Neuroimmune Signaling in Neural Transplantation

描述（申请人提供）：参与免疫细胞信号传导的分子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主动免疫信号环境中。一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呈递外，MHC1和同源受体通过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的表达也被存在于损伤或退行性脑中的免疫细胞因子病理上调。本研究探讨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，但我们发现神经祖细胞移植物中的神经元丰度明显低于同基因移植物。这可能是由于选择性

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.