Harnessing B lymphocytes as Antigen-Specific Regulators of Islet Tolerance

简介(由申请人提供)：PI寻求通过延长他在范德比尔特大学医学中心特殊环境中的科学培训，发展他的职业生涯，成为一名内科科学家，专注于恢复和维持1型糖尿病(T1D)患者的免疫耐受问题。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。申请者将通过对最常见的儿科自身免疫性疾病-T1D的基础调查，专注于这一科学挑战。T1D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淋巴细胞在疾病过程中也发挥着关键作用，既通过产生预测疾病风险的自身抗体，也通过B淋巴细胞作为必需的抗原提呈细胞的作用。用B细胞耗尽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细胞靶向药物，如抗CD3一样有效。此外，在人类T1D的相关小鼠模型中的研究表明，调节性B细胞在这种有益的作用中发挥了作用。B细胞的这些调节功能在其他自身免疫性疾病的模型中也观察到了，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被破坏。这项建议调查了可测试的假说，这些假说将集中于定义有助于胰岛耐受的B淋巴细胞的调节功能，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(目标1)，以及它们的细胞靶点和调节功能被控制的机制(目标2)。考虑到范德比尔特大学在B淋巴细胞免疫生物学方面的本地专业知识、范德比尔特糖尿病中心创造的特殊培训氛围以及儿科、微生物学和免疫学系对医生-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的生物学问题。在一个杰出的指导委员会的指导下，在这些杰出资源的支持下，对这些新的假设进行研究，将使PI认识到在这一与临床相关的研究领域--T1D耐受性丧失的根本问题--中的新发现的重大机会。 与公共卫生相关：1型糖尿病是一种无法避免的终生疾病，没有已知的治疗方法，也是一种不完美的治疗方法，明年将有超过1.5万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，因此必须寻求针对和纠正免疫紊乱的治疗方法。在这项提案中，我们将制定一份路线图，创新应用B淋巴细胞的调节能力来克服这种疾病。

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.