Restoration of Immune Tolerance in Type 1 Diabetes

1 型糖尿病免疫耐受的恢复

• 批准号: 8428207
• 负责人: Daniel J. Moore
• 金额: $ 7.8万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8428207
• 关键词: Allogenic; American; Antigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; B-Lymphocytes; Bone Marrow; Cells; Chemicals; Child; Childhood; Complement; Data; Development; Diabetes Mellitus; Disease; Failure; Functional disorder; Generations; Genetic; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; Immune system; Immunity; Inbred NOD Mice; Inflammation Mediators; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans Transplantation; Knowledge; Lead; Life; Lymphocyte; Maintenance; Marrow; Mediating; Methods; Modeling; Molecular; Monoclonal Antibodies; Mouse Strains; Mus; Nervous system structure; Organ; Osteoblasts; Osteoclasts; Pathway interactions; Patients; Predisposition; Process; Protocols documentation; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Role; Series; Signal Transduction; Site; Stem cells; Sympathetic Nervous System; System; Testing; Thymus Gland; Time; Transgenic Organisms; Transplantation; Transplantation Tolerance; arm; cellular targeting; innovation; islet; mouse model; novel strategies; prevent; progenitor; public health relevance; response; restoration

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.

描述（由申请人提供）：免疫耐受性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球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型1糖尿病的基本研究来重点关注这一科学挑战，该糖尿病遭受了200万以上的美国人。为了预防和扭转这种疾病，有必要恢复对胰岛抗原的免疫耐受性。 PI的K08奖的重点是调节性B淋巴细胞在免疫耐受性的诱导和维持中的作用。由于B淋巴细胞发育主要针对骨髓，因此我们研究了骨髓对耐受性诱导的反应。如初步数据所述，我们已经证明，耐受性疗法在耐受性，非自动免疫性B6小鼠中诱导造血干细胞动员，但在耐耐受性，抗糖尿病，可糖尿病可产生的小鼠中未能做到这一点。骨髓的动员依赖于通过单克隆抗体抗CD45RB激活的交感神经系统的信号。在此提案中，我们将确定造血干细胞动员在耐受性诱导过程中的作用，骨髓固有和外部因素的控制，以及交感对骨髓的交感神经影响的影响。在AIM 1中，我们将确定导致HSC动员，这种作用机理及其在免疫耐受性中的作用的抗CD45RB治疗的细胞靶标。在AIM 2中，我们将应用这些发现来纠正免疫功能障碍并恢复NOD小鼠（人类1型糖尿病的主要模型）中的移植耐受性。总体而言，这些研究探讨了一种新的范式，用于诱导和维持免疫耐受性，其中需要在骨髓中动员干细胞以维持免疫系统调节臂的稳态。此过程中的崩溃可能导致耐受性随着时间的流逝而侵蚀，并导致自身免疫性的产生。该提案将推进PI的独立研究，成为重新编程免疫系统的领先研究人员，以实现1型糖尿病逆转的持久免疫耐受性。