Harnessing B lymphocytes as Antigen-Specific Regulators of Islet Tolerance

利用 B 淋巴细胞作为胰岛耐受性的抗原特异性调节剂

基本信息

批准号：
8254458
负责人：
Daniel J. Moore
金额：
$ 14.46万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254458
关键词：
Academic Medical Centers Address Adoptive Transfer Allogenic American Antigen Presentation Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B cell repertoire B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Beta Cell CD3 Antigens Cell physiology Cells Child Childhood Data Dedications Development Diabetes Mellitus Disease Environment Evoked Potentials Exhibits Failure Fostering Frequencies Functional disorder Genetic Human Hyperglycemia Immune Immune System Diseases Immune Tolerance Immune system Immunity Immunobiology Immunology Inbred NOD Mice Individual Injury Insulin Insulin-Dependent Diabetes Mellitus Investigation Islet Cell Knowledge Life Lymphocyte Maintenance Mediating Mentors Methods Microbiology Modeling Molecular Molecular Profiling Monitor Mouse Strains Mus Organ Outcome Pathogenesis Patients Peripheral Physicians Play Process Production Receptor Signaling Regulation Research Design Residual state Resistance Resources Role Scientist Seminal Signal Transduction Skin Specificity Stimulus System T-Lymphocyte Therapeutic Toll-like receptors Training Transgenic Animals Transplantation Transplantation Tolerance Universities career career development cellular targeting clinically relevant disorder risk innovation insulin dependent diabetes mellitus onset islet novel pediatric department peripheral tolerance planetary Atmosphere prevent programs public health relevance rituximab

项目摘要

DESCRIPTION (provided by applicant): The PI seeks to develop a career as a physician-scientist focused on the problem of restoring and maintaining immune tolerance in individuals with Type 1 diabetes (T1D) by extending his scientific training in the exceptional environment at Vanderbilt University Medical Center. The failure of immune tolerance is an important underpinning of all human autoimmune diseases. When tolerance fails, autoimmune processes damage vital organs in tens of millions of patients worldwide. The applicant will focus on this scientific challenge through fundamental investigation of the most common pediatric autoimmune disorder-T1D, which afflicts more than 2 million Americans. To prevent and reverse this disease, it is necessary to restore immune tolerance to islet antigens. Most present efforts focus on either limiting the activation of islet-destructive T lymphocytes or enhancing the capacity of certain islet-protective T cells for immune regulation. Significantly, B lymphocytes also play a key role in the disease process both through the production of autoantibodies, which predict disease risk, and by the action of B lymphocytes as requisite antigen presenting cells. Targeting these cells with the B cell depleting agent rituximab has been at least as effective as T cell targeted agents, such as anti-CD3, in slowing the progression of new-onset diabetes. Moreover, studies in a relevant murine model of human T1D suggest a role of regulatory B cells in this salutary effect. These regulatory functions of B cells have also been observed in other models of autoimmune disease, and the applicant has previously characterized their role in transplantation tolerance. Building on these seminal data, we hypothesize that B lymphocytes play a regulatory role in the establishment and maintenance of peripheral immune tolerance and that this capacity is disrupted in T1D. This proposal investigates testable hypotheses which will focus on defining the regulatory functions of B lymphocytes that contribute to islet tolerance by determining: the role of classical B cell subsets, antigen specificity and developmental signals in regulatory B cell function (Aim 1), and their cellular targets and the mechanisms through which their regulatory function is controlled (Aim 2). The environment at Vanderbilt University is poised to address this fundamental biologic question given the local expertise in B lymphocyte immunobiology, the exceptional training atmosphere created by the Vanderbilt Diabetes Center, and the dedication to physician-scientist development exemplified by the Departments of Pediatrics and Microbiology and Immunology. Investigation of these novel hypotheses under the guidance of an exceptional mentoring committee and supported by these outstanding resources will allow the PI to realize a significant opportunity for new discovery in this clinically relevant field of inquiry-the fundamental problem of lost tolerance in T1D. PUBLIC HEALTH RELEVANCE: Type 1 diabetes is an unavoidable, life-long illness with no known cure and an imperfect treatment from which more than 15,000 new children will begin to suffer in the next year. The disease results from incorrect function of the patient's immune system and thus therapies that target and correct disordered immunity must be sought. In this proposal, we will develop a roadmap for the innovative application of the regulatory power of B lymphocytes to overcome this disease.

描述（由申请人提供）：PI 寻求通过在范德比尔特大学的特殊环境中扩展他的科学培训，发展成为一名医师科学家的职业生涯，专注于恢复和维持 1 型糖尿病 (T1D) 患者的免疫耐受问题医疗中心。免疫耐受失败是所有人类自身免疫性疾病的重要基础。当耐受性失败时，自身免疫过程会损害全球数千万患者的重要器官。申请人将通过对最常见的儿童自身免疫性疾病——T1D（困扰超过 200 万美国人）的基础研究来关注这一科学挑战。为了预防和逆转这种疾病，有必要恢复对胰岛抗原的免疫耐受。目前大多数努力集中在限制胰岛破坏性 T 淋巴细胞的激活或增强某些胰岛保护性 T 细胞的免疫调节能力。值得注意的是，B 淋巴细胞还通过产生预测疾病风险的自身抗体以及 B 淋巴细胞作为必需的抗原呈递细胞的作用，在疾病过程中发挥着关键作用。使用 B 细胞耗竭剂利妥昔单抗（rituximab）靶向这些细胞在减缓新发糖尿病的进展方面至少与 T 细胞靶向药物（例如抗 CD3）一样有效。此外，对人类 T1D 相关小鼠模型的研究表明，调节性 B 细胞在这种有益作用中发挥着作用。 B细胞的这些调节功能也在其他自身免疫性疾病模型中观察到，并且申请人之前已经表征了它们在移植耐受中的作用。基于这些开创性数据，我们假设 B 淋巴细胞在外周免疫耐受的建立和维持中发挥调节作用，并且这种能力在 T1D 中被破坏。该提案研究了可测试的假设，重点是通过确定以下内容来定义有助于胰岛耐受的 B 淋巴细胞的调节功能：经典 B 细胞亚群、抗原特异性和发育信号在调节 B 细胞功能中的作用（目标 1）及其细胞目标及其调控功能的控制机制（目标 2）。鉴于 B 淋巴细胞免疫生物学方面的当地专业知识、范德比尔特糖尿病中心营造的卓越培训氛围，以及以儿科和微生物学系为代表的对医师科学家发展的奉献精神，范德比尔特大学的环境已准备好解决这一基本生物学问题。免疫学。在杰出的指导委员会的指导下并在这些优秀资源的支持下对这些新颖的假设进行调查将使 PI 能够在这一临床相关研究领域（T1D 失去耐受性的根本问题）中实现新发现的重大机会。公众健康相关性：1 型糖尿病是一种不可避免的终生疾病，目前尚无已知的治愈方法，而且治疗方法也不完善，明年将有超过 15,000 名新生儿开始受苦。该疾病是由患者免疫系统功能不正常引起的，因此必须寻求针对和纠正免疫紊乱的治疗方法。在本提案中，我们将制定一个路线图，用于创新应用 B 淋巴细胞的调节能力来克服这种疾病。