Particulate-based in vivo modulation for immunotherapy of Rheumatoid Arthritis

基于微粒的免疫调节治疗风湿性关节炎 项目概要/摘要 风湿性关节炎（RA）是一种慢性、全身性、自身炎症性疾病， 全世界成年人的关节炎，通常会导致关节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）活化， 驱动对滑膜的炎症反应，其典型特征是增生， 增加的血管分布、炎性细胞浸润和促炎细胞因子（特别是 IL-1、IL-6和TNF-α）。由于其在RA中的关键作用， 随着疾病的进展，这些细胞因子已成为RA治疗的主要治疗靶点。其它治疗 方法包括施用类固醇以及抗血管生成药物。然而，这些战略 不能解决DC对T淋巴细胞的RA刺激的根本原因。已知有许多因素 在自身免疫性疾病的实验系统中促进有利的树突细胞应答。然而，在这方面， 这些药剂的全身递送经常导致显著有害的脱靶效应。加州大学的刘易斯实验室， 戴维斯正在开发一种新的，基于生物材料的，微粒“抗疫苗”，用于体内共递送促耐受 因子和自身抗原，靶向DC。具有某些免疫调节剂的DC的外源性调节 已经显示药物诱导促耐受DC表型，以及改善RA。然而，在这方面， 用微粒抗疫苗接种有望纠正异常的自身免疫反应， 避免了与基于DC的细胞疗法相关的问题，例如DC表型稳定性， 存活性和自身抗原多样性。长期目标是开发一种模块化的抗疫苗系统， 自身免疫性疾病治疗本R01提案的总体目标是设计一个多组件MP 抗疫苗以减弱侵袭性鼠RA模型中的RA进展，并研究 抗疫苗接种后的免疫调节。中心假设是这种MP抗疫苗将诱导 通过模型相关自身抗原和耐受诱导因子的靶向递送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tDC， 反应和促进RA的缓解。这一假设将通过追求四个具体目标来检验： 评估材料特性和抗疫苗剂呈递对DC耐受性的影响 2）在FIA-CIA小鼠模型中评估该平台系统限制RA的能力; 3） 使用明确的抗原特异性小鼠模型研究免疫耐受机制;以及4） 调查初步的制造和安全指标，着眼于临床转化。的方法 在申请人看来，这是创新的，因为它通过产生特定的公差而脱离现状- 通过简单的皮下注射聚合物微粒在体内诱导细胞介质。最后， 该系统的研究和开发有可能大大遏制日益蔓延的 美国的自身免疫

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.