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: 8505320
• 负责人: Jun Tan
• 金额: $ 26.93万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505320
• 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.

描述（由申请人提供）：人脐带血细胞（HUCBC）是众所周知的特异性免疫调节剂，可平衡（即无完全免疫抑制、GVHD或排斥反应）外周和中枢免疫应答的改变。其他研究者已经证明它们促进成人骨髓（BM）祖细胞的动员。此外，我们最近证明，来自HUCBC输注PSAPP小鼠的血清显着抑制IFN-γ诱导的小胶质细胞CD 40表达？并显著增加了小胶质细胞A？吞噬活性，而没有不可接受的免疫损害。在确认中，这种作用被CD 40与CD 40 L蛋白的连接所抑制。重要的是，来自这些HUCBC输注小鼠的原代成年小胶质细胞也显示出增加的A？吞噬活性和强的A？IgG滴度。总之，这些数据表明，由HUCBC诱导的CD 40信号转导抑制和A？IgG产生增强介导的先天性和体液免疫微环境的平衡改变。与神经毒性先天性反应的下调和有益的体液反应的上调雅阁，A-淀粉样蛋白沉积和脑淀粉样血管病（CAA;对血管淀粉样蛋白沉积的炎症反应）在体内通过HUCBC输注减少，伴随着：（a）增加血清A？1-40，42，表明从CNS流出（B）降低可溶性CD 40 L血清水平，（c）降低小胶质细胞CD 40表达，最后，（d）CNS/血清抗炎（IL-10和TGF-21）水平升高，促炎细胞因子（IL-1和TNF-α）降低。最后，我们的初步数据表明，与对照原代BM来源的单核细胞/巨噬细胞（MO/X）相比，来自HUCBC输注的PSAPP小鼠的MO/X显示出增强的A？吞噬活性。这些数据沿着我们先前的发现，即将Tg 2576小鼠与CD 40 L缺失小鼠杂交或用CD 40 L抗体治疗PSAPP小鼠降低了A？负荷，使我们假设HUCBC输注可减轻A？/？。- 阿尔茨海默病（AD）小鼠中的淀粉样蛋白病理学，其通过由CD 40-CD 40 L破坏介导的先天和体液免疫的改变导致BM衍生的祖细胞MO/X的动员，增加抗炎细胞因子的产生和增加淀粉样蛋白从脑中的清除。在这里，我们建议通过研究输注HUCBC的PSAPP小鼠中的CD 40信号转导来检验HUCBC介导的CD 40-CD 40 L相互作用的抑制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给予IL- 10、TGF-β 1和NGF-β来重建HUCBC输注的效果;我们发现这些关键因素对于HUCBC调节CD 40活性和淀粉样变性的能力是必不可少的，而不需要全身性免疫抑制、排斥反应或GVHD。此外，我们将测试HUCBC输注动员BM衍生的MO/X，导致转分化为巨噬细胞，巨噬细胞进入CNS并进一步分化为具有增强的A？吞噬能力的小胶质细胞的假设。我们的长期目标是将这种联合治疗纳入轻度至中度AD患者的I期人体试验。

项目成果

Restoring Soluble Amyloid Precursor Protein α Functions as a Potential Treatment for Alzheimer's Disease.

• DOI: 10.1002/jnr.23823
• 发表时间: 2017-04
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Habib A;Sawmiller D;Tan J
• 通讯作者: Tan J

GFAP expression and social deficits in transgenic mice overexpressing human sAPPα.

• DOI: 10.1002/glia.22544
• 发表时间: 2013-09
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Bailey, Antoinette R.;Hou, Huayan;Song, Min;Obregon, Demian F.;Portis, Samantha;Barger, Steven;Shytle, Doug;Stock, Saundra;Mori, Takashi;Sanberg, Paul G.;Murphy, Tanya;Tan, Jun
• 通讯作者: Tan, Jun

Microglia activation as a biomarker for traumatic brain injury.

• DOI: 10.3389/fneur.2013.00030
• 发表时间: 2013
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Hernandez-Ontiveros DG;Tajiri N;Acosta S;Giunta B;Tan J;Borlongan CV
• 通讯作者: Borlongan CV

Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro.

• DOI: 10.1007/s12017-017-8446-x
• 发表时间: 2017-09
• 期刊: Neuromolecular medicine
• 影响因子: 3.5
• 作者: Hou H;Habib A;Zi D;Tian K;Tian J;Giunta B;Sawmiller D;Tan J
• 通讯作者: Tan J

Human umbilical cord blood-derived monocytes improve cognitive deficits and reduce amyloid-β pathology in PSAPP mice.

• DOI: 10.3727/096368915x688894
• 发表时间: 2015
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Darlington D;Li S;Hou H;Habib A;Tian J;Gao Y;Ehrhart J;Sanberg PR;Sawmiller D;Giunta B;Mori T;Tan J
• 通讯作者: Tan J