Particulate-based in vivo modulation for immunotherapy of Rheumatoid Arthritis

项目摘要/摘要 类风湿性关节炎(RA)是一种慢性、全身性、自发性炎症性疾病，影响约1% 对全世界成年人的影响，通常会造成共同破坏和生活质量的严重损害。 RA的根本原因是关节中抗原特异性T细胞亚群的树突状细胞(DC)激活，这是 推动滑膜的炎症反应，典型的特征是增生， 血管增多、炎性细胞浸润和促炎细胞因子的过度产生(尤其是 单核细胞、巨噬细胞和滑膜成纤维细胞表达IL-1、IL-6和肿瘤坏死因子-α)。由于他们在RA中扮演的关键角色 其他治疗方法 治疗方法包括使用类固醇，以及抗血管生成药物。然而，这些战略 不解决类风湿性关节炎的根本原因--DC刺激T淋巴细胞。已知有许多因素会导致 在自身免疫性疾病的实验系统中促进有利的树突状细胞反应。然而， 加州大学刘易斯实验室， Davis正在开发一种新型的、基于生物材料的、微粒子的“抗疫苗”，用于体内联合传递亲耐受 针对DC的因子和自身抗原。具有一定免疫调节作用的树突状细胞的外源性调节作用 药物已被证明可以诱导前耐受树突状细胞表型，以及改善类风湿关节炎。然而， 接种微粒抗疫苗有望纠正异常的自身免疫反应，同时 避免与DC细胞治疗相关的问题，如DC表型稳定性和 存活率和自身抗原的多元性。长期目标是开发一种模块化的抗疫苗系统，用于 自身免疫性疾病治疗。该R01提案的总体目标是设计一个多组件MP 在侵袭性的小鼠RA模型中抑制RA进展的抗疫苗，并调查 抗疫苗接种后的免疫调节。 靶向递送模型相关自身抗原和耐受诱导因子的自身抗原特异性耐受 免疫细胞，特别是DC，从而产生AAG特异性的tDCs，它将再训练下游适应 并促进类风湿关节炎的缓解。这一假设将通过追求四个具体目标来检验：1) 评价材料特性和抗疫苗制剂对DC耐受性的影响 免疫治疗；2)在FIA-CIA小鼠模型中评价该平台系统限制RA的能力；3) 使用明确定义的抗原特异性小鼠模型研究免疫耐受的机制； 调查初步的制造和安全指标，着眼于临床翻译。该方法 在申请人看来，这是创新的，因为它通过产生特定的容忍度来偏离现状- 通过简单的皮下注射聚合物微粒在体内诱导细胞介体。最终， 美国的自动豁免权。

PARTICULATE-BASED IN VIVO MODULATION FOR IMMUNOTHERAPY OF RHEUMATOID ARTHRITIS PROJECT SUMMARY/ ABSTRACT Rheumatoid arthritis (RA) is a chronic, systemic, auto-inflammatory disease that affects approximately 1% of adults worldwide, and commonly results in joint destruction and significant impairment in the quality of life. The underlying cause of RA is dendritic cell (DC) activation of antigen-specific T cell subsets in the joints, which drive inflammatory responses to the synovial membrane that are typically characterized by hyperplasia, increased vascularity, inflammatory cell infiltration and over production of pro-inflammatory cytokines (particularly IL-1, IL-6 and TNF-α) by monocytes, macrophages and synovial fibroblasts. Due to their critical role in RA progression, these cytokines have become the major therapeutic targets for RA therapy. Other therapeutic approaches include administration of steroids, as well as, anti-angiogenesis drugs. However, these strategies do not address the root cause of RA – stimulation of T lymphocytes by DCs. A number of factors are known to promote advantageous dendritic cell responses in experimental systems for autoimmune diseases. However, systemic delivery of these agents often results in significant harmful off-target effects. The Lewis Lab at UC, Davis is developing a novel, biomaterial-based, microparticle `anti-vaccine' for in vivo co-delivery of pro-tolerance factors and autoantigens, targeted to DCs. Exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro-tolerance DC phenotype, as well as, ameliorate RA. However, vaccination with a microparticle anti-vaccine promises to correct aberrant autoimmune responses, whilst circumventing problems associated with DC-based cellular therapy such as DC phenotypic stability and survivability, and autoantigen plurality. The long-term goal is to develop a modular, anti-vaccine system for autoimmune disease therapy. The overall objective of this R01 proposal is to engineer a multi-component, MP anti-vaccine to attenuate RA progression in an aggressive, murine RA model, and investigate the extent of immune modulation following anti-vaccination. The central hypothesis is that this MP anti-vaccine will induce autoantigen-specific tolerance by targeted delivery of model-relevant autoantigen and tolerance-inducing factors to immune cells, especially DCs, thereby generating aAg-specific tDCs that will retrain downstream adaptive responses and promote the remission of RA. This hypothesis will be tested by pursuing four specific aims: 1) Assess the effect of material properties and anti-vaccine agent presentation on the tolerogenicity of DC immunotherapy; 2) Evaluate the capacity of this platform system to limit RA in the FIA-CIA mouse model; 3) Investigate mechanisms of immune tolerance using well-defined antigen-specific mouse models; and 4) Investigate preliminary manufacturing and safety metrics with an eye towards clinical translation. The approach is innovative, in the applicant's opinion, because it departs from the status quo by generating specific tolerance- inducing cellular mediators in vivo with a simple subcutaneous injection of polymeric microparticles. Ultimately, the research and development of this system has the potential to significantly stem the growing epidemic of autoimmunity in the US.