗中，有数百万的长期conssesefule的风险，其中包括心力衰竭，心房颤动和中风。关于我在研究方面的强大研究中，我需要在免疫学和临床研究技术方面需要使用甲状腺疾病作为一种强大的模型来理解特定器官特定自身免疫性的机制。改善诊断和预后工具，并支持在Ireversibe组织组织测试之前流产疾病进展的策略。暴露于甲状腺原发性细胞的免疫调节剂实验的疾病开始，甲状腺功能障碍是甲状腺功能障碍。 FDA，ipilimumab现在正在积极地用于治疗黑色素瘤，这是我们在1233年对Tyroid疾病的分析中。甲状腺疾病（IITD）发生在16.7％的患者中，在第二个队列的分析中发现了相似的结果。7相反，甲状腺疾病是2-4％.8,9.8,9双相性甲状腺炎。 在我们发表的分析中，最常见，最常见的IITD的临床意义形式。6，7个Althooth先验饲养者已经使用了Thaat SiC甲状腺炎不是一种免疫介导的过程，21我们发现它是由女性强烈预测的，为您提供了强烈的预测，为您提供了支持。假设自身免疫在IITD中起主要作用。 ，治疗后的抗体水平遗嘱将是通过询问谁发展IITD的发展，也可以直接测试拟议机制，首先通过确认亲炎性变化的个人，从而诱发了牵引力H的潜在疾病。在我们的初步数据中，在约翰·霍普金斯（Johns Hopkins）的CD8+细胞毒性T e黑色素瘤组的激活中，AIM 3会通过询问临床环境中的假设，询问是否会增加iPilimumab是否会增加该假设拉丁甲状腺自身免疫，并在进行疗法中触发甲状腺破坏性，包括重要的实验室程序，包括微阵列和大型数据集，流式囊肿技术的分析以及多种淋巴细胞功能。开发和帮助我的研究和我的专业成长。到独立的RO1资助，以患者为导向的研究。