Treating collagen-induced arthritis (CIA) with immunoregulatory nanoparticles

 描述（申请人提供）：本项目名称为“Fcγ受体激活纳米颗粒治疗胶原诱导的关节炎”。我们和其他人已经鉴定并鉴定了一群具有强免疫调节活性的巨噬细胞。本提案的目标是诱导小鼠中调节性巨噬细胞（R-M巨噬细胞）的产生，并确定它们的诱导是否可以减少与胶原诱导的关节炎（CIA）相关的病理。为了诱导R-M β，将向小鼠注射Fcγ受体活化纳米颗粒（FcγRANP）。我们已经建立了一个合作安排，LeukoSight将生产和纯化与巨噬细胞上的Fcγ受体结合的专有多肽。在与马里兰州大学的克里斯托弗朱厄尔博士的合作中，这些多肽将被拴在纳米颗粒上，并测试它们将巨噬细胞“重编程”为R-M的能力。然后在两种CIA模型中检测具有最高重编程活性的FcγRANP。在第一个模型中，将向小鼠注射II型胶原的CFA溶液，然后在诱导疾病前给予FcγRANP。将在接下来的几周内测量疾病发作的延迟或严重程度的降低（目标1）。在第二个模型中，通过注射C-II的CFA溶液诱导小鼠出现临床上明显的CIA，然后在小鼠显示出已确立疾病的症状后，注射FcγRANP。在接下来的两周内，将检查和量化症状的缓解和病理学的减少（目标2）。病理学的减少与关节滑膜中R-M的出现相关。LeukoSight，Inc已投入大量时间和精力来鉴定与巨噬细胞FcγR紧密结合的重组多肽，并开发了一种可靠的测定方法来测量调节性巨噬细胞“重编程”。莫瑟博士和朱厄尔博士的大学研究实验室精通各种自身免疫性疾病模型，包括CIA。该大学已提供IACUC批准进行这些研究。这些研究的目的是证明使用基于纳米颗粒的巨噬细胞重编程作为治疗自身免疫性疾病的治疗策略的可行性。

 DESCRIPTION (provided by applicant): The title of this project is "Treating Collagen-induced Arthritis with Fcγ Receptor Activating Nanoparticles". We and others have identified and characterized a population of macrophages with potent immunorergulatory activity. The goal of the present proposal is to induce the production of regulatory macrophages (R-M) in mice, and determine whether their induction can decrease pathology associated with collagen-induced arthritis (CIA). To induce R-M, mice will be injected with Fcγ Receptor Activating Nanoparticle (FcγRANP). We have established a collaborative arrangement in which LeukoSight will produce and purify proprietary polypeptides that bind to Fcγ receptors on macrophages. In collaboration with Dr. Christopher Jewell, at the University of Maryland, these polypeptides will be tethered to nanoparticles and tested for their ability to "reprogram" macrophages into R-M. FcγRANP with the highest reprogramming activity will then be tested in two models of CIA. In the first model, mice will be injected with Type II Collagen in CFA and then administered FcγRANP prior to the induction of disease. A delay in the onset of disease or a decrease in severity will be measured over the next several weeks (Aim 1). In the second model, clinically apparent CIA will be induced in mice by the injection of C-II in CFA and then after the mice show symptoms of established disease, they will be injected with FcγRANP. Over the next two weeks the resolution of symptoms and a decrease in pathology will be examined and quantified (Aim 2). The decrease in pathology will be correlated with the appearance of R-M in the joint synovium. LeukoSight, Inc has invested substantial time and effort into identifying recombinant polypeptides that bind avidly to macrophage FcγR and they have developed a reliable assay to measure regulatory macrophage "reprogramming". The university research laboratories of Drs. Mosser and Jewell have proficiency in a variety of autoimmune disease models, including CIA. The University has provided IACUC approval to perform these studies. The goal of these studies is to demonstrate the feasibility of using nanoparticle-based macrophage reprogramming as a therapeutic strategy to treat autoimmune diseases.