Neuroimmune Signaling in Neural Transplantation

神经移植中的神经免疫信号传导

• 批准号: 8653851
• 负责人: Theo D Palmer
• 金额: $ 62.08万
• 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/8653851
• 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.

描述（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。这些分子在细胞治疗中可能具有双重作用，其中神经祖细胞被移植到患病或受伤大脑的活性免疫信号传导环境中。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实例。除了介导免疫细胞的抗原呈递外，MHC1和同源受体还由神经元表达，并影响轴突生长和突触形成和消除。 神经元中的MHC表达也被存在于受损或退化的脑中的免疫细胞因子病理性上调。该建议检查MHC1在移植中的免疫和神经发育作用。同种异体细胞或组织移植物被用于许多临床环境中，并且虽然纯化的同种异体细胞可以在CNS中良好地存活，但是我们已经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著降低。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改变结果。相比之下，我们发现减弱先天免疫信号传导和细胞因子产生更有效，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。这突出了越来越多的人认识到，T细胞介导的移植物排斥反应只是一个更复杂的免疫学方程中的一个变量，影响细胞治疗中移植物源性神经元的功能。免疫机制可能是多种多样的，但历史数据突出了I类MHC在免疫识别和神经发育中的相对重要性。 本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。