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）：作为约翰霍普金斯大学内分泌科的一名教员，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，以甲状腺疾病为模型系统，了解环境因素在器官特异性自身免疫发展中的分子机制和作用。自身免疫性甲状腺疾病影响数百万人，被认为是主要的自身免疫性疾病。在 NHANESIII 调查中，4.7% 的美国人自我报告患有甲状腺疾病，5.9% 的人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。这意味着治疗错误会使数百万人面临甲状腺功能障碍长期后果的风险，其中可能包括心力衰竭、心房颤动和中风。在获奖期间，我将在坚实的研究基础上建立基础，获得免疫学和临床研究技术方面所需的额外专业知识，以发展专注于利用甲状腺疾病作为了解器官特异性自身免疫机制的强大模型的职业生涯。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的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/增殖以及促进持续炎症的靶组织微环境的改变。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，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，并在体外使用原代甲状腺细胞进行平行机制实验。甲状腺功能障碍是干扰素 α (IFN�) 等广谱免疫调节疗法的常见且可能严重的副作用。专门作用于 T 细胞调节途径的新疗法似乎可以降低甲状腺疾病的发病率。第一个获得 FDA 批准的药物是易普利姆玛 (Ipilimumab)，目前正积极用于治疗黑色素瘤，而 IFNα 也是这种疾病的标准疗法。在 ACHIEVE 研究中，我们对 1233 名最初甲状腺功能正常且接受 IFNα 治疗丙型肝炎的受试者进行了长达一年的甲状腺疾病分析，6 16.7% 的患者出现了干扰素诱发的甲状腺疾病 (IITD)，第二个队列的分析中也发现了类似的结果。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 在我们发表的分析中，IITD 是最常见、最常见的具有临床意义的形式。 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 我们发现女性强烈预测它，支持自身免疫在 IITD 中起主导作用的假设。因此，目标 1 将通过询问治疗前抗甲状腺自身抗体（潜在自身免疫标志物）的存在来预测 IITD 的哪些亚型，从而检验 IITD 诱导的破坏性甲状腺炎在 IFNα 治疗的 ACHIEVE 队列中具有自身免疫性的假设。将测量治疗后抗体水平，以调查暴露引起潜在疾病的程度，并询问发生 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，例如我们初步数据中看到的主要组织相容性复合物 1 表达增加，发生在暴露于 IFNα 的甲状腺细胞中。然后我们将测试改变的微环境是否足以增强 CD8+ 细胞毒性 T 细胞的体外激活。通过与约翰·霍普金斯大学黑色素瘤小组癌症免疫治疗领域的国际领导者合作，Aim 3 将在临床环境中检验这一假设，即在接受治疗的前瞻性分析的黑色素瘤患者队列中，询问 Ipilimumab 是否能够增加潜在抗甲状腺自身免疫的发生率，而不引发甲状腺破坏。我拥有丰富的机构资源，可以获取免疫学、统计学和临床​​试验方面的专业知识，并通过重要的实验室程序（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）来提高我的技术能力。我拥有一支出色的导师团队来指导我的发展并在研究和专业成长的各个方面为我提供帮助。我的导师保罗·拉登森博士和安东尼·罗森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。该提案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。