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，赋予外周和中枢免疫反应平衡（即没有完全的免疫抑制，GVHD或排斥）改变。其他研究人员已经证明它们促进成人骨髓（BM）祖细胞的动员。此外，我们最近证明了hubc注入papp小鼠的血清显著抑制IFN-？并显著增加小胶质细胞A¿的吞噬活性，而没有不可接受的免疫损害。证实，CD40与CD40L蛋白的连接可以抑制这种作用。重要的是，这些hubc注入小鼠的初级成年小胶质细胞也显示出增加的A¿吞噬活性和强A¿IgG滴度。综上所述，这些数据表明，由HUCBC诱导的CD40信号抑制和a¿IgG产生增强介导的先天和体液免疫微环境的平衡改变。与神经毒性先天反应的下调和有益体液反应的上调一致，A¿水平/¿-淀粉样蛋白沉积和脑淀粉样蛋白血管病(CAA；体内输注HUCBC可降低血管淀粉样蛋白沉积的炎症反应，同时伴有：(a)血清a¿1- 40,42水平升高，提示来自中枢神经系统的外排(b)血清可溶性CD40L水平降低，(c)小胶质细胞CD40表达降低，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-a）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，hubc输注的papp小鼠的MO/X显示出增强的A¿吞噬活性。这些数据以及我们之前的研究结果，即Tg2576小鼠与CD40L缺失小鼠杂交或用CD40L抗体治疗papp小鼠可减少A¿负荷，使我们假设，通过CD40-CD40L破坏介导的先天和体液免疫的改变，导致bm来源的祖细胞MO/X的动员，增加抗炎细胞因子的产生，HUCBC输注可以减轻阿尔茨海默病（AD）小鼠的A¿/¿-淀粉样蛋白病理。大脑中淀粉样蛋白的清除也增加了。在这里，我们提出通过研究hubc注入的papp小鼠中的CD40信号传导来验证hubc介导的CD40- cd40l相互作用抑制淀粉样变性的假设。根据我们的初步数据，我们还计划通过单独或联合给药IL- 10、TGF-¿1和NGF-¿来重建HUCBC输注的作用；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，而不会产生全身免疫抑制、排斥或GVHD。此外，我们将验证hubc输注调动bm来源的MO/X的假设，导致巨噬细胞转分化进入中枢神经系统，并进一步分化为具有增强的A¿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推向轻度至中度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

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

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

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