Spatiotemporal tuning of myelin antigens and rapamycin for enhanced antigen-specific immune tolerance in multiple sclerosis.

项目摘要 多发性硬化症（MS）是一种自身免疫性疾病，被认为是由自我攻击引起的。 髓鞘被自身反应性T细胞破坏。尽管技术的进步， 抑制免疫系统以减轻MS攻击的复发，目前没有解决方案 这解决了MS中潜在的自身免疫反应。例如，现有的可注射 诸如β-干扰素之类的疗法只是暂时的，仅持续约六个月。而 ocrelizumab是第一个在进行性MS中显示效果的CD 20治疗性抗体，其 临床效果相当温和，在12例患者中，与安慰剂相比， 24周残疾进展。制定指导再教育的方法 因此，MS中免疫系统对自身抗原的耐受性是一个未满足的需求。在 为了产生对髓鞘自身抗原的选择性特异性免疫耐受， 将抗原和免疫抑制药物（例如雷帕霉素）递送至抗原呈递细胞是 一个强有力的方法。然而，抗原和雷帕霉素的双重递送提高了空间和生物学特性。 时间考虑，因为抗原/雷帕霉素的定位（空间）和序列（时间）可以 决定了抗原呈递细胞顺式引发的程度。为了引发抗原呈递 通过操纵雷帕霉素的有利时空模式， 抗原，我们以前制定了一种新的纳米载体平台，时空调谐 颗粒（STP），其将雷帕霉素和抗原特异性地递送至抗原呈递细胞， 首选序列我们调节抗原和雷帕霉素时空传递的能力 导致小鼠免疫耐受性的显著改善， 改善实验性自身免疫性脑脊髓炎（EAE）的临床症状。在这 计划，我们将利用我们有前途的平台，产生髓鞘自身抗原特异性 脊髓髓鞘中发现的多种抗原诱导EAE耐受 组织匀浆，其代表人类MS。在目标1中，我们制造和表征 包封髓磷脂肽和雷帕霉素的STP候选物。在目标2中，我们验证了 STP候选物在脊髓匀浆EAE中的治疗效果，并研究抗原- 特异性和免疫细胞浸润。总的来说，我们提出的方法最终将允许 研究人员利用我们的平台，有针对性地连续提供多种治疗药物， 药物，以释放其在MS和其他自身免疫性疾病中的全部潜力。

Project Summary Multiple sclerosis (MS) is an autoimmune disorder thought to be caused by the self-attack on myelin sheath by autoreactive T cells. Despite improvements in technologies to temporarily suppress the immune system to mitigate the recurrence of MS attacks, there is no current solution that addresses the underlying autoimmune response in MS. For instance, existing injectable therapies such as beta-interferons are only temporary, lasting only about six months. While ocrelizumab is the first CD20 therapeutic antibody to show an effect in progressive MS, its clinical effects are rather modest, only showing a 6% reduction compared to placebo in both 12 and 24 week disability progression. Development of approaches that direct re-education of the immune system to be tolerogenic to self-antigens in MS is therefore an unmet need. In order to generate selective specific immune tolerance to myelin autoantigens, combinatorial delivery of antigen and immunosuppressive drugs (e.g. rapamycin) to antigen presenting cells is a powerful approach. However, dual delivery of antigen and rapamycin raises spatial and temporal considerations, as localization (space) and sequence (time) of antigen/rapamycin can dictate the magnitude of cis-priming of antigen presenting cells. To prime antigen presenting cells more efficiently by maneuvering the favorable spatiotemporal modality of rapamycin and antigen, we previously formulated a novel nanocarrier platform, Spatiotemporally Tuned Particle (STP), that delivers rapamycin and antigen specifically to antigen presenting cells in a preferred sequence. Our ability to tune the spatiotemporal delivery of antigen and rapamycin resulted in significant improvement of immune tolerance in mice, expanding Tregs and improving clinical symptoms in experimental autoimmune encephalomyelitis (EAE). In this program, we will utilize our promising platform to generate myelin autoantigen specific tolerance in EAE induced by multiple antigens found in the myelin sheath of spinal cord homogenate, which is representative of MS in humans. In aim 1, we fabricate and characterize STP candidates encapsulating myelin peptides and rapamycin. In aim 2, we validate the therapeutic efficacy of STP candidates in spinal cord homogenate EAE and investigate antigen- specificity and immune cell infiltration. Overall, our proposed approaches will ultimately allow researchers to leverage our platform for targeted and sequential delivery of multiple therapeutic agents to unlock their full potentials in MS and other autoimmune diseases.