Engineering Immunomodulatory Nanoscale Coatings for Protecting Islet Transplants

用于保护胰岛移植物的工程免疫调节纳米涂层

• 批准号: 10263374
• 负责人: Cherie L Stabler
• 金额: $ 33.87万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263374
• 关键词: Allogenic; Allografting; Animal Model; Antibodies; Antigens; Benign; Biocompatible Materials; Biological; CD47 gene; Cell Surface Proteins; Cell surface; Cells; Chemistry; Chronic; Clinical; Complex; Custom; Diffusion; Disease Management; Distress; Encapsulated; Engineering; Engraftment; Environment; Failure; Foreign Bodies; Generations; Glucose; Human; Hypoxia; Immune; Immune response; Immune system; Immunologics; Immunomodulators; Immunosuppression; Immunosuppressive Agents; Impairment; Implant; In Vitro; Inflammatory; Inflammatory Response; Infusion procedures; Innate Immune Response; Insulin; Insulin Infusion Systems; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Islet Cell; Islets of Langerhans Transplantation; Laboratories; Liver; Local Therapy; Malnutrition; Masks; Microencapsulations; Mission; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Nutritional; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phenotype; Physiological; Placenta; Polymers; Population; Proteins; Public Health; Quality of life; Reactive Oxygen Species; Replacement Therapy; Risk; Signal Transduction; Site; Surface; Surface Antigens; System; Techniques; Testing; Therapeutic immunosuppression; Tissues; Transforming Growth Factor beta; Translations; Transplantation; Validation; base; blood glucose regulation; capsule; clinical efficacy; cohort; curative treatments; design; diabetic; glucose sensor; glycemic control; hypoglycemia unawareness; immunoregulation; implantation; improved; in vivo; innovation; interest; intrahepatic; islet; mouse model; nanoparticle; nanoscale; novel; prevent; prototype; response; screening; therapy development; translational approach; tumor

Project Summary Clinical islet transplantation (CIT), the infusion of allogeneic islets into the liver, has shown significant promise in the long-term treatment of Type I diabetes by providing a cell-based means to mimic the normal physiological response to glucose. While promising, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological responses to the transplant, primarily instigated by cell surface proteins and antigens. While polymeric encapsulation has shown strong potential in murine models, clinical translational of this approach is poor. Insufficient clinical efficacy is attributed to the significant nutritional deficiencies imposed by standard microencapsulation, as well as immunorecognition and subsequent innate and adaptive responses to the foreign graft. In this proposal, we seek to shift this standard encapsulation paradigm by incorporating both innovative nano-scale polymeric coatings and novel functionalization strategies to distinctly modulate immune responses. With evidence that encapsulation can be highly synergistic with immunomodulatory agents, we seek to generate bioactive, immunomodulatory coatings through bio-orthogonal chemistry that serves to not only to mask donor cell surface proteins but also direct the local immune response towards a tolerogenic phenotype through the generation of a supportive milieu. We hypothesize that the polymer grafting of islets to express functional handles for the conjugation of immunomodulatory agents and/or nanoparticles will enhance islet engraftment and functional duration by both masking host recognition of surface antigens and generating a local immunoregulatory environment to support the long-term survival of the transplanted islets. To test this hypothesis, immunomodulatory agents will be bio- orthogonally tethered to nano-scale coatings on the islet surface and screened for their capacity to skew host immune responses towards tolerogenic phenotypes in vitro and in diabetic murine models (Aim 1). Further, to generate a supportive graft microenvironment and protective coating, reactive oxygen species (ROS) nanoparticles will be into nano-scale coatings (Aim 2). Using innovative in vitro screening platforms, ideal immunomodulatory coatings will be selected, with subsequent validation in diabetic murine models. The design of effective strategies to combine stable nano-scale coatings with local immunomoduation could significantly improve the efficacy and long-term stability of islet transplants in the absence of chronic, systemic immunosuppression.

项目摘要 临床胰岛移植（CIT），同种异体胰岛输注到肝脏中，在 通过提供基于细胞的手段来模仿正常生理的长期治疗I型糖尿病 对葡萄糖的反应。尽管有希望，但它因功能受损而损害 植入。这种损失归因于对移植的强烈炎症和免疫学反应， 主要由细胞表面蛋白和抗原促进。虽然聚合物封装表现出很强的 在鼠模型中的潜力，这种方法的临床翻译很差。临床功效不足 标准微囊塑造施加的明显营养缺乏以及免疫识别 随后对外国移植物的先天和适应性反应。在此提案中，我们试图改变这一标准 通过合并创新的纳米级聚合涂层和新颖的封装范式 功能化策略以明显调节免疫反应。有证据表明封装可以是 与免疫调节剂高度协同作用，我们试图产生生物活性，免疫调节涂层 通过生物正交化学反应，不仅可以掩盖供体细胞表面蛋白，还可以指导 局部免疫反应通过产生支持的环境对耐受性表型。我们 假设胰岛的聚合物嫁接以表达功能手柄 免疫调节剂和/或纳米颗粒将增强胰岛植入和功能持续时间 掩盖宿主对表面抗原的识别并产生局部免疫调节环境以支持 移植胰岛的长期生存。为了检验该假设，免疫调节剂将是生物 正交绑在胰岛表面上的纳米尺度涂料上，并筛选其偏向宿主的能力 在体外和糖尿病鼠模型中对耐受性表型的免疫反应（AIM 1）。此外，要 产生支撑性移植的微环境和保护性涂层，活性氧（ROS） 纳米颗粒将进入纳米尺度涂料（AIM 2）。使用创新的体外筛选平台，理想 将选择免疫调节涂层，随后在糖尿病鼠模型中进行验证。设计 将稳定的纳米级涂料与局部免疫编码相结合的有效策略可以显着 在没有慢性全身性的情况下，提高胰岛移植的疗效和长期稳定性 免疫抑制。