Intra-Lymph Node Delivery of Tolerogenic Microparticles for Modulating Disease in a Model of Multiple Sclerosis

项目摘要 多发性硬化症（MS）是一种使人衰弱的疾病，当身体的免疫系统错误地识别髓鞘时， 将中枢神经系统（CNS）中的神经元隔离为外来物的基质。目前的MS治疗旨在减少 疾病的严重程度，但不治疗病因，需要在患者的一生中持续频繁的治疗 以维持疾病的缓解，尽管疾病最终会发展。不幸的是，这些现有的治疗选择是 也是非特异性的-它们不能区分髓鞘特异性炎性免疫细胞和其它淋巴细胞， 使患者容易受到机会性感染。髓鞘特异性炎症细胞在淋巴结中被激活 (LNs)协调控制免疫细胞表型的免疫细胞相互作用的位点。在淋巴结中，抗原呈递 包括树突状细胞（DC）在内的细胞将抗原（如MS中的髓磷脂）呈递给T细胞和B细胞。根据信号 在这种相互作用期间，T细胞可以成为控制炎症的炎症效应细胞或调节细胞（TREGS）。 炎症细胞的活动。在MS期间，这些髓鞘特异性效应细胞有助于炎症， CNS中的神经变性。为了克服现有治疗方法的局限性，该建议侧重于开发 通过诱导抗原特异性TREGS促进对髓鞘的选择性免疫耐受的疗法， 疾病为了实现这一目标，直接LN注射技术将用于存款聚合物颗粒共载有髓鞘 自身抗原和免疫调节剂雷帕霉素在MS复发-缓解模型诱导的小鼠LN中的作用。 已经表明，在T细胞引发期间，雷帕霉素的存在可以促进TREGS。我们的实验表明， 将颗粒单次注入LN允许LN微环境的局部编程以促进TREGS， 在进行性MS模型中， 最初表现为MS的复发-缓解型，其中免疫系统对不同部分产生反应 髓磷脂的变化这种表位扩散使治疗方案复杂化，并且治疗根本不一致 疾病的阶段。因此，复发-缓解模型将允许研究表位扩散，以及疾病是如何传播的。 当在疾病的早期阶段对表位赋予保护作用时，疾病进展。初步数据显示，治疗期间， 第一波疾病是单次iLN注射共负载雷帕霉素和髓磷脂表位的颗粒 可以逆转疾病并防止复发。这项提案将研究如何在不同阶段的治疗 不同髓鞘抗原决定基的疾病改变了疾病的进展，并防止复发。

PROJECT SUMMARY Multiple Sclerosis (MS) is a debilitating disease that occurs when the body’s immune system incorrectly recognizes myelin, the matrix that insulates neurons in the central nervous system (CNS) as foreign. Current treatments for MS aim to reduce the severity of disease, but do not treat the cause, and require continual, frequent treatments over the lifetime of the patient to maintain disease remission, though the disease ultimately will progress. Unfortunately, these existing therapy options are also non-specific – they cannot differentiate between myelin-specific inflammatory immune cells and other lymphocytes, leaving patients susceptible to opportunistic infections. Myelin-specific inflammatory cells are activated in lymph nodes (LNs), sites which coordinate immune cell interactions that control immune cell phenotypes. In the LNs, antigen presenting cells, including dendritic cells (DCs), present antigens – such as myelin in MS – to T and B cells. Depending on the signals present during this interaction, T cells can become inflammatory effector cells or regulatory cells (TREGS) that control the activity of inflammatory cells. During MS, these myelin-specific effector cells contribute to inflammation and neurodegeneration in the CNS. To overcome the limitations of current treatments, this proposal focuses on developing therapies that promote selective immune tolerance to myelin by inducing antigen-specific TREGS that can selectively control disease. To meet this goal, a direct LN injection technique will be used to deposit polymer particles co-loaded with myelin self-antigens and rapamycin, an immunomodulator, in LNs of mice induced with a relapsing-remitting model of MS. Studies have shown that the presence of Rapamycin, during the priming of a T cell can promote TREGS. Our lab has shown that a single injection of particles into LNs allows local programming of the LN microenvironment to promote TREGS, which permanently stopped and reversed disease-induced paralysis in a model of progressive MS. However, 85% of patients initially present with the relapsing-remitting form of MS, in which the immune system becomes reactive to different sections of myelin over time. This epitope spreading complicates treatment regimens, and therapies do not consistently work at all stages of disease. Thus, a relapsing-remitting model will allow for the study of epitope spreading, and how disease progresses when protection is conferred to an epitope at an earlier disease stage. Preliminary data shows that treating during the first wave of disease with a single iLN injection of particles co-loaded with rapamycin and the myelin epitope attacked during that wave can reverse disease and prevent relapse. This proposal will investigate how treatments at different stages of disease with different myelin epitopes alters disease progression and prevents relapse.