Treating collagen-induced arthritis (CIA) with immunoregulatory nanoparticles

用免疫调节纳米颗粒治疗胶原诱导的关节炎 (CIA)

• 批准号: 9047174
• 负责人: DAVID M MOSSER
• 金额: $ 17.95万
• 依托单位: LEUKOSIGHT, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047174
• 关键词: Acute; Affect; Aftercare; Agreement; American; Angiogenic Factor; Animals; Ankle; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Binding; Biological Assay; Biological Markers; Biomedical Engineering; Cells; Chairperson; Chronic; Collaborations; Collagen Type II; Collagen-Induced Arthritis; Conflict of Interest; Development; Disease; Disease model; Dose; Etiology; Goals; Growth; Healthcare Systems; Histology; Human; IACUC; Immune response; Immunization; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-1; Interleukin-18; Joints; Laboratories; Laboratory Research; Licensing; Maryland; Measures; Modeling; Monitor; Mus; Natural regeneration; Onset of illness; Pathology; Phase; Population; Production; Recombinants; Research; Resolution; Rheumatoid Arthritis; Role; Saline; Senior Scientist; Series; Severities; Severity of illness; Small Business Technology Transfer Research; Swelling; Symptoms; Synovial Membrane; Testing; Therapeutic; Time; Tissues; Universities; Visual; Work; adaptive immunity; base; cost; foot; immunopathology; improved; inhibitor/antagonist; innovation; macrophage; materials science; migration; mouse model; nanoparticle; polypeptide; professor; public health relevance; receptor; response

 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.

 描述（申请人提供）：该项目的标题是“用Fcγ受体激活纳米颗粒治疗胶原蛋白诱导的关节炎”。我们和其他人已经鉴定并鉴定了具有强大免疫调节活性的巨噬细胞群。本提案的目标是诱导小鼠中调节性巨噬细胞（R-M）的产生，并确定其诱导是否可以减少与胶原诱导的关节炎（CIA）相关的病理学。为了诱导 R-M，将给小鼠注射 Fcγ 受体激活纳米颗粒 (FcγRANP)。我们已经建立了一项合作安排，其中 LeukoSight 将生产和纯化与巨噬细胞上的 Fcγ 受体结合的专有多肽。与马里兰大学的 Christopher Jewell 博士合作，这些多肽将被束缚在纳米粒子上，并测试它们将巨噬细胞“重新编程”为 R-M 的能力。然后将在两种 CIA 模型中测试具有最高重编程活性的 FcγRANP。在第一个模型中，小鼠将被注射 CFA 中的 II 型胶原蛋白，然后在诱导疾病之前施用 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）。在第二种模型中，通过注射 CFA 中的 C-II 在小鼠中诱导临床明显的 CIA，然后在小鼠表现出既定疾病的症状后，将注射 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）。病理学的减少将与关节滑膜中 R-M 的出现相关。 LeukoSight, Inc 投入了大量时间和精力来鉴定与巨噬细胞 FcγR 强烈结合的重组多肽，并且他们开发了一种可靠的测定法来测量调节性巨噬细胞“重编程”。博士的大学研究实验室。 Mosser 和 Jewell 精通多种自身免疫性疾病模型，包括 CIA。该大学已获得 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。