Mechanisms of autoimmune thyroid disease and the role of interferon-alpha

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师，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器官特异性自身免疫发展中的分子机制和环境因素的作用，以甲状腺疾病为模型系统。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%的美国人口自我报告甲状腺疾病，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人妇女有甲状腺抗体，表明可能易感NHANESIII研究还发现，三分之一接受甲状腺疾病治疗的患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，包括心力衰竭、心房颤动和中风。在获奖期间，我将在我坚实的研究基础上，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，以发展一个专注于将甲状腺疾病作为一个强大模型来理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转的组织破坏之前阻止疾病进展的策略的发展。这一建议将验证我们的假设，即自身免疫性疾病既需要自身反应性淋巴细胞的激活/增殖，也需要改变靶组织微环境，从而促进持续的炎症。我们的方法利用药理学触发甲状腺疾病的独特疾病模型，在暴露于免疫调节剂的临床人群中前瞻性地检查疾病的发病，并在体外对原代甲状腺细胞进行平行的机制实验。甲状腺功能障碍是干扰素α （IFN¿）等广谱免疫调节疗法常见且可能严重的副作用。特异作用于t细胞调节通路的新疗法似乎具有较低的甲状腺疾病发病率。Ipilimumab是FDA批准的首个药物，目前正积极用于治疗黑色素瘤，IFN¿也是一种标准治疗方法。在ACHIEVE研究中，我们对1233名最初甲状腺功能正常的丙型肝炎患者进行了长达一年的干扰素治疗，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也发现了类似的结果相比之下，Ipilimumab的3期试验报告甲状腺功能障碍率为2-4%双期甲状腺炎被证实为

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.