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（由应用程序提供）：作为约翰·霍普金斯内分泌学部的教职员工，具有实验室研究的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翻译方法来了解环境因素在使用甲状腺疾病A A Model An Model Angote Autobunity中的分子机制和环境因素在特定自身免疫性的开发中的作用。自身免疫性甲状腺疾病会影响数百万人，被认为是主要的自身免疫性疾病。在NHANESIII调查中，4.7％的美国人口自我报告的甲状腺疾病，有5.9％的甲状腺功能检查异常，15.6％的甲状腺白人妇女具有甲状腺抗体，表明甲状腺抗体表明可能的易感性。1NHANESIII研究还发现NHANESIII研究的三分之一还发现那些因thyroids而受到治疗的人。这意味着，治疗中的错误使数百万的人有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。在奖励期间，我将以强大的研究为基础，以获取我在免疫学和临床研究技术中需要的其他专业知识，以发展专注于使用甲状腺疾病作为一种强大模型，以了解器官特异性自身免疫的机制。这项工作的长期目标是改善诊断和预后工具，并支持在不可逆的组织破坏之前发展疾病进展的策略。该提案将检验我们的假设，即自身免疫性疾病需要自反应性淋巴细胞的激活/增殖和促进持续炎症的目标组织微环境的改变。我们的方法利用了药物的独特疾病模型，触发甲状腺疾病，在暴露于免疫调节剂的临床种群中前瞻性检查疾病的发作，并在体外与原代甲状腺细胞进行了平行的机械实验。甲状腺功能障碍是广谱免疫调节疗法（例如干扰素α（IFN））的经常且潜在严重的副作用。专门针对T细胞调节途径的新型疗法似乎患有甲状腺疾病率较低。其中第一个由FDA批准的ipilimumab批准，现在正在积极地用于治疗黑色素瘤，这是一种IFN也是标准疗法的疾病。在我们对1233名甲状腺疾病的分析中，最初在成就研究中接受IFN的IFN治疗长达一年的甲状腺功能障碍受试者，有6例干扰素诱导的甲状腺疾病（IITD）发生在16.7％的患者中，在第二个同伴中发现了相似的结果，相似的结果是，相似的结果是，相似的结果是3阶段的3次率，相当3次。 2-4％.8,9双相性甲状腺炎被证明是 在我们发表的分析中，最常见，最常见的IITD形式是。6,7虽然先前的作者提出双相性甲状腺炎不是免疫介导的过程，但21我们发现，女性性别强烈预测，支持自身免疫性在IITD中占主导地位的假设。因此，AIM 1将检验以下假设：IITD诱导的破坏性甲状腺炎在IFN处理的同类人群中通过询问IITD的哪些亚型可以通过存在预处理前抗脑染色体自身抗体来预测的IITD来实现。将测量治疗后抗体水平，以研究暴露于暴露引起潜在疾病的程度，并询问发展IITD的抗阴性患者是否还会发展自身免疫性的证据。 AIM 2开始直接测试提出的机制，首先是通过确认促炎性变化的个人，例如在我们的初步数据中看到的主要组织相容性复合物1的表达，发生在IFN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CD8+细胞毒性T细胞的激活。通过与约翰·霍普金斯（John Hopkins）在黑色素瘤组的国际癌症免疫疗法方面的合作，AIM 3将通过询问ipilimumab是否能够增加潜在的抗甲状腺自身免疫性的发病率来检验临床环境中的假设，而无需触发甲状腺疾病的甲状腺损害，而在不断分析的糖尿病患者中进行了治疗。我拥有现象的机构资源，可用于获得免疫学，统计和临床试验方面的专业知识，并通过重要的实验室程序来增进我的技术能力，包括微阵列和大型数据集，流式细胞仪技术以及各种淋巴细胞功能的刺客。我有一个出色的心态团队来指导我的发展，并帮助我研究研究的各个方面和专业成长。我的导师保罗·拉德森（Paul Ladenson）博士和安东尼·罗森（Antony Rosen）博士分别在甲状腺学和自身免疫性领域的世界领导人为我提供了巨大的智力和财务资源。该提案包括开发体外评估系统，临床人群和知识深度，这将支持我成功过渡到独立的，由RO1资助的，以患者为导向的研究。