Restoration of Immune Tolerance in Type 1 Diabetes

描述(申请人提供)：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-1型糖尿病的基础调查，专注于这一科学挑战。1型糖尿病困扰着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。PI的K08奖的重点是调节性B淋巴细胞在诱导和维持免疫耐受中的作用。因为B淋巴细胞的发育主要是在骨髓中进行的，所以我们研究了骨髓对耐受诱导的反应。正如在初步数据中所描述的，我们已经证明，在耐受敏感、非自身免疫的B6小鼠中，耐受治疗可以诱导造血干细胞的动员，但在耐受耐受、易患糖尿病的NOD小鼠中却无法做到这一点。骨髓的动员依赖于交感神经系统的信号，这些信号通过抗CD45RB单抗的耐受治疗而激活。在这个方案中，我们将确定造血干细胞动员在耐受诱导中的作用，它受骨髓内在和外在因素的控制，以及交感神经传入对骨髓的调节作用。在目标1中，我们将确定抗CD45RB治疗导致HSC动员的细胞靶点，这种作用的机制，以及它在免疫耐受中的作用。在目标2中，我们将应用这些发现来纠正NOD小鼠的免疫功能障碍并恢复移植耐受，NOD小鼠是人类1型糖尿病的主要模型。总体而言，这些研究探索了一种诱导和维持免疫耐受的新范式，其中需要动员骨髓中的干细胞来维持免疫系统调节臂的动态平衡。这一过程中的故障可能会导致耐受性随着时间的推移而侵蚀，从而导致自身免疫的发展。这项建议将推动PI的独立研究，成为专注于免疫系统重新编程以实现逆转1型糖尿病的持久免疫耐受的领先研究人员。

DESCRIPTION (provided by applicant): 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-Type 1 diabetes, which afflicts more than 2 million Americans. To prevent and reverse this disease, it is necessary to restore immune tolerance to islet antigens. The PI's K08 award has focused on the role of regulatory B lymphocytes in the induction and maintenance of immune tolerance. Because B lymphocyte development is directed primarily in the bone marrow, we have investigated the bone marrow response to tolerance induction. As described in the preliminary data, we have demonstrated that tolerogenic therapy induces mobilization of hematopoietic stem cells in tolerance-susceptible, non-autoimmune B6 mice but fails to do so in tolerance-resistant, diabetes-prone NOD mice. The mobilization of the bone marrow is dependent upon signals from the sympathetic nervous system that are activated by tolerogenic therapy with monoclonal antibody anti-CD45RB. In this proposal, we will determine the role of hematopoietic stem cell mobilization during tolerance induction, its control by bone marrow intrinsic and extrinsic factors, and the effect of the modulating influence of sympathetic input to the marrow. In aim 1, we will determine the cellular target of anti-CD45RB therapy that results in HSC mobilization, the mechanism of this effect, and its role in immune tolerance. In Aim 2, we will apply these findings to correct immune dysfunction and restore transplantation tolerance in NOD mice, the primary model of human Type 1 diabetes. Overall, these studies explore a new paradigm for the induction and maintenance of immune tolerance in which mobilization of stem cells in the bone marrow is needed to maintain homeostasis in the regulatory arm of the immune system. Breakdowns in this process may lead to erosion of tolerance over time and the resultant development of autoimmunity. This proposal will advance the independent studies of the PI to become a leading investigator focused on reprogramming of the immune system to achieve lasting immune tolerance for reversal of Type 1 diabetes.