Implication of HUCBC: a novel therapeutic strategy for Alzheimer's disease

HUCBC 的意义：阿尔茨海默病的一种新治疗策略

• 批准号: 8305549
• 负责人: Jun Tan
• 金额: $ 28.49万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305549
• 关键词: Adult; Adverse effects; Affect; Agonist; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Presenting Cells; Blood Cells; Blood Vessels; Bone Marrow; Brain; CD40 Antigens; Cell Therapy; Cells; Cerebral Amyloid Angiopathy; Cerebrum; Clinical; Cognitive deficits; Cytotoxic T-Lymphocytes; Data; Deposition; Down-Regulation; Equilibrium; Generations; Goals; Health; Human; Humoral Immunities; Immune; Immune response; Immunoglobulin G; Immunosuppression; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Interferons; Interleukin-10; Knockout Mice; Lead; Ligation; Mediating; Mediator of activation protein; Microglia; Monitor; Mononuclear; Mus; Natural Immunity; Pathology; Patients; Peptides; Peripheral; Phagocytosis; Phase; Phenotype; Principal Investigator; Production; Proteins; Research Personnel; Role; Senile Plaques; Serum; Short-Term Memory; Signal Pathway; Signal Transduction; Stem cells; Stimulus; System; TNF gene; TNFRSF5 gene; TNFSF5 gene; Technology; Testing; Tg2576; Therapeutic; Transgenic Mice; Umbilical Cord Blood; Up-Regulation; Vaccination; Validation; amyloid pathology; base; cytokine; design; experience; graft vs host disease; hyperphosphorylated tau; improved; in vivo; macrophage; monocyte; mouse model; neurotoxic; neurotrophic factor; novel therapeutics; progenitor; programs; reconstitution; response; synthetic polymer Bioplex; tau Proteins; transdifferentiation

DESCRIPTION (provided by applicant): Human umbilical cord blood cells (HUCBC) are well known specific immunomodutators that confer a balanced (i.e. without complete immunosuppression, GVHD, or rejection) alteration of both peripheral and central immune responses. Other investigators have demonstrated they promote mobilization of adult bone marrow (BM) progenitor cells. In addition we recently demonstrated sera derived from HUCBC-infused PSAPP mice significantly inhibited microglial CD40 expression induced by IFN-? and markedly increased microglial A¿ phagocytic activity without unacceptable immune compromise. In confirmation, this effect was inhibited by the ligation of CD40 with CD40L protein. Importantly, primary adult microglia from these HUCBC-infused mice also showed increased A¿ phagocytic activity, and a strong A¿ IgG titer. Together these data suggest a balanced alteration of both innate and humoral immune microenvironments mediated by an HUCBC induced suppression of CD40 signaling and enhancement of A¿ IgG production. In accord with this downregulation of neurotoxic innate responses and upregulation of salutary humoral responses, A¿ levels/¿- amyloid deposits and cerebral amyloid angiopathy (CAA; an inflammatory response to vascular amyloid deposits) are reduced by HUCBC infusion in vivo, with attendant: (a) increased serum levels of A¿1-40, 42, suggesting efflux from the CNS (b) decreased soluble CD40L serum levels, (c) decreased microglial CD40 expression, and finally, (d) elevated CNS/serum levels of anti-inflammatory (IL-10 and TGF-21) with decrease pro-inflammatory cytokines (IL-1¿ and TNF-a). Finally, our preliminary data suggests that, compared with control primary BM derived monocytes/macrophages (MO/X), MO/X from HUCBC-infused PSAPP mice show enhanced A¿ phagocytic activity. These data along with our previous findings that crossing Tg2576 mice with CD40L null mice or treating PSAPP mice with CD40L antibody reduced A¿ loads, lead us to hypothesize that HUCBC infusion confers a mitigation of A¿/¿-amyloid pathology in Alzheimer's disease (AD) mice by alterations in innate and humoral immunity mediated by CD40-CD40L disruption resulting in mobilization of BM-derived progenitor MO/X, increased anti-inflammatory cytokine production, and increased amyloid clearance from the brain. Here we propose to test the hypothesis that HUCBC mediated dampening of the CD40-CD40L interaction reduces amyloidosis by investigating CD40 signaling in HUCBC infused PSAPP mice. Based on our preliminary data, we additionally plan to reconstitute the effects of HUCBC infusion by administering IL- 10, TGF-¿1 and NGF-¿ alone and in combinations; key factors we found to be essential for HUCBC ability to modulate CD40 activity and amyloidosis without systemic immunosuppression, rejection, or GVHD. Also, we will test the hypothesis that HUCBC infusion mobilizes BM-derived MO/X, leading to transdifferentiation into macrophages which enter the CNS and further differentiate into microglia with enhanced A¿ phagocytic capacity. It is our long-term goal to move this combination treatment into phase I human trials for patients with mild to moderate AD. PUBLIC HEALTH RELEVANCE: In the past years, we have shown that disruption of signaling through the CD40-CD40L system reduces amyloid deposition in the brains of APP (amyloid precursor protein) overproducing transgenic mice while ameliorating cognitive deficits. The CD40 blockade acts by slowing maturation of activated microglia thereby maintaining a phagocytic phenotype with concurrent decreased production of potentially neurotoxic cytokines (IL-¿2 and TNF-¿), and increased production of therapeutic anti-inflammatory cytokines (IL-10 and TGF-21) in the CNS. Most importantly this we demonstrated this phagocytic microglial phenotype enhances clearance of amyloid plaques from the brain parenchyma. Unfortunately CD40 blockade carries with it unacceptable immune-depleting side effects which makes this strategy less than optimal for transfer to the clinical setting. Human umbilical cord blood cells (HUCBC) are well known specific immunomodutators that confer a balanced alteration of peripheral and central, innate and humoral immune responses without rejection or systemic immunosuppression. In support, our preliminary data showed that CD40 expression and its signaling functions in peripheral antigen presenting cells (APCs) from HUCBC-infused mice are not affected, while those in the CNS experience increased phagocytic activity, down regulation of toxic cytokines, and increased generation of anti-inflammatory cytokines. Thus, this application proposes to investigate the hypothesis that HUCBC mediated dampening of the CD40-CD40L interaction reduces amyloidosis by investigating CD40 signaling in HUCBC infused PSAPP mice. Furthermore, we plan to investigate the soluble factors, including IL-10, TGF-¿1 and NGF-¿ (these factors significantly elevated in HUCBC-infused mice), which modulate the CD40-CD40L interaction and reduced amyloid parenchymal load in this context with the long term goal of developing a combination treatment for use in human trials. Finally, the contribution of bone marrow-derived MO/X after HUCBC infusion into PSAPP mice will be determined. In summary, the expected results will suggest that HUCBC or, isolated soluble factors that HUCBC induce, would be a novel therapeutic strategy for AD.

描述（由申请人证明）：人脐带血细胞（HUCBC）是众所周知的特定的免疫调节剂，赋予外围和中心免疫反应的平衡（即没有压缩，GVHD或排斥）的变化。 （BM）此外，我们最近证明了源自HUCBC的PSAPP小鼠的血清显着的小胶质细胞CD40表达是由IFN-诱导的，并显着增加了小胶质细胞的A¿吞噬活性具有不可接受的免疫损害，重要的是，来自HUCBC的小鼠的原发性小胶质细胞也显示出a。吞噬活性和强大的IgG滴度表明，CD40信号和增强的均衡的均衡和体液上的免疫微环境IgG产生。级别/¿ - 淀粉样蛋白沉积物淀粉样蛋白血管病IVO，与服务员：（a）A a a a a。 1-40，42，提示CNS（b）降低可溶性CD40L血清水平，（c）降低了小胶质细胞CD40表达，最后D CNS/血清抗炎（IL-10和TGF-21）随着降低 - 炎症细胞因子（IL-1和TNF-A）。吞噬活性。负载，导致我们假设HUCBC输注赋予了缓解措施/通过CD40-CD40L介导BM衍生的祖细胞MO/X介导的先天和体液免疫的改变，阿尔茨海默氏病（AD）小鼠中的淀粉样蛋白病理学增加，抗炎细胞因子的产生增加，并增加了大脑的淀粉样假设CD40-CD40L相互作用介导的HUCBC通过在HUCBC注入的PSAPP小鼠中研究CD40来降低淀粉样蛋白，我们还计划通过管理IL-10，TGF-10，TGF-10的效应1和ngf--单独的和组合；我们对HucBC的CD40活性和淀粉样变性的能力至关重要中枢神经系统并进一步分化为小胶质细胞，并增强了a。吞噬性胶囊。细胞因子（IL-2和2和TNF-），以及CNS中治疗性抗炎细胞因子的产生（IL-10和TGF-21）与临床固定的最佳动力相比，具有不可接受的免疫动力侧的侧面是最佳的。数据表明，CD40表达并在外周中的信号传导功能提出的假设是，HUCBC通过研究hucbc注入的PSAPP小鼠中的CD40信号来介绍CD40L相互作用的dampeng。 1和ngf-- （SIGBC注入的小鼠的因素）调节CD40L相互作用并减少同型同源性载荷，其长期目标是开发用于人类试验的组合处理，最终是骨髓衍生的MO/X的贡献。将HUCBC输注为PSAPP小鼠，总结，预期的结果将表明HUCBC或孤立的可溶性CTOR诱导的可溶性CTOR将是一种新型的AD治疗策略。