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，可实现外周和中枢免疫反应的平衡（即无完全免疫抑制、GVHD 或排斥）改变。其他研究人员已证明它们可促进外周和中枢免疫反应。成年骨髓（BM）祖细胞的动员此外，我们最近证明来自输注 HUCBC 的 PSAPP 小鼠的血清显着抑制诱导的小胶质细胞 CD40 表达。 IFN-? 和小胶质细胞 A 显着增加重要的是，这些 HUCBC 输注小鼠的原代成年小胶质细胞也显示出 A¿吞噬细胞活性和强A¿这些数据共同表明 HUCBC 诱导的 CD40 信号传导抑制和 A¿ 增强介导的先天免疫微环境和体液免疫微环境的平衡改变。 IgG 的产生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¿级别/¿ - HUCBC 体内输注可减少淀粉样蛋白沉积和脑淀粉样蛋白血管病（CAA；对血管淀粉样蛋白沉积物的炎症反应），并伴随：(a) 血清 A¿ 水平增加如图 1-40、42 所示，表明从 CNS 流出 (b) 降低了可溶性 CD40L 血清水平，(c) 降低了小胶质细胞 CD40 表达，最后，(d) 升高了 CNS/抗炎血清水平（IL-10 和 TGF-β） 21) 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 衍生的单核细胞/巨噬细胞相比。 (MO/X)，来自 HUCBC 输注的 PSAPP 小鼠的 MO/X 显示出增强的 A¿这些数据与我们之前的发现相结合，即 Tg2576 小鼠与 CD40L 缺失小鼠杂交或用 CD40L 抗体处理 PSAPP 小鼠降低了 A¿负载，使我们竞争 HUCBC 输注可减轻 A¿ /¿ -阿尔茨海默病 (AD) 小鼠中淀粉样蛋白病理学的改变是通过 CD40-CD40L 破坏介导的先天免疫和体液免疫的改变导致 BM 来源的祖细胞 MO/X 的动员、抗炎细胞因子的产生增加以及大脑中淀粉样蛋白的清除增加。在这里，我们建议通过研究 HUCBC 输注的 PSAPP 小鼠中的 CD40 信号传导来检验 HUCBC 介导的 CD40-CD40L 相互作用的抑制减少淀粉样变性的假设。根据我们的初步数据，我们还计划通过施用 IL-10、TGF-¿ 来重建 HUCBC 输注的效果1 和 NGF-¿单独和联合使用；我们发现 HUCBC 能够调节 CD40 活性和淀粉样变性而不引起全身免疫抑制、排斥或 GVHD 的关键因素。此外，我们将检验 HUCBC 输注动员 BM 衍生的 MO/X 的假设，从而导致转分化为进入中枢神经系统的巨噬细胞，并进一步分化为具有增强的A¿的小胶质细胞我们的长期目标是将这种联合治疗进入针对轻度至中度 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

Peripheral biomarkers in Autism: secreted amyloid precursor protein-alpha as a probable key player in early diagnosis.

自闭症的外周生物标志物：分泌的淀粉样前体蛋白-α可能在早期诊断中发挥关键作用。

• 发表时间: 2008
• 期刊: International journal of clinical and experimental medicine
• 影响因子: 0.1
• 作者: Bailey,AntoinetteR;Giunta,BrianN;Obregon,Demian;Nikolic,WilliamV;Tian,Jun;Sanberg,CyndyD;Sutton,DanielleT;Tan,Jun
• 通讯作者: Tan,Jun