Treating collagen-induced arthritis (CIA) with immunoregulatory nanoparticles

 描述(申请人提供)：本项目的题目是“用Fcγ受体激活纳米粒治疗胶原性关节炎”。我们和其他人已经确定并表征了一组具有强大免疫调节活性的巨噬细胞。本方案的目的是诱导小鼠调节性巨噬细胞(R-M)的产生，并确定它们的诱导是否可以减少与胶原性关节炎(CIA)相关的病理。为诱导R-M，给小鼠注射Fcγ受体激活纳米粒(FcγRANP)。我们已经建立了一项合作安排，在这项安排中，LeukoSight将生产和纯化与巨噬细胞上的Fcγ受体结合的专有多肽。在马里兰大学克里斯托弗·朱厄尔博士的合作下，这些多肽将被绑在纳米颗粒上，并测试它们将巨噬细胞重新编程为R-M的能力。然后，具有最高重新编程活动的FCγRANP将在两个型号的中央情报局进行测试。在第一个模型中，小鼠将在CFA中注射II型胶原，然后在致病前给小鼠注射FcγRANP。将在今后几周内衡量发病延迟或严重程度的降低(目标1)。在第二种模型中，小鼠在CFA内注射C-II诱导出临床明显的CIA，当小鼠出现既定疾病症状后，再注射FcγRANP。在接下来的两周内，将对症状的缓解和病理的减少进行检查和量化(目标2)。病理改变与关节滑膜中R-M的出现有关。LeukoSight，Inc.投入了大量的时间和精力来鉴定与巨噬细胞FcγR密切结合的重组多肽，他们已经开发出一种可靠的方法来测量调节巨噬细胞的“重编程”。莫瑟博士和朱厄尔博士的大学研究实验室精通包括CIA在内的各种自身免疫性疾病模型。该大学已经向IACUC提供了进行这些研究的批准。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.