Harnessing B lymphocytes as Antigen-Specific Regulators of Islet Tolerance

描述（由申请人提供）：主要研究者希望通过在范德比尔特大学医学中心的特殊环境中扩展其科学培训，发展作为一名医生-科学家的职业生涯，专注于恢复和维持1型糖尿病（T1 D）患者的免疫耐受性问题。免疫耐受的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世界数千万患者的重要器官。申请人将通过对最常见的儿科自身免疫性疾病-T1 D的基础研究来关注这一科学挑战，T1 D困扰着200多万美国人。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。目前的大多数努力集中在限制胰岛破坏性T淋巴细胞的活化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淋巴细胞还通过自身抗体的产生和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关键作用，所述自身抗体可预测疾病风险。用B细胞耗竭剂利妥昔单抗靶向这些细胞在减缓新发糖尿病的进展方面至少与T细胞靶向剂如抗CD 3一样有效。此外，在人T1 D的相关鼠模型中的研究表明调节B细胞在这种有益作用中的作用。B细胞的这些调节功能也已在其他自身免疫性疾病模型中观察到，并且申请人先前已表征了它们在移植耐受中的作用。基于这些基础数据，我们假设B淋巴细胞在外周免疫耐受的建立和维持中起调节作用，并且这种能力在T1 D中被破坏。本提案调查了可检验的假设，其将集中于通过确定以下因素来定义有助于胰岛耐受的B淋巴细胞的调节功能：经典B细胞亚群的作用、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控制它们的调节功能的机制（目的2）。在范德比尔特大学的环境是准备解决这个基本的生物学问题，在B淋巴细胞免疫生物学的本地专业知识，由范德比尔特糖尿病中心创造的特殊的培训氛围，并致力于医生科学家的发展，例如儿科和微生物学和免疫学的部门。在特殊指导委员会的指导下，并在这些优秀资源的支持下，对这些新假设进行研究，将使PI在这一临床相关研究领域-T1 D耐受性丧失的基本问题-实现新发现的重要机会。 公共卫生相关性：1型糖尿病是一种不可避免的终身疾病，没有已知的治愈方法，而且治疗方法不完善，明年将有15，000多名新儿童开始患上这种疾病。这种疾病是由患者免疫系统的不正确功能引起的，因此必须寻求靶向和纠正免疫紊乱的疗法。在本提案中，我们将为B淋巴细胞的调节能力的创新应用制定路线图，以克服这种疾病。

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.