Targeted nanoscale antigen arrays for treating autoimmune diseases

用于治疗自身免疫性疾病的靶向纳米级抗原阵列

• 批准号: 8513574
• 负责人: Cory Berkland
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513574
• 关键词: Address; Affect; Animals; Antigens; Attenuated; Autoimmune Diseases; Autoimmune Responses; Automobile Driving; Back; Binding; Biodistribution; Biological Assay; Biological Markers; Cell Adhesion; Cells; Clinical; Clinical Trials; Communities; Data; Development; Disease; Disease Outcome; Disease Progression; Drainage procedure; Exhibits; Experimental Autoimmune Encephalomyelitis; Goals; Health; Hyaluronic Acid; Immune; Immune Tolerance; Immune response; Immune system; Immunology; Immunosuppression; Immunotherapy; Injection of therapeutic agent; Ligands; Lymphoid; Mediator of activation protein; Modeling; Molecular Weight; Multiple Sclerosis; Mus; Myelin Sheath; Nanostructures; Neuraxis; Organ; Outcome; Peptides; Performance; Pharmaceutical Preparations; Plant Roots; Polymers; Property; Proteolipids; Research; Research Personnel; Scheme; Sentinel Lymph Node; Signal Transduction; Site; Subcutaneous Injections; Symptoms; Therapeutic; Vaccination; Vaccines; Vertebral column; arm; chemical property; cytokine; density; design; experience; immunogenic; immunological synapse; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; lymph nodes; nano; nanomaterials; nanoparticle; nanoscale; nanotherapeutic; novel; novel strategies; physical property; small molecule

DESCRIPTION (provided by applicant): A critical step in the development of autoimmune diseases is the stimulation of immune cells against endogenous antigen. Here, we investigate soluble antigen arrays (SAgAs) capable of suppressing autoimmune response to antigen. When properly designed, these nanomaterials facilitate: 1) drainage to lymph nodes (site of antigen priming) and 2) multivalent presentation of both antigen and an immune cell adhesion inhibitor (to suppress immune response to the co- grafted antigen). Compelling preliminary data show that SAgAs significantly attenuated disease progression in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. The objective of this study is to systematically study how the nanomaterial properties of SAgAs affect the local biodistribution and in vivo outcomes. Our central hypothesis is that, Targeted-SAgAs from 20-100 kDa will compartmentalize to regional lymph nodes and will significantly improve clinical outcomes and shift biomarkers towards immune tolerance. We propose four Specific Aims: Specific Aim #1: Synthesize and characterize Soluble Antigen Arrays (SAgAs). Specific Aim #2: Evaluate the therapeutic performance of SAgAs in EAE mice. Specific Aim #3: Identify the local biodistribution of SAgAs. Specific Aim #4: Define immune cells and soluble mediators that control EAE following treatment with the SAgAs. Nanomaterials that localize to lymph nodes and present antigens to induce immune tolerance represent an unexplored therapeutic approach for treating autoimmune diseases. This unique therapeutic approach addresses national health interests by firmly establishing the potential for innovative nanomaterial immunotherapies capable of inducing immune tolerance and extendable to novel vaccination schemes.

描述（由申请人提供）：自身免疫性疾病发展的关键步骤是刺激免疫细胞对抗内源性抗原。在这里，我们研究了能够抑制对抗原的自身免疫反应的可溶性抗原阵列（SAgAs）。如果设计得当，这些纳米材料有助于：1）引流至淋巴结（抗原引发部位），2）抗原和免疫细胞粘附抑制剂的多价呈递（以抑制对共移植抗原的免疫反应）。令人信服的初步数据表明，SAgAs 显着减轻了实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症模型）小鼠的疾病进展。本研究的目的是系统地研究 SAgAs 的纳米材料特性如何影响局部生物分布和体内结果。我们的中心假设是，20-100 kDa 的靶向 SAgAs 将划分为区域淋巴结，并将显着改善临床结果并将生物标志物转向免疫耐受。我们提出了四个具体目标： 具体目标#1：合成和表征可溶性抗原阵列 (SAgAs)。具体目标#2：评估 SAgAs 在 EAE 小鼠中的治疗效果。具体目标#3：确定 SAgAs 的局部生物分布。具体目标#4：定义 SAgAs 治疗后控制 EAE 的免疫细胞和可溶性介质。 定位于淋巴结并呈递抗原以诱导免疫耐受的纳米材料代表了一种尚未探索的治疗自身免疫性疾病的治疗方法。这种独特的治疗方法通过牢固确立创新纳米材料免疫疗法的潜力来解决国家健康利益，该疗法能够诱导免疫耐受并可扩展到新型疫苗接种方案。

项目成果

Multivalent nanomaterials: learning from vaccines and progressing to antigen-specific immunotherapies.

• DOI: 10.1002/jps.24273
• 发表时间: 2015-02-01
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: B. Hartwell;L. Antunez;B. Sullivan;Sharadvi Thati;J. Sestak;C. Berkl
• 通讯作者: C. Berkl

Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis.

多价可溶性抗原阵列的分子动力学支持治疗实验性自身免疫性脑脊髓炎的双信号共同传递机制。

• 发表时间: 2016-02-01
• 影响因子: 4.9
• 作者: Hartwell, Brittany L;Smalter Hall, Aaron;Swafford, David;Sullivan, Bradley P;Garza, Aaron;Sestak, Joshua O;Northrup, Laura;Berkland, Cory
• 通讯作者: Berkland, Cory

Antigen-Specific Binding of Multivalent Soluble Antigen Arrays Induces Receptor Clustering and Impedes B Cell Receptor Mediated Signaling.

多价可溶性抗原阵列的抗原特异性结合诱导受体聚集并阻碍 B 细胞受体介导的信号传导。

• 发表时间: 2016-03-14
• 影响因子: 6.2
• 作者: Hartwell, Brittany L;Martinez;Chen, Jun;Shinogle, Heather;Sarnowski, Michelle;Moore, David S;Berkland, Cory
• 通讯作者: Berkland, Cory