Neuroimmune Signaling in Neural Transplantation

描述(由申请人提供)：参与免疫细胞信号传递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，即神经前体细胞被移植到患病或受伤大脑的主动免疫信号环境中。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反应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提呈外，MHC1和同源受体还由神经元表达，并影响轴突生长和突触的形成和消除。神经元中MHC的表达在病理上也受到损伤或退化大脑中存在的免疫细胞因子的上调。这项建议研究了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在许多临床环境中被使用，虽然纯化的同种异体细胞可以在中枢神经系统中很好地存活，但我们发现神经前体细胞移植物中的神经元丰度比同基因移植物显著降低。这可能是由于选择性地 通过同种异体特异性T细胞消除MHC表达的神经元，但经典的免疫抑制不会改变结果。相反，我们发现减弱先天性免疫信号和细胞因子的产生更有效，可以增加同种异体神经元的丰度，达到接近同基因移植物的水平。这突显了人们日益意识到T细胞介导的移植物排斥只是更复杂的免疫方程式中的一个变量，该方程式影响细胞治疗中移植物衍生神经元的功能。免疫机制可能是多样的，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。该方案中的实验重点是确定MHC1在经典的先天和获得性免疫识别中的特定作用，以及在移植到成人大脑后在神经元连接和存活中的非免疫学作用。

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.