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童自身免疫性疾病——1 型糖尿病（困扰超过 200 万美国人）的基础研究来关注这一科学挑战。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 奖重点关注调节性 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。正如初步数据中所述，我们已经证明，耐受性治疗可在耐受性敏感、非自身免疫的 B6 小鼠中诱导造血干细胞动员，但在耐受性抵抗、易患糖尿病的 NOD 小鼠中却无法做到这一点。骨髓的动员取决于来自交感神经系统的信号，该信号由单克隆抗体抗 CD45RB 的耐受性治疗激活。在本提案中，我们将确定造血干细胞动员在耐受诱导过程中的作用、骨髓内在和外在因素对其的控制，以及交感神经输入对骨髓的调节影响。在目标 1 中，我们将确定导致 HSC 动员的抗 CD45RB 疗法的细胞靶点、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（人类 1 型糖尿病的主要模型）的免疫功能障碍并恢复移植耐受性。总的来说，这些研究探索了诱导和维持免疫耐受的新范例，其中需要动员骨髓中的干细胞来维持免疫系统调节臂的稳态。随着时间的推移，这个过程的崩溃可能会导致耐受性受到侵蚀，从而导致自身免疫的发展。该提案将推动 PI 的独立研究，使其成为专注于免疫系统重新编程的领先研究人员，以实现逆转 1 型糖尿病的持久免疫耐受。