Neuroimmune Signaling in Neural Transplantation

神经移植中的神经免疫信号传导

• 批准号: 8369326
• 负责人: Theo D Palmer
• 金额: $ 63.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369326
• 关键词: Address; Adult; Allogenic; Allografting; Animals; Anti-Inflammatory Agents; Antigen Presentation; Astrocytes; Attenuated; Autologous; Awareness; Brain; Cell Survival; Cell Transplants; Cell surface; Cells; Clinical; Complex; Cyclosporine; Cytokine Activation; Cytokine Signaling; Cytolysis; Cytotoxic T-Lymphocytes; Data; Development; Disease; Environment; Equation; Extravasation; Graft Rejection; Histocompatibility Antigens Class I; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Inflammatory; Injection of therapeutic agent; Injury; Intervention; Ligands; Lymphocyte; MHC Class I Genes; Major Histocompatibility Complex; Mediating; Modeling; NK Cell Activation; Natural Killer Cells; Neuraxis; Neurites; Neurologic; Neurons; Oligodendroglia; Outcome; Parkinson Disease; Pharmaceutical Preparations; Production; Receptor Activation; Relative (related person); Role; Signal Transduction; Stem cells; Synapses; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transplantation; Transplanted tissue; Up-Regulation; allograft rejection; axon growth; combinatorial; cytokine; dopaminergic neuron; graft function; improved; injured; interest; killings; nerve stem cell; nerve supply; neural graft; neurodevelopment; neuron loss; novel; progenitor; programs; receptor; reconstitution; relating to nervous system; research study; response; synaptogenesis

DESCRIPTION (provided by applicant): Molecules involved in immune cell signaling can have independent functions in the central nervous system. Such molecules may have dual roles in cellular therapy where neural progenitor cells are transplanted into the active immune signaling environment of the diseased or injured brain. Class I major histocompatibility complex (MHC1) molecules are prominent examples with well defined function in both allograft rejection and in neurodevelopment. In addition to mediating antigen presentation by immune cells, MHC1 and cognate receptors are expressed by neurons and influence axonal growth and synapse formation and elimination. MHC expression in neurons is also pathologically up-regulated by immune cytokines present in the injured or degenerating brain. This proposal examines both immunological and neurodevelopmental roles of MHC1 in transplantation. Allogeneic cell or tissue transplants are being used in numerous clinical settings and while purified allogeneic cells can survive well in the CNS, we have found that neuron abundance in neural progenitor cell grafts is significantly reduced relative to syngeneic grafts. This may be due to the selective elimination of MHC-expressing neurons by an allo-specific T cells but classical immunosuppression does not alter outcome. In contrast, we find that attenuating innate immune signaling and cytokine production is more effective and can increase the abundance of allogeneic neurons to levels approaching syngeneic grafts. This highlights a growing awareness that T cell mediated graft rejection is only one variable in a more complex immunological equation that influences the function of graft-derived neurons in cellular therapy. The immune mechanisms may be diverse but historical data highlights the relative importance of class I MHC in both immune recognition and neurodevelopment. Experiments in this proposal focus on defining the specific roles of MHC1 in classical innate and adaptive immune recognition as well as the non-immunological roles in neuron connectivity and survival following transplant to the adult brain. PUBLIC HEALTH RELEVANCE: There is growing interest in the use of stem cells or neural progenitor cells in neurological therapy. Allogeneic cell or tissue transplants are being used in numerous clinical settings and while purified allogeneic cells can survive well in the CNS, we have found that neuron abundance in neural progenitor cell grafts is impacted by immune signaling mechanisms beyond those addressed with immunosuppressive drugs. Experiments in this proposal focus on defining the specific roles of classical innate and adaptive immune recognition as well as the non-immunological roles of neuronal class I MHC molecules in altering neural progenitor cell survival and connectivity following transplantation in models of stem cell reconstitution and neuron replacement in Parkinson's disease.

描述（由申请人提供）：参与免疫细胞信号传导的分子可以在中枢神经系统中具有独立的功能。这些分子可能在细胞治疗中发挥双重作用，其中神经祖细胞被移植到患病或受伤大脑的活跃免疫信号环境中。 I 类主要组织相容性复合体 (MHC1) 分子是在同种异体移植排斥和神经发育中具有明确功能的突出例子。除了介导免疫细胞的抗原呈递之外，MHC1 和同源受体还由神经元表达，并影响轴突生长以及突触的形成和消除。 受损或退化大脑中存在的免疫细胞因子也会病理性上调神经元中的 MHC 表达。该提案检查了 MHC1 在移植中的免疫学和神经发育作用。同种异体细胞或组织移植正在许多临床环境中使用，虽然纯化的同种异体细胞可以在中枢神经系统中良好存活，但我们发现神经祖细胞移植物中的神经元丰度相对于同基因移植物显着减少。这可能是由于选择性 通过同种异体特异性 T 细胞消除表达 MHC 的神经元，但经典的免疫抑制不会改变结果。相比之下，我们发现减弱先天免疫信号和细胞因子的产生更有效，并且可以将同种异体神经元的丰度增加到接近同基因移植物的水平。这突显了人们日益认识到，T 细胞介导的移植排斥只是影响细胞治疗中移植源性神经元功能的更复杂的免疫学方程中的一个变量。免疫机制可能多种多样，但历史数据强调了 I 类 MHC 在免疫识别和神经发育中的相对重要性。 该提案中的实验重点是定义 MHC1 在经典先天性和适应性免疫识别中的特定作用，以及移植到成人大脑后神经元连接和存活中的非免疫作用。 公共卫生相关性：人们对在神经治疗中使用干细胞或神经祖细胞越来越感兴趣。同种异体细胞或组织移植正在许多临床环境中使用，虽然纯化的同种异体细胞可以在中枢神经系统中良好存活，但我们发现神经祖细胞移植物中的神经元丰度受到免疫信号机制的影响，超出了免疫抑制药物所解决的影响。本提案中的实验重点是定义经典先天性和适应性免疫识别的特定作用，以及神经元 I 类 MHC 分子在帕金森病干细胞重建和神经元替代模型移植后改变神经祖细胞存活和连接性中的非免疫作用。