Targeted nanoscale antigen arrays for treating autoimmune diseases

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，我们调查可溶性抗原阵列（SAGAs）能够抑制自身免疫反应的抗原。当适当设计时，这些纳米材料促进：1）引流至淋巴结（抗原引发部位）和2）抗原和免疫细胞粘附抑制剂两者的多价呈递（以抑制对共移植抗原的免疫应答）。令人信服的初步数据表明，SAgAs显着衰减疾病进展的小鼠实验性自身免疫性脑脊髓炎（EAE），多发性硬化症的模型。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将区室化至区域淋巴结，并将显著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：评价SAgAs在EAE小鼠中的治疗性能。具体目标#3：确定SAGA的局部生物分布。具体目标#4：定义用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用于治疗自身免疫性疾病的未探索的治疗方法。这种独特的治疗方法通过牢固地建立能够诱导免疫耐受并可扩展到新型疫苗接种计划的创新纳米材料免疫疗法的潜力来解决国家健康利益。

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.