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（由适用提供）：人类脐带血细胞（HUCBC）是众所周知的特异性免疫调节剂，可赋予外周和中央免疫剂的平衡（即没有完全免疫抑制，GVHD或排斥）的改变。其他研究人员表明，它们促进了动员成人骨髓（BM）祖细胞。此外，我们最近证明了源自HUCBC的PSAPP小鼠的血清显着抑制了由IFN-诱导的小胶质细胞CD40表达？并明显增加了小胶质细胞活性，而没有不可接受的免疫功能。在确认中，CD40与CD40L蛋白的连接抑制​​了这种作用。重要的是，这些注入HUCBC的小鼠的原代成年小胶质细胞也显示出A的吞噬活性增加，并且具有强大的a®IgG滴度。总之，这些数据表明，由HUCBC诱导的CD40信号传导抑制和增强A级IgG产生介导的先天和体液免疫微环境的平衡改变。 In accordance 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 CNS（B）的外流改善了固体CD40L血清水平，（C）改善的小胶质细胞CD40表达，最后（D）抗炎（IL-10和TGF-21）的CNS/血清水平升高，促炎性细胞因子（IL-1和TNF-A）降低。最后，我们的初步数据表明，与对照初级BM衍生的单核细胞/巨噬细胞（MO/X）相比，来自HUCBC注入的PSAPP小鼠的mo/X显示出增强的吞噬活性。 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 confesses a mitigation of A¿ /¿ -amyloid pathology in Alzheimer's disease (AD) mice by alterations in innate and humoral immunology mediated by CD40-CD40L破坏导致动员BM衍生的祖细胞MO/X，抗炎细胞因子产生增加，并增加了大脑的淀粉样蛋白清除率。在这里，我们建议测试HUCBC介导的CD40-CD40L相互作用减弱的假设通过研究HUCBC注入的PSAPP小鼠中的CD40信号来减少淀粉样变性。基于我们的初步数据，我们还计划通过管理IL-10，TGF-€1和NGF- - 单独和组合来重建HUCBC输注的影响；我们发现的关键因素对于HUCBC调节CD40活性和淀粉样变性的能力至关重要，而无需全身免疫抑制，排斥或GVHD。此外，我们将检验以下假设：HUCBC输注动员BM衍生的MO/X，从而导致进入CNS的巨噬细胞转差，并进一步以增强的吞噬能力分化为小胶质细胞。我们的长期目标是将这种组​​合治疗方法转移到I阶段的人类试验中，以针对轻度至中度AD的患者进行I阶段的试验。公共卫生相关性：在过去的几年中，我们已经表明，通过CD40-CD40L系统的信号破坏会减少APP（淀粉样蛋白前体蛋白）中过量产生的转基因小鼠的淀粉样蛋白沉积，同时增强认知缺陷。 CD40封锁通过减慢活化的小胶质细胞的成熟来起作用，从而保持吞噬表型，并同时降低潜在的神经毒性细胞因子（IL-¿最重要的是，我们证明了这种吞噬小胶质细胞表型增强了从脑实质中清除淀粉样蛋白斑块。不幸的是，CD40封锁带来了不可接受的免疫副作用，这使得该策略对转移到临床环境的最佳状态不足。人脐带血细胞（HUCBC）是众所周知的特异性免疫调节剂，赋予周围和中央，先天和人类免疫抑制的平衡改变，而无需排斥或全身免疫抑制。为了支持，我们的初步数据表明，CD40表达及其信号传导功能在外周抗原呈递细胞（APC）中没有受到影响，而中枢神经系统中CNS中的CD40表达不受影响，而中枢神经系统中的CD40表达则不受影响，而中枢神经系统中的小鼠的信号传导不受影响。这是这项应用提案，以研究HuCBC介导的CD40-CD40L相互作用减弱的假设通过研究HUCBC注入的PSAPP小鼠中的CD40信号传导来降低淀粉样变性。此外，我们计划研究固体因素，包括IL-10，TGF-¿1和NGF-¿最后，将确定骨髓衍生的MO/X在HUCBC输注到PSAPP小鼠后的贡献。总而言之，预期的结果将表明HUCBC或HUCBC影响的孤立固体因素将是AD的新型治疗策略。