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: 8699376
• 负责人: Jennifer Sophie Mammen
• 金额: $ 17.47万
• 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/8699376
• 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; 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; patient oriented research; peripheral tolerance; prognostic; public health relevance; research study; sex; statistics; therapy development; tool; 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）：作为约翰·霍普金斯大学内分泌学部的一名教员，具有实验室研究背景并致力于公共卫生，我的科学和临床重点是使用创新的转化方法来了解环境的分子机制和作用。器官特异性自身免疫发展的因素，使用甲状腺疾病作为模型系统 自身免疫性甲状腺疾病影响着数百万人，并且在 NHANESIII 调查中被认为是主要的自身免疫性疾病。人群自我报告的甲状腺疾病中，5.9% 的甲状腺功能测试异常，15.6% 甲状腺功能正常的白人女性有甲状腺抗体，表明可能易感。1 NHANESIII 研究还发现，接受甲状腺疾病治疗的人中有三分之一甲状腺功能不正常。意味着治疗错误会使数百万人面临甲状腺功能障碍的长期后果的风险，其中可能包括心力衰竭、心房颤动和中风。基于我在研究方面的坚实基础，以获得我在免疫学和临床研究技术方面所需的额外专业知识，以发展专注于使用甲状腺疾病作为强大模型来了解器官特异性自身免疫机制的职业。这项工作的长期目标是。改进诊断和预后工具，并支持制定在出现不可逆组织破坏之前中止疾病进展的策略。该提案将检验我们的假设，即自身免疫性疾病需要自身反应性淋巴细胞的激活/增殖和靶组织微环境。我们的方法利用药理学触发的甲状腺疾病的独特疾病模型来前瞻性地检查暴露于免疫调节剂的临床人群中的疾病发作，并在体外对原代甲状腺细胞进行平行机制实验。以及广谱免疫调节疗法（如干扰素 α (IFN¿) 的潜在严重副作用专门作用于 T 细胞调节途径的新疗法似乎具有较低的甲状腺疾病发病率，其中第一个获得 FDA 批准的疗法是 Ipilimumab，目前正积极用于治疗黑色素瘤。干扰素??在我们对 1233 名最初接受 IFN 治疗的甲状腺功能正常受试者的甲状腺疾病分析中，它也是一种标准疗法。在 ACHIEVE 研究中，对于丙型肝炎，6 16.7% 的患者发生干扰素诱发的甲状腺疾病 (IITD)，第二个队列的分析结果相似。7 相反，Ipilimumab 的 3 期试验报告甲状腺功能障碍发生率为2-4%.8,9 双相性甲状腺炎被证明是 在我们大力发表的分析中，这是最常见、最常见的具有临床意义的 IITD 形式。 6,7 尽管之前的作者提出双相甲状腺炎不是免疫介导的过程，21 我们发现它是由女性预测的，支持了假设自身免疫在 IITD 中起主导作用 因此，目标 1 将检验 IITD 诱导的破坏性甲状腺炎在 IFN 中是自身免疫的假设。 - 通过询问治疗前抗甲状腺自身抗体的存在来预测哪些 IITD 亚型，将测量治疗后抗体水平，以研究暴露诱发潜在疾病的程度。并询问患有 IITD 的抗体阴性患者是否也出现自身免疫的证据，目标 2 继续直接测试所提出的机制，首先通过在个体之间确认促炎症变化，例如主要组织相容性复合物的增加。 1 在我们的初步数据中看到的表达，出现在 IFN¿然后，我们将测试改变的微环境是否足以在体外增强 CD8+ 细胞毒性 T 细胞的激活，通过与约翰霍普金斯大学黑色素瘤小组的癌症免疫治疗领域的国际领导者合作，目标 3 将检验这一假设。在临床环境中，通过询问伊匹单抗是否能够在接受治疗的前瞻性分析的黑色素瘤患者队列中增加潜在的抗甲状腺自身免疫的发生率而不引发甲状腺破坏，我拥有大量可用的机构资源。为了获得免疫学、统计学和临床​​试验方面的专业知识，并提高我在重要实验室程序方面的技术能力，包括微阵列和大数据集分析、流式细胞术技术以及各种淋巴细胞功能测定，我拥有一支出色的指导团队。我的导师 Paul Ladenson 博士和 Antony Rosen 博士分别是甲状腺学和自身免疫领域的世界领先者，他们为我提供了巨大的智力和财政资源。 .建议包括开发体外测定系统、临床队列和知识深度，这将支持我成功过渡到独立、RO1 资助、以患者为导向的研究。