BDNF-engineered stem cell mediated neuroprotection in EAE

描述（由申请人提供）：目前公认多发性硬化症（MS）不仅是一种炎性脱髓鞘疾病，也是一种伴有早期轴突横断的中枢神经系统（CNS）退行性疾病，随后随着疾病进展出现神经元丢失。临床、病理和影像学研究表明，在继发性进展性MS中，炎症和神经元变性可能与独立的潜在过程解耦。虽然免疫调节药物控制MS复发期的复发，但继发性进展性MS通常对这种治疗无反应。因此，随着疾病的进展，需要神经保护策略。脑源性神经营养因子（BDNF）是支持神经元和轴突存活的神经营养蛋白家族的成员。已经证明，BDNF在MS的炎性脑损伤中表达，并且在浸润细胞（特别是T细胞、B细胞和巨噬细胞）以及神经元和星形胶质细胞中观察到其表达。在复发期间，PBMC的BDNF产生增加，同时促炎细胞因子的产生增加。在EAE中，BDNF的产生在恢复之前升高。这些研究表明，浸润的细胞具有双重功能，组织损伤和组织修复。由浸润细胞产生的促炎细胞因子引起组织损伤，相反，由浸润细胞产生的抗炎细胞因子和神经营养因子促进组织修复。因此，可以通过浸润细胞产生的细胞因子和神经营养因子的净效应来确定疾病过程。由于免疫浸润在慢性疾病（神经退行性阶段）中减少，因此神经营养因子的产生随后可能减少。因此，将神经营养因子递送到CNS病变中可能对MS和EAE的慢性期有益。骨髓干细胞（BMSCs）移植可以改善实验性自身免疫性脑脊髓炎（EAE）的发生发展。这种治疗效果是由于BMSC的免疫抑制活性。骨髓间充质干细胞可以通过抑制促炎细胞因子的产生和/或促进CD 4 + CD 25+调节性T细胞（TCFs）的分化来诱导致病性T细胞的耐受。此外，骨髓间充质干细胞可用作治疗性蛋白质如神经营养因子和抗炎细胞因子进入CNS的递送载体。在本申请中，我们建议研究表达转基因BDNF基因的BMSCs是否可以介导免疫抑制和神经再生的双重功能，以及移植表达转基因BDNF的BMSCs是否可以改善急性和慢性EAE。公共卫生相关性：我们拟研究表达转基因BDNF基因的骨髓干细胞是否具有免疫抑制和神经再生的双重功能，以及移植表达转基因BDNF的骨髓干细胞是否能改善急、慢性EAE。

DESCRIPTION (provided by applicant): It is now accepted that Multiple Sclerosis (MS) is not just an inflammatory demyelinating but also a degenerative disease of the central nervous system (CNS) with early axonal transection, followed by neuronal loss as the disease progresses. Clinical, pathological and imaging studies suggest that in secondary progressive MS, inflammation and neuronal degeneration may be de-coupled with independent underlying processes. While immunomodulatory drugs control relapses in the relapsing phase of MS, secondary progressive MS is generally unresponsive to such treatment. Therefore, neuroprotective strategies are needed as the disease advances. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophins family that supports neuronal and axonal survival. It has been demonstrated that BDNF is expressed in inflammatory brain lesions of MS and its expression is observed in infiltrating cells, especially T cells, B cells, and macrophages, as well as in neurons and astrocytes. During relapse, BDNF production by PBMCs is increased together with increase in production of proinflammatory cytokines. In EAE, BDNF-production is elevated before recovery. These studies suggested that the infiltrated cells exhibit dual function, tissue damage and tissue repair. Proinflammatory cytokines produced by infiltrated cells cause tissue damage, in contrast anti-inflammatory cytokines and neurotrophic factors produced by the infiltrated cells facilitate tissue repair. Therefore, disease course could be determined by the net effect of cytokines and neurotrophic factors produced by the infiltrated cells. Since immune infiltration is reduced in chronic disease (neurodegenerative stage), production of neurotrophic factors could subsequently be reduced. Thus, delivery of neurotrophic factors into the CNS lesions could be beneficial in the chronic phase of MS and EAE. It has been demonstrated that transplantation of bone marrow stem cells (BMSCs) can ameliorate the development of experimental autoimmune encephalomyelitis (EAE). This therapeutic effect is due to the immunosuppressive activity of BMSCs. BMSCs can induce tolerance in pathogenic T cells by suppressing production of proinflammatory cytokines and/or promoting differentiation of CD4+CD25+ regulatory T cells (Tregs). In addition, the BMSCs can be utilized as delivery vehicles for therapeutic proteins such as neurotrophic factors and anti-inflammatory cytokines into the CNS. In this application, we propose to investigate whether BMSCs expressing transgenic BDNF gene can mediate a dual function, immune suppression and neuroregeneration, and whether transplantation of BMSCs expressing transgenic BDNF can ameliorate acute and chronic EAE. PUBLIC HEALTH RELEVANCE: We propose to investigate whether bone marrow stem cells expressing transgenic BDNF gene can mediate a dual function, immune suppression and neuroregeneration, and whether transplantation of BMSCs expressing transgenic BDNF can ameliorate acute and chronic EAE.