Restoration of Immune Tolerance in Type 1 Diabetes

描述（由申请人提供）：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-1型糖尿病的基础研究来关注这一科学挑战，该疾病困扰着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K 08奖主要关注调节性B淋巴细胞在诱导和维持免疫耐受中的作用。由于B淋巴细胞的发育主要在骨髓中进行，因此我们研究了骨髓对耐受诱导的反应。如在初步数据中所述，我们已经证明，致耐受性治疗诱导造血干细胞在耐受易感的非自身免疫性B6小鼠中动员，但在耐受抗性的糖尿病易感NOD小鼠中不能这样做。骨髓的动员依赖于交感神经系统的信号，这些信号被单克隆抗体抗CD 45 RB的致耐受性治疗激活。在这个建议中，我们将确定造血干细胞动员在耐受诱导过程中的作用，其控制骨髓的内在和外在因素，以及交感神经输入到骨髓的调节影响的效果。在目标1中，我们将确定导致HSC动员的抗CD 45 RB治疗的细胞靶点，这种作用的机制及其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。总的来说，这些研究探索了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以维持免疫系统调节臂中的稳态。这一过程的破坏可能导致耐受性随时间的推移而减弱，并最终发展为自身免疫。该提案将推动PI的独立研究，使其成为专注于免疫系统重编程的主要研究者，以实现逆转1型糖尿病的持久免疫耐受。

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.