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: 9378465
• 负责人: DAVID M MOSSER
• 金额: $ 4.55万
• 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/9378465
• 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; Clinical; Collaborations; Collagen Type II; Collagen-Induced Arthritis; Conflict of Interest; Development; Disease; Disease model; Dose; Etiology; Goals; Growth Factor; Healthcare Systems; Histology; Human; IACUC; Immunization; Immunize; Inflammation; Inflammatory; Injectable; Injection of therapeutic agent; Innate Immune Response; Interleukin-1; Interleukin-18; Joints; Laboratories; Laboratory Research; Licensing; Maryland; Measures; Modeling; Monitor; Mus; Natural regeneration; Onset of illness; Pathogenicity; 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 immune response; adaptive immunity; base; cost; foot; immunopathology; immunoregulation; 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（由申请人提供）：该项目的标题是“用 Fcγ 受体激活纳米颗粒治疗胶原诱导的关节炎”。我们和其他人已经鉴定并表征了具有有效免疫调节活性的巨噬细胞群。诱导小鼠调节性巨噬细胞 (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。 R-M，小鼠将被注射 Fcγ 受体激活纳米颗粒 (FcγRANP)，我们已建立了一项合作安排，其中 LeukoSight 将与大学的 Christopher Jewell 博士合作生产和纯化与巨噬细胞上的 Fcγ 受体结合的专有多肽。马里兰州，这些多肽将被束缚在纳米颗粒上，并测试它们将巨噬细胞“重新编程”成的能力然后将在两个 CIA 模型中测试具有最高重编程活性的 R-M。在第一个模型中，将在 CFA 中注射 II 型胶原，然后在诱导疾病发作之前施用 FcγRANP。在接下来的几周内将测量疾病的减轻或严重程度的减轻（目标 1），在第二个模型中，通过在 CFA 和 C-II 中注射，将在小鼠中诱导临床明显的 CIA。然后，在小鼠表现出已确定疾病的症状后，将在接下来的两周内对它们注射 FcγRANP，对症状的缓解和病理学的减少进行检查和量化（目标 2）。 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，并开发了一种可靠的检测方法。 Mosser 和 Jewell 博士的大学研究实验室精通多种自身免疫性疾病模型，其中包括 CIA 批准进行的这些研究。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。