Regulation of Autoimmune Encephalomyelitis

自身免疫性脑脊髓炎的调节

• 批准号: 8656155
• 负责人: HABIB ZAGHOUANI
• 金额: $ 32.23万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656155
• 关键词: Affect; Antigen-Presenting Cells; Antigens; Atypical lymphocyte; Bone Marrow; Bone Marrow Stem Cell; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Dendritic Cells; Development; Disease; Experimental Autoimmune Encephalomyelitis; Frequencies; Generations; Human; ITGAM gene; Immune system; Inflammatory; Interleukin-13; Light; MHC Class I Genes; MHC Class II Genes; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin; Myelogenous; Myeloid Cells; Neuraxis; Outcome; Output; Peripheral; Play; Process; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Stem cells; T cell response; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; central tolerance; defined contribution; design; insight; interleukin-13 receptor; novel; peripheral tolerance; progenitor; public health relevance; receptor; reconstitution; response

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) serves as a model for human multiple sclerosis (MS). Both EAE and MS manifest as a consequence of an inflammatory process within the central nervous system (CNS) that is mediated by cells of the immune system. The disease develops when T regulatory cells (Tregs) are no longer able to control activation of myelin-reactive effector T cells. It is thus crucial to understand why Tregs become unable to keep effector T cells in check and how the myelin-reactive lymphocytes evade such control in order to develop approaches that could contain the disease. Recently, we discovered a novel class of thymic stem cell progenitors expressing IL-13 receptor ¿1 (IL-13R¿1) that contribute to the development and function of both Tregs and effector T cells. The lineage negative (Lin-) IL-13R¿1+ stem cells, which arise in the bone marrow (BM), migrate to the thymus and become early thymic progenitors (ETPs). However, these IL-13R¿1+ ETPs do not mature into T lymphocytes. Rather, they give rise to CD11b+ myeloid cells that are retained in the thymus and function as antigen-presenting cells (APCs) that contribute to the selection process of both Tregs and effector T cells. The IL-13R¿1+ BM stem cells that do not migrate to the thymus also give rise to IL-13R¿1+ myeloid cells as well as dendritic cells (DCs) that likely function as peripheral APCs and contribute to the function of Tregs and effector T cells. The long term objective in this proposal is to define the contribution of IL-13R¿1+ ETPs to thymic T cell selection and to determine how the IL-13R¿1+ BM stem cell-derived peripheral APCs (myeloid and DCs) regulate the function of the ETP-selected Tregs and effector T cells. The major hypothesis in this proposal postulates that IL-13R¿1+ETP-derived myeloid cells function as APCs for thymic selection and display discrepancies among effector and regulatory T cells as well as self versus foreign antigens. Ultimately, the thymic outcome dictates T cell output to the periphery and, in coordination with the IL- 13R¿1+ peripheral APCs, regulates myelin-reactivity and EAE. Three aims are proposed to test these hypotheses. Aim 1 will define the role IL-13R¿1+ETPs play in thymic T cell selection, aim 2 will assess the role IL-13R¿1+ ETPs play in the development of peripheral T cell responses and EAE, and aim 3 will determine how IL-13R¿1+ Lin- BM stem cells regulate T cell responses and EAE. This study is of high impact because it could yield mechanistic insights useful for the generation of therapeutics against EAE and MS.

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）作为人类多发性硬化症（MS）的模型，EAE和MS均表现为中枢神经系统（CNS）内由细胞介导的炎症过程的结果。当 T 调节细胞 (Treg) 不再能够控制髓磷脂反应性效应 T 细胞的激活时，该疾病就会发生。 了解为什么 Tregs 无法控制效应 T 细胞以及髓磷脂反应性淋巴细胞如何逃避这种控制，以开发遏制该疾病的方法。最近，我们发现了一类表达 IL-13 受体的新型胸腺干细胞祖细胞。 ¿ 1 (IL-13R¿1) 有助于 Tregs 和效应 T 细胞的发育和功能 谱系阴性 (Lin-) IL-13R¿产生于骨髓 (BM) 的 1+ 干细胞迁移至胸腺并成为早期胸腺祖细胞 (ETP)，然而，这些 IL-13R¿ 1+ ETP 不会成熟为 T 淋巴细胞，而是产生保留在胸腺中的 CD11b+ 骨髓细胞，并充当抗原呈递细胞 (APC)，从而有助于 Treg 细胞和效应 T 细胞的选择过程。 -13R¿ 1+ 不迁移至胸腺的 BM 干细胞也会产生 IL-13R¿ 1+ 骨髓细胞以及树突状细胞 (DC) 可能充当外周 APC，并有助于 Tregs 和效应 T 细胞的功能。本提案的长期目标是确定 IL-13R 的贡献。 1+ ETP 用于胸腺 T 细胞选择并确定 IL-13R 如何1+ BM 干细胞衍生的外周 APC（骨髓和 DC）调节 ETP 选择的 Tregs 和效应 T 细胞的功能 该提议中的主要假设假设 IL-13R¿ 1+ETP 衍生的骨髓细胞充当胸腺选择的 APC，并显示效应 T 细胞和调节 T 细胞以及自身与外来抗原之间的差异，最终，胸腺结果决定 T 细胞输出到外周，并与 IL- 协调。 13R?? 1+ 外周 APC，调节髓磷脂反应性和 EAE。目标 1 将定义 IL-13R 的作用。 1+ETP 在胸腺 T 细胞选择中发挥作用，目标 2 将评估 IL-13R 的作用¿ 1+ ETP 在外周 T 细胞反应和 EAE 的发展中发挥作用，目标 3 将决定 IL-13R 如何发挥作用1+ Lin- BM 干细胞调节 T 细胞反应和 EAE 这项研究具有很高的影响力，因为它可以产生有助于产生针对 EAE 和 MS 的治疗方法的机制见解。