Engineering Immunomodulatory Nanoscale Coatings for Protecting Islet Transplants

项目摘要 临床胰岛移植（CIT），将同种异体胰岛输注到肝脏中，已经显示出显著的前景， 通过提供基于细胞的手段来模拟正常的生理学过程， 对葡萄糖的反应。虽然有希望，但它受到以下胰岛功能受损和损失的抑制 置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引起。虽然聚合物封装已经显示出强的 尽管该方法在小鼠模型中具有潜在的应用潜力，但该方法的临床转化较差。临床疗效不足归因于 标准微囊化造成的显著营养缺乏，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。在本提案中，我们寻求改变这一标准 通过结合创新的纳米级聚合物涂层和新的 功能化策略以明显调节免疫应答。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，不仅用于掩蔽供体细胞表面蛋白， 通过产生支持性环境，对耐受原性表型产生局部免疫应答。我们 假设胰岛的聚合物接枝表达用于缀合的功能柄， 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 移植胰岛的长期存活。为了检验这一假设，免疫调节剂将是生物- 正交拴系到胰岛表面的纳米级涂层，并筛选它们的能力， 在体外和糖尿病鼠模型中对致耐受性表型的免疫应答（目的1）。进一步谈谈 产生支持性移植物微环境和保护性涂层，活性氧（ROS） 纳米颗粒将进入纳米级涂层（目标2）。使用创新的体外筛选平台， 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 将稳定的纳米级涂层与局部免疫调节相结合的有效策略可以显着 改善胰岛移植的疗效和长期稳定性， 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.