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学分部的一名教员，具有实验室研究背景并致力于公共健康，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器官特异性自身免疫发展中的分子机制和作用，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，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%的正常甲状腺白人妇女具有表明可能易患甲状腺疾病的甲状腺抗体。1 NHANESIII调查还发现，接受甲状腺疾病治疗的人中有三分之一不是甲状腺正常。这意味着治疗中的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、房颤和中风。在获奖期间，我将在我雄厚的研究基础上获得免疫学和临床研究技术方面所需的额外专业知识，以发展专注于将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转的组织破坏之前中止疾病进展的战略。这一提议将检验我们的假设，即自身免疫性疾病既需要自我反应性淋巴细胞的激活/增殖，也需要促进持续炎症的目标组织微环境的改变。我们的方法利用药物触发的甲状腺疾病这一独特的疾病模型，通过体外原代甲状腺细胞平行机制实验，前瞻性地检查暴露于免疫调节剂的临床人群中疾病的发病情况。甲状腺功能障碍是广谱免疫调节治疗(如干扰素�)的常见且可能严重的副作用。专门作用于T细胞调节通路的新疗法似乎具有较低的甲状腺疾病发生率。其中第一个被fda批准的药物，伊匹单抗，现在正在积极用于黑色素瘤的治疗，干扰素�也是这种疾病的标准治疗方法。在我们对1233名最初使用干扰素�治疗丙型肝炎一年的甲状腺功能正常的受试者进行的甲状腺疾病分析中，16.7%的患者发生了干扰素诱导的甲状腺疾病，与第二个队列分析中发现的结果相似。7相比之下，Ipiimumab的3期试验报告甲状腺功能障碍的发生率为2-4%。8，9双相甲状腺炎被证明是 6，7尽管先前的作者提出双相甲状腺炎不是一个免疫调节的过程，21我们发现女性对其有很强的预测性，这支持了自身免疫在IITD中起主导作用的假设。因此，Aim 1将通过询问治疗前抗甲状腺自身抗体(潜在自身免疫的标志)的存在来预测IITD的哪些亚型，从而在接受干扰素�治疗的AACHE队列中检验IITD诱导的破坏性甲状腺炎是自身免疫的假设。治疗后的抗体水平将被测量，以调查暴露在何种程度上诱发潜伏性疾病，并询问患有IITD的抗体阴性患者是否也有自身免疫的证据。目的2开始直接测试所提出的机制，首先通过确认在干扰素�暴露的甲状腺细胞中发生了促炎变化，例如我们初步数据中看到的主要组织相容性复合体1的表达增加。然后，我们将测试改变后的微环境是否足以在体外增强CD8+细胞毒T细胞的激活。通过与约翰·霍普金斯大学黑色素瘤研究组的癌症免疫治疗领域的国际领先者合作，AIM 3将在临床环境中验证这一假设，方法是在接受治疗的黑色素瘤患者的前瞻性分析队列中，询问Ipiimumab是否能够在不引发甲状腺破坏的情况下增加潜在的抗甲状腺自身免疫的发生率。我拥有惊人的机构资源，可以获得免疫学、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增长我的技术能力，包括微阵列和大数据集分析、流式细胞仪技术和各种淋巴细胞功能分析。我有一个优秀的导师团队来指导我的发展，并在研究和职业成长的各个方面协助我。我的导师保罗·拉登森博士和安东尼·罗森博士分别在各自的甲状腺学和自身免疫学领域处于世界领先地位，他们为我提供了巨大的智力和财政资源。该建议包括开发体外分析系统、临床队列和知识深度，以支持我成功过渡到独立的、RO1资助的、以患者为导向的研究。