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

• 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
• 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

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医学中心的特殊环境中扩展他的科学训练，以发展作为一名专注于恢复和维持1型糖尿病（T1D）患者免疫耐受问题的医生科学家的职业生涯。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，全球数千万患者的自身免疫过程会损害重要器官。申请人将通过对最常见的儿童自身免疫性疾病t1d的基础研究来关注这一科学挑战，该疾病折磨着超过200万美国人。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。目前的研究大多集中在限制破坏胰岛的T淋巴细胞的激活或增强某些保护胰岛的T细胞的免疫调节能力。值得注意的是，B淋巴细胞在疾病过程中也发挥关键作用，通过产生自身抗体，预测疾病风险，并通过B淋巴细胞作为必要的抗原提呈细胞的作用。在减缓新发糖尿病的进展方面，用B细胞消耗剂利妥昔单抗靶向这些细胞至少与T细胞靶向药物（如抗cd3）一样有效。此外，在人类T1D的相关小鼠模型中进行的研究表明，调节性B细胞在这种有益作用中发挥了作用。B细胞的这些调节功能也在其他自身免疫性疾病模型中被观察到，申请人之前已经描述了它们在移植耐受中的作用。基于这些开创性的数据，我们假设B淋巴细胞在建立和维持外周免疫耐受中发挥调节作用，并且这种能力在T1D中被破坏。本研究将研究可验证的假设，通过确定经典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（目的1），以及它们的细胞靶点和调节功能被控制的机制（目的2），重点研究B淋巴细胞对胰岛耐受的调节功能。范德比尔特大学的环境是准备好解决这个基本的生物学问题，考虑到当地B淋巴细胞免疫生物学的专业知识，范德比尔特糖尿病中心创造的特殊培训氛围，以及儿科、微生物学和免疫学部门对医生科学家发展的奉献精神。在一个特殊的指导委员会的指导下，在这些优秀资源的支持下，对这些新的假设进行调查，将使PI在这个与临床相关的研究领域——T1D中失去耐受性的基本问题——实现新发现的重要机会。