Regulation of Autoimmune Encephalomyelitis

自身免疫性脑脊髓炎的调节

• 批准号: 8574649
• 负责人: HABIB ZAGHOUANI
• 金额: $ 32.56万
• 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/8574649
• 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（由申请人证明）：实验性自身免疫性脑脊髓炎（EAE）是人类多重扇形的模型（MS）。免疫系统。 理解为什么无法在肠素反应性淋巴细胞中保持效应T细胞，以逃避这种对照，以供可能包含该疾病的TOL PAROP AP。 1（IL-13R¿1）有助于发育和效果t细胞。在骨髓（BM）中出现的1+干细胞迁移到胸腺并成为早期胸腺祖细胞（ETP）。 1+ ETP不成熟，而是会产生CD11b+髓样细胞，该细胞保留在胸腺和函数 - 蛋白酶 - 蛋白蛋白原蛋白酶中，并促进treg的选择。细胞。不迁移胸腺的1+ BM细胞也会引起IL-13R。 1+髓样细胞和树突状细胞（DC），可能功能APC并有助于Tregs和效应子的功能。 1+ ETPS胸腺T细胞卖出并确定IL-13R？ 1+ BM细胞衍生的外围APC（髓样和DC）ETP选择的Treg和效应T细胞。 1+TP衍生的髓样作为APC作为胸腺的APC在效应子和调节性T细胞中作为自我外国抗原的浸入症状，最终将胸腺呈现为外围的胸腺抗原。 1+外围APC，定期为Mylin反应性和EAE。 1+ETP在胸腺T细胞销售中发挥作用，AIM 2将评估IL-13R¿的角色1+ ETP在周围T细胞响应和EAE的发展中发挥作用，AIM 3将决定IL-13R？ 1+ lin-bm细胞反应和EAE。