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针对内源性抗原。在这里，我们研究了能够抑制自身免疫反应对抗原的可溶性抗原阵列（SAGA）。经过适当设计后，这些纳米材料有助于：1）淋巴结引流（抗原启动位点）和2）抗原和免疫细胞粘附抑制剂的多价表示（抑制对辅助抗原抗原的免疫反应）。引人注目的初步数据表明，通过实验性自身免疫性脑脊髓炎（EAE），萨加斯显着减弱了疾病进展，这是多发性硬化症的模型。这项研究的目的是系统地研究萨加斯的纳米材料特性如何影响局部生物分布和体内结局。我们的中心假设是，从20-100 kDa的靶向萨加斯将分裂为区域淋巴结，并将显着改善临床结果，并将生物标志物转移到免疫耐受性。我们提出了四个特定目标：特定目标＃1：合成并表征可溶性抗原阵列（Sagas）。特定目的＃2：评估Sagas在EAE小鼠中的治疗性能。特定目的＃3：确定萨加斯的局部生物分布。特定目的＃4：定义用萨加斯治疗后控制EAE的免疫细胞和可溶性介质。 纳米材料定位于淋巴结并呈现抗原以诱导免疫耐受性，代表了一种无法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定能够诱导免疫耐受性并可以扩展到新型疫苗接种方案的创新纳米材料免疫疗法来解决国家健康利益。