Engineering Immunomodulatory Nanoscale Coatings for Protecting Islet Transplants

项目摘要 临床胰岛移植(CIT)，即将同种异体胰岛注入肝脏，在 通过提供一种基于细胞的方法来模拟正常生理状态的I型糖尿病的长期治疗 对葡萄糖的反应。虽然有希望，但由于以下胰岛功能受损和丧失，它受到了抑制 植入。这种损失归因于对移植的强烈炎症和免疫反应， 主要由细胞表面蛋白和抗原激发。而聚合物封装已经显示出很强的 在小鼠模型中，这种方法的临床转译效果很差。临床疗效不足归因于 标准微胶囊造成的严重营养不足，以及免疫识别 以及随后对外来移植物的先天和适应性反应。在这项提案中，我们试图改变这一标准 通过结合创新的纳米级聚合物涂层和新颖的 功能化策略，以明显调节免疫反应。有证据表明封装可以 与免疫调节剂高度协同，我们寻求产生生物活性、免疫调节涂层 通过生物正交化学不仅可以掩盖供体细胞表面的蛋白质，还可以引导 通过支持环境的产生，对耐受性表型的局部免疫反应。我们 假设胰岛的聚合物嫁接表达用于结合的功能手柄 免疫调节剂和/或纳米粒将通过以下两种方式增强胰岛植入和功能持续时间 掩蔽宿主对表面抗原的识别并产生局部免疫调节环境以支持 移植的胰岛的长期存活。为了验证这一假设，免疫调节剂将是生物- 与胰岛表面的纳米涂层垂直捆绑，并筛选其倾斜宿主的能力 在体外和糖尿病小鼠模型中对耐受表型的免疫反应(目标1)。此外，还可以 产生支持性的嫁接微环境和保护性涂层，活性氧物种(ROS) 纳米粒子将被制成纳米级涂层(目标2)。使用创新的体外筛选平台，理想 将选择免疫调节涂层，随后在糖尿病小鼠模型中进行验证。设计 将稳定的纳米涂层与局部免疫调节相结合的有效策略可能会显著 在没有慢性、系统性疾病的情况下提高胰岛移植的有效性和长期稳定性 免疫抑制。

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.