Multifunctional Biomaterial for Amelioration of MS in Murine EAE Model

 描述(申请人提供)：多发性硬化症(MS)是一种自身免疫性疾病，导致神经功能障碍，与炎症介导的覆盖大脑和脊髓神经元的髓鞘损伤有关。轴突损伤现在被认为发生在病程的早期，在每一个新的病变中，累积性轴突丢失导致进行性和不可逆转的残疾。MS患者对中枢神经系统(CNS)的自身免疫攻击被认为是CNS损伤诱发的继发性致病因素。针对髓鞘抗原的自身免疫进一步加剧了神经退化的自身催化过程。本文提出的方法旨在将MS治疗方法的两个必要组成部分结合成一个单一的策略，以解决树突状细胞(DC)表型失衡和促进神经保护。本研究的总体目标是阐明一种生物材料策略的生物材料和免疫学基础，该策略通过聚乙二醇水凝胶内MS抗原特异性免疫抑制DC的传递并结合神经保护因子NeuRegin-1(NRG-1)的传递来改善MS的小鼠实验性自身免疫性脑脊髓炎(EAE)模型。本研究的假设是，在体外免疫抑制分子治疗时通过与MS抗原接触而产生抗原特异性和耐受性的DC可以使用局部水凝胶系统应用于颈淋巴结(CLN)，同时释放神经保护剂NRG-1，以通过免疫调节和神经保护改善EAE疾病的预后。在这项研究中，一种简化的生物材料策略，如初步结果所述，证明了有效性，是基于在原位凝胶聚乙二醇水凝胶中将免疫抑制MS抗原特异性小鼠树突状细胞输送到小鼠颈部位置，并对其进行最小程度的修改以呈现细胞粘附肽RGD。提出了两个具体的目标：1)展示组装的多功能生物材料的关键组件的功能性，以运送免疫抑制、MS抗原特异性DC和NRG-1；以及2)阐明该多功能生物材料通过免疫调节和神经保护改善小鼠EAE的有效性，并确定关键的构建组件。

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune disease causing neurological deficits associated with inflammation- mediated damage to myelin sheaths covering brain and spinal cord neurons. Axonal damage is now believed to occur early in the disease course, in every new lesion, with progressive and irreversible disability arising from cumulative axonal loss. The autoimmune attack on the central nervous system (CNS) in MS has been suggested to be a secondary pathogenic factor evoked by CNS injury. Autoimmunity against myelin antigens further exacerbates the autocatalytic process of neurodegeneration. The approach proposed herein aims to combine the two necessary components of MS therapeutic approaches into a single strategy addressing the dendritic cell (DC) phenotype imbalance and promotion of neuroprotection. The overall goal is elucidate the biomaterial and immunological basis of a biomaterial strategy for immunomodulation through MS-antigen specific immunosuppressive DC delivery within a polyethylene glycol (PEG) hydrogel and combined with delivery of the neuroprotective factor, neuregulin-1 (NRG-1), to ameliorate the murine experimental autoimmune encephalomyelitis (EAE) model of MS. The hypothesis for this research is that DCs, rendered antigen specific and tolerogenic by contact with an MS antigen upon immunosuppressive molecule treatment in vitro, can be applied to the cervical lymph nodes (cLNs), using a localized hydrogel system, along with release of the neuroprotective agent, NRG-1, to ameliorate EAE disease outcomes through immunomodulation and neuroprotection. In this study, a simplified biomaterial strategy, with demonstrated efficacy as described in the preliminary results, is based on the delivery of immunosuppressive MS antigen-specific murine DCs to the neck location of mice within an in situ gelling PEG hydrogel, minimally modified to present the cell adhesion peptide, RGD. Two specific aims are proposed: 1) demonstrate functionality of critical components of the assembled multifunctional biomaterial for delivery of immunosuppressive, MS antigen-specific DCs and NRG-1; and 2) elucidate efficacy of the multifunctional biomaterial for amelioration of murine EAE through immunomodulation and neuroprotection and identify critical construct components.