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: 9262903
• 负责人: Jennifer Sophie Mammen
• 金额: $ 19.55万
• 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/9262903
• 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; 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; 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; Pharmacology; Phase III Clinical Trials; Play; Population; Predisposition; Prevalence; Prevention strategy; Primary Cell Cultures; Process; Progressive Disease; Prospective Studies; Public Health; Publishing; Regression Analysis; Regulatory Pathway; Regulatory T-Lymphocyte; 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; experimental study; high risk; immunoregulation; improved; in vitro Assay; inflammatory milieu; innovation; melanoma; member; novel; novel therapeutics; organ growth; patient oriented research; peripheral tolerance; prognostic tool; prospective; public health relevance; 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）：作为约翰霍普金斯内分泌科的教员，具有实验室研究背景和对公共卫生的承诺，我的科学和临床重点是使用创新的转化方法来了解器官特异性自身免疫发展中环境因素的分子机制和作用，使用甲状腺疾病模型系统。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%的美国人口自报患有甲状腺疾病，5.9%的人甲状腺功能检查异常，15.6%的甲状腺功能正常的白色女性有甲状腺抗体，表明可能存在易感性。1 NHANESIII研究还发现，三分之一的甲状腺疾病治疗者甲状腺功能不正常。这意味着治疗中的错误使数百万人面临甲状腺功能障碍的长期后果的风险，这些后果可能包括心力衰竭，房颤和中风。在获奖期间，我将建立在我强大的研究基础上，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，以发展一个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生涯。这项工作的长期目标是改善诊断和预后工具，并支持在出现不可逆的组织破坏之前中止疾病进展的策略的发展。这项提议将检验我们的假设，即自身免疫性疾病需要自身反应性淋巴细胞的活化/增殖和促进持续炎症的改变的靶组织微环境。我们的方法利用独特的疾病模型的甲状腺疾病的发病率，前瞻性地检查暴露于免疫调节剂的临床人群中的疾病的发病率，与原代甲状腺细胞在体外平行的机制实验。甲状腺功能障碍是一种常见的和潜在的严重副作用的广谱免疫调节治疗，如干扰素α（IFN γ）。特异性作用于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。其中第一个被FDA批准的药物是Ipilimumab，目前正积极用于治疗黑色素瘤，IFN γ也是一种标准疗法。在ACHIEVE研究中，我们对1233名最初甲状腺功能正常的受试者进行了长达一年的干扰素治疗丙型肝炎的甲状腺疾病分析，6干扰素诱导的甲状腺疾病（IITD）发生在16.7%的患者中，在第二个队列的分析中发现了类似的结果。7相反，Ipilimumab的3期试验报告甲状腺功能障碍率为2- 4%。8，9例双相甲状腺炎被证实为 在我们发表的分析中，这是最常见和最常见的临床显著的IITD形式。6，7尽管先前的作者提出双相甲状腺炎不是免疫介导的过程，21但我们发现它强烈预测女性，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（潜伏性自身免疫的标志物）的存在预测IITD的哪些亚型，来检验IITD诱导的破坏性甲状腺炎在IFN γ治疗的ACHIEVE队列中是自身免疫性的假设。将测量治疗后抗体水平，以研究暴露诱导潜伏性疾病的程度，并询问发生IITD的抗体阴性患者是否也出现自身免疫证据。目的2继续直接测试所提出的机制，首先通过在个体中证实促炎性变化，例如在我们的初步数据中观察到的主要组织相容性复合体1表达增加，发生在IFN γ暴露的甲状腺细胞中。然后，我们将测试改变的微环境是否足以在体外增强CD 8+细胞毒性T细胞的活化。通过与约翰霍普金斯黑色素瘤组癌症免疫治疗的国际领导者合作，Aim 3将在临床环境中测试这一假设，通过询问Ipilimumab是否能够增加潜伏性抗甲状腺自身免疫的发生率，而不会引发正在接受治疗的黑色素瘤患者的前瞻性分析队列中的甲状腺破坏。我有惊人的机构资源，可获得免疫学，统计学和临床试验的专业知识，以及增长我的技术能力与重要的实验室程序，包括微阵列和大型数据集的分析，流式细胞术技术，和各种淋巴细胞功能的测定。我有一个优秀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帮助我。我的导师，保罗·拉登森博士和安东尼罗森博士，他们分别是甲状腺学和自身免疫领域的世界领导者，为我提供了巨大的智力和财力资源。该提案包括开发体外分析系统，临床队列和知识深度，这将支持我成功过渡到独立的，RO 1资助的，以患者为导向的研究。