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(申请人提供)：人脐血细胞(HUCBC)是众所周知的特异性免疫调节剂，能够平衡(即没有完全免疫抑制、移植物抗宿主病或排斥反应)改变外周和中枢免疫反应。其他研究人员已经证明，它们可以促进成人骨髓(BM)祖细胞的动员。此外，我们最近证实，来自输注HUCBC的PSAPP小鼠的血清显着抑制了由干扰素-？并显著增强小胶质细胞的吞噬活性，而不会造成不可接受的免疫损害。证实了CD40与CD40L蛋白的结合抑制了这种作用。重要的是，这些注射了HUCBC的小鼠的原代成年小胶质细胞也显示出增强的A？吞噬活性和强大的A？Ig G滴度。综上所述，这些数据表明，天然和体液免疫微环境的平衡改变是由HUCBC诱导的抑制CD40信号和增强A？IgG产生所介导的。与这种神经毒性先天反应的下调和有益体液反应的上调相一致，HUCBC体内注射降低了Aβ水平/淀粉样沉积和脑淀粉样血管病(CAA；血管淀粉样沉积的炎性反应)，伴随着：(A)血清A？1-40，42水平升高，提示A？1-40，42，提示中枢神经系统外流，(B)降低可溶性CD40L血清水平，(C)减少小胶质细胞CD40的表达，最后，(D)CNS/血清抗炎(IL-10和转化生长因子21)水平升高，促炎细胞因子(IL-1β和TNF-α)减少。最后，我们的初步数据表明，与对照原代BM来源的单核/巨噬细胞(MO/X)相比，注入HUCBC的PSAPP小鼠的MO/X显示出更强的A吞噬活性。这些数据，加上我们之前的发现，将Tg2576小鼠与CD40L缺失小鼠杂交，或用CD40L抗体处理PSAPP小鼠，可减少A？负荷，使我们推测HUCBC输注可缓解阿尔茨海默病(AD)小鼠的A？/？-淀粉样病变，其机制是CD40-CD40L中断导致BM来源的祖细胞MO/X动员起来，抗炎细胞因子的产生增加，淀粉样蛋白从大脑中清除。在这里，我们建议通过研究注入HUCBC的PSAPP小鼠的CD40信号来检验HUCBC介导的抑制CD40-CD40L相互作用减少淀粉样变性的假设。基于我们的初步数据，我们还计划通过单独和联合应用IL-10、转化生长因子β1和神经生长因子β来重建HUCBC输注的效果；我们发现这些关键因素是HUCBC在没有全身免疫抑制、排斥反应或GVHD的情况下调节CD40活性和淀粉样变性的能力所必需的。此外，我们还将验证这样一种假设，即输注HUCBC动员骨髓来源的MO/X，导致转分化为巨噬细胞，巨噬细胞进入中枢神经系统，并进一步分化为具有增强吞噬能力的小胶质细胞。我们的长期目标是将这种联合治疗方法转移到轻中度AD患者的I期人体试验中。公共卫生相关性：在过去的几年里，我们已经证明，通过CD40-CD40L系统中断信号可以减少过量生产淀粉样前体蛋白(APP)转基因小鼠大脑中的淀粉样沉积，同时改善认知缺陷。CD40阻断的作用是通过减缓激活的小胶质细胞的成熟，从而维持吞噬表型，同时减少潜在的神经毒性细胞因子(IL-2和TNF-β)的产生，并增加中枢神经系统中治疗性抗炎细胞因子(IL-10和TGF-21)的产生。最重要的是，我们证明了这种吞噬的小胶质细胞表型增强了淀粉样斑块从脑实质中的清除。不幸的是，CD40阻断带来了不可接受的免疫消耗副作用，这使得这一策略不太适合转移到临床环境中。人脐血细胞(HUCBC)是公认的特异性免疫调节剂，能够平衡地改变外周和中枢、先天和体液免疫反应，而不会发生排斥反应或全身免疫抑制。在支持方面，我们的初步数据显示，输注HUCBC的小鼠外周抗原提呈细胞(APC)的CD40表达及其信号功能没有受到影响，而在CNS中的APC经历了吞噬活性增加，毒性细胞因子下调，以及抗炎细胞因子的生成增加。因此，这项应用建议通过研究HUCBC注入PSAPP小鼠的CD40信号来研究HUCBC介导的抑制CD40-CD40L相互作用减少淀粉样变性的假设。此外，我们计划研究调节CD40-CD40L相互作用并降低淀粉样实质负荷的可溶性因子，包括IL-10、TGF-β1和NGF-β(这些因子在注射HUCBC的小鼠中显著升高)，长期目标是开发一种用于人体试验的联合治疗方法。最后，将确定HUCBC输注PSAPP小鼠后骨髓来源的MO/X的贡献。综上所述，预期的结果将提示HUCBC或由HUCBC诱导的分离的可溶性因子将是一种治疗AD的新策略。