Immunological Basis of Autoimmune Addison's Disease in a Novel Canine Model System

新型犬模型系统中自身免疫阿狄森氏病的免疫学基础

• 批准号: 10536617
• 负责人: Steven Gene Friedenberg
• 金额: $ 13.03万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536617
• 关键词: Addison' s disease; Adrenal Cortex; Adrenal Glands; Affect; Animal Disease Models; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Bacteria; Biological Assay; Biological Models; Bone Density; Breeding; CD4 Positive T Lymphocytes; Canis familiaris; Cell Line; Cell Proliferation; Cells; Cellular biology; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Electrolytes; Endocrine System Diseases; Enzymes; Escherichia coli; Exposure to; Fostering; Funding; Future; Genes; Genetic; Goals; Heritability; Homeostasis; Hormones; Human; Hybridomas; Hypertension; Hypotensives; Immune System Diseases; Immune mediated destruction; Immune response; Immunoglobulin Class Switching; Immunologics; Immunology; Immunotherapy; Impairment; Individual; Interferon Type II; Interferons; Interleukin-2; Learning; Life; Lymphocyte; MHC Class II Genes; Measures; Mediating; Methods; Minnesota; Molecular; Mus; Onset of illness; Patients; Peptides; Population; Process; Proteins; Research; Role; Shock; Sleep Disorders; Sorting; Stains; Steroids; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Training; Transfection; Universities; Vomiting; Work; antigen-specific T cells; autoreactive T cell; autoreactivity; cDNA Library; canine model; cytokine; design; high risk; insight; lipid metabolism; model organism; next generation; novel; novel therapeutics; protein aminoacid sequence; response; tool; training opportunity; translational scientist

Project Summary/Abstract Autoimmune Addison’s Disease (AAD) is a life-threatening endocrine disorder caused by the immune- mediated destruction of the adrenal cortex. Affected individuals lack key hormones that are critical for normal homeostasis. Because of this, patients with AAD are at high risk of developing a potentially deadly adrenal crisis characterized by hypotensive shock, vomiting, and life-threatening electrolyte abnormalities. Limited progress has been made over the past half-century in developing new therapies for AAD, in part because there is no actively studied animal model for the disease. Fortunately, dogs provide an opportunity for this very purpose. The disease is naturally occurring in both humans and dogs, and shares similar clinical, genetic, and immunologic underpinnings in both species. The goal of this study is to lay the groundwork for a canine model system to study AAD by characterizing the antigen-specific T cells that trigger the disease and determining the peptide sequences recognized by these T cells. Specifically, we will test the hypothesis that AAD is triggered by IFN-g- producing CD4+ T cells that are activated by peptides derived from steroid-producing enzymes in the adrenal cortex. Once we have identified and characterized these key players involved in triggering the immune system dysfunction in AAD, we can begin to develop approaches that manipulate or downregulate the aberrant immune response. Ultimately, we expect to use this canine model system to drive advances in our understanding of AAD and to foster the development of novel immunotherapies for humans. The work proposed in this application will be conducted at the renowned Center for Immunology at the University of Minnesota, and will provide a critical training opportunity in T cell biology, autoimmune disorders, and the benchtop methods required to study these topics comprehensively.

项目总结/摘要 自身免疫性阿狄森氏病（AAD）是一种由免疫系统引起的危及生命的内分泌疾病， 介导的肾上腺皮质的破坏。受影响的个体缺乏对正常发育至关重要的关键激素。 体内平衡。正因为如此，AAD患者有很高的风险发展成一种潜在致命的肾上腺 以休克、呕吐和危及生命的电解质异常为特征的危象。有限 在过去的半个世纪里，在开发AAD的新疗法方面取得了进展，部分原因是 目前还没有积极研究这种疾病的动物模型。幸运的是，狗提供了一个机会， 目的.该疾病在人类和狗中自然发生，并且具有相似的临床，遗传和免疫学特征。 两个物种的免疫基础。这项研究的目的是为犬模型奠定基础 系统通过表征触发疾病的抗原特异性T细胞并确定 这些T细胞识别的肽序列。具体来说，我们将测试AAD被触发的假设 由产生IFN-g的CD 4 + T细胞激活，这些细胞被源自体内类固醇产生酶的肽激活 肾上腺皮质一旦我们确定并描述了这些参与触发免疫的关键参与者， AAD中的系统功能障碍，我们可以开始开发操纵或下调异常的 免疫反应最终，我们希望使用这种犬模型系统来推动我们的研究进展。 了解AAD并促进人类新型免疫疗法的开发。工作 本申请中提出的将在著名的免疫学中心进行， 明尼苏达州，并将提供T细胞生物学，自身免疫性疾病， 全面研究这些主题所需的台式方法。