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，其赋予外周和中枢免疫反应平衡的（即没有完全免疫抑制、GVHD或排斥）改变。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，我们最近证明来自 HUCBC 输注的 PSAPP 小鼠的血清显着抑制由 IFN-α 诱导的小胶质细胞 CD40 表达。并显着增加小胶质细胞 A 的吞噬活性，而不会造成不可接受的免疫损害。经证实，CD40 与 CD40L 蛋白的连接抑制​​了这种效应。重要的是，来自这些 HUCBC 输注小鼠的原代成年小胶质细胞也表现出增强的 A¿ 吞噬活性和强的 A¿ IgG 滴度。这些数据共同表明，HUCBC 介导的先天免疫微环境和体液免疫微环境的平衡改变诱导了 CD40 信号传导的抑制和 A¿ IgG 产生的增强。与神经毒性先天反应的下调和有益体液反应的上调相一致，体内 HUCBC 输注可降低 A¿ 水平 / ¡- 淀粉样蛋白沉积物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），并随之而来：（a） A¿1-40、42 的血清水平增加，表明 CNS 的流出物 (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/血清抗炎细胞因子（IL-10 和 TGF-21）水平，同时降低了促炎细胞因子（IL-1¿ 和 TNF-a）。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。这些数据以及我们之前的研究结果，即将 Tg2576 小鼠与 CD40L 缺失小鼠杂交或用 CD40L 抗体治疗 PSAPP 小鼠减少了 A¿ 负载，使我们推测 HUCBC 输注可通过改变先天免疫和体液免疫介导的 A¿ CD40-CD40L 破坏导致 BM 来源的祖细胞 MO/X 动员，增加抗炎细胞因子的产生，并增加大脑中淀粉样蛋白的清除。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，我们还计划通过单独或联合施用 IL-10、TGF-¿1 和 NGF-¿ 来重建 HUCBC 输注的效果；我们发现关键因素对于 HUCBC 调节 CD40 活性和淀粉样变性而无需全身免疫抑制、排斥或 GVHD 的能力至关重要。此外，我们将测试以下假设：HUCBC 输注动员 BM 衍生的 MO/X，导致转分化为进入 CNS 的巨噬细胞，并进一步分化为具有增强 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进入针对轻度至中度 AD 患者的 I 期人体试验。公共健康相关性：在过去的几年中，我们已经证明，通过 CD40-CD40L 系统中断信号传导可以减少 APP（淀粉样前体蛋白）过量产生的转基因小鼠大脑中的淀粉样蛋白沉积，同时改善认知缺陷。 CD40 阻断通过减缓活化小胶质细胞的成熟来发挥作用，从而维持吞噬细胞表型，同时减少中枢神经系统中潜在神经毒性细胞因子（IL-2 和 TNF-¿）的产生，并增加治疗性抗炎细胞因子（IL-10 和 TGF-21）的产生。最重要的是，我们证明这种吞噬小胶质细胞表型增强了淀粉样斑块从脑实质的清除。不幸的是，CD40 阻断会带来不可接受的免疫消耗副作用，这使得该策略不太适合转移到临床环境。人脐带血细胞 (HUCBC) 是众所周知的特异性免疫调节剂，可平衡改变外周和中枢、先天和体液免疫反应，而不会产生排斥或全身免疫抑制。作为支持，我们的初步数据表明，HUCBC 输注小鼠的外周抗原呈递细胞 (APC) 中的 CD40 表达及其信号传导功能不受影响，而中枢神经系统中的细胞吞噬活性增加，毒性细胞因子下调，并增加抗炎细胞因子的产生。因此，本申请提出通过研究 HUCBC 输注的 PSAPP 小鼠中的 CD40 信号转导来研究 HUCBC 介导的 CD40-CD40L 相互作用的抑制减少淀粉样变性的假设。此外，我们计划研究可溶性因子，包括 IL-10、TGF-¿1 和 NGF-¿（这些因子在 HUCBC 输注的小鼠中显着升高），这些因子在这种情况下调节 CD40-CD40L 相互作用并减少淀粉样蛋白实质负荷，长期目标是开发用于人体试验的联合治疗。最后，将确定 HUCBC 输注至 PSAPP 小鼠后骨髓来源的 MO/X 的贡献。总之，预期结果表明 HUCBC 或 HUCBC 诱导的分离可溶性因子将成为 AD 的一种新治疗策略。