BDNF-engineered stem cell mediated neuroprotection in EAE

BDNF 工程干细胞介导的 EAE 神经保护

• 批准号: 7939578
• 负责人: SUHAYL S. DHIB-JALBUT
• 金额: $ 19.5万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939578
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; B-Lymphocytes; Bone Marrow Stem Cell; Bone Marrow Stem Cell Transplantation; Brain; Brain-Derived Neurotrophic Factor; Cells; Central Nervous System Degenerative Diseases; Chronic; Chronic Disease; Chronic Phase; Clinical; Development; Disease; Drug Controls; Encephalomyelitis; Engineering; Exhibits; Experimental Autoimmune Encephalomyelitis; Family; Genes; Image; Immune; Immunosuppression; Immunosuppressive Agents; Implant; Infiltration; Inflammation; Inflammatory; Lesion; Mediating; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Nerve Degeneration; Neuraxis; Neurons; Phase; Principal Investigator; Process; Production; Recovery; Regulatory T-Lymphocyte; Relapse; Retroviridae; Secondary Progressive Multiple Sclerosis; Staging; Stem cells; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Therapeutic Effect; Tissues; Transgenes; Transgenic Organisms; Transplantation; Wild Type Mouse; Wound Healing; advanced disease; cytokine; macrophage; member; migration; neuron loss; neuroprotection; neurotrophic factor; programs; public health relevance; therapeutic protein

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.

描述(申请人提供)：现在公认的是，多发性硬化症(MS)不仅是一种炎性脱髓鞘，而且是一种中枢神经系统(CNS)的退行性疾病，早期轴突横断，随着疾病的进展，随后会出现神经元丢失。临床、病理和影像研究表明，在继发性进展性多发性硬化症中，炎症和神经元变性可能与独立的潜在过程脱钩。虽然免疫调节药物控制了MS复发阶段的复发，但继发性进展性MS通常对这种治疗没有反应。因此，随着疾病的进展，神经保护策略是必要的。脑源性神经营养因子(BDNF)是神经营养因子家族的一员，支持神经元和轴突存活。已有研究表明，BDNF在MS的炎性脑组织病变中有表达，在浸润性细胞，尤其是T细胞、B细胞、巨噬细胞以及神经元和星形胶质细胞中均有表达。在复发期间，PBMCs产生的BDNF增加，同时促炎细胞因子的产生增加。在EAE中，BDNF-产生在恢复前升高。这些研究表明，浸润性细胞具有组织损伤和组织修复的双重功能。浸润性细胞产生的促炎细胞因子会造成组织损伤，相反，浸润性细胞产生的抗炎性细胞因子和神经营养因子有助于组织修复。因此，病程可由浸润性细胞产生的细胞因子和神经营养因子的净作用决定。由于慢性疾病(神经退行性变阶段)的免疫渗透减少，神经营养因子的产生可能会减少。因此，在MS和EAE慢性期，将神经营养因子输送到中枢神经系统病变中可能是有益的。已有研究表明，骨髓干细胞移植可以改善实验性自身免疫性脑脊髓炎(EAE)的发展。这种治疗效果是由于骨髓间充质干细胞具有免疫抑制活性。骨髓间充质干细胞可以通过抑制致炎细胞因子的产生和/或促进CD4+CD25+调节性T细胞(Tregs)的分化来诱导致病T细胞的耐受。此外，骨髓间充质干细胞还可以作为治疗蛋白的载体，如神经营养因子和抗炎细胞因子等进入中枢神经系统。在本研究中，我们拟探讨表达BDNF基因的BMSCs能否发挥免疫抑制和神经再生的双重功能，以及表达BDNF基因的BMSCs移植能否改善急、慢性EAE。公共卫生相关性：我们建议研究表达转基因BDNF基因的骨髓干细胞是否能够介导免疫抑制和神经再生的双重功能，以及表达转基因BDNF的BMSCs移植是否可以改善急慢性EAE。