Local immunosuppression to improve the welfare of animals in neural transplantation experiments

细胞移植是一种治疗神经系统疾病如帕金森病的新疗法，其目的是通过替换因疾病而退化的细胞来改善症状。为了确定移植到患者体内的细胞是否安全并具有功能功效，必须首先在动物模型（通常是啮齿动物）中进行严格的测试。由于这些实验需要将人细胞移植到啮齿动物宿主中，因此需要抑制免疫系统以防止移植细胞的排斥并允许评估整合和功能。目前，这需要通过每日注射给予免疫抑制剂药物进行长期治疗，这可能会导致动物的压力和副作用。我们提出的研究旨在通过在一种新型微粒药物递送系统中与移植细胞一起递送免疫抑制剂治疗，完全避免或减少对这些日常注射的需要。这将大大减少用于一系列疾病的细胞疗法的细胞的基本临床前测试所需的动物程序的数量。我们已经成功地开发了微粒，可以成功地注射到啮齿动物的大脑中，而不会引起炎症。这些已经装载了免疫抑制剂他克莫司，一种经常用于器官移植的药物，并缓慢释放药物至少一个月。我们还表明，这种剂量的药物可以有效地预防大鼠对周围神经移植的免疫反应。因此，在本项目中，我们的目标是在帕金森病大鼠模型中测试我们的新型微粒免疫抑制剂递送系统，其中大鼠将接受人类细胞移植到大脑中。我们将比较治疗和未治疗动物在3周时对移植细胞的免疫应答，以及16周后的移植物存活和整合。

Cell transplantation is a novel therapy for disorders of the nervous system such as Parkinson's disease, where the aim is to improve symptoms by replacing cells which have degenerated due to the disease. In order to determine that cells to be transplanted in patients are safe and have functional efficacy, they must first be rigorously tested in animal models, frequently rodents. As these experiments require the transplantation of human cells into rodent hosts, suppression of the immune system is required to prevent rejection of transplanted cells and allow integration and function to be assessed. This currently requires long term treatment with immunosuppressant drugs delivered via daily injections, which can lead to stress and side effects in the animals. Our proposed research aims to avoid altogether or reduce the need for these daily injections, by delivering the immunosuppressant treatment alongside transplanted cells in a novel microparticle drug delivery system. This will dramatically reduce the number of animal procedures required in the essential pre-clinical testing of cells to be used in cell therapies for a range of diseases. We have successfully developed microparticles which can be successfully injected into the rodent brain without causing inflammation. These have been loaded with the immunosuppressant tacrolimus, a drug frequently used in organ transplantation, and slowly release the drug for at least one month. We have also shown this dose of drug to be effective at preventing the immune response to peripheral nerve transplants in rats. Therefore, in this project we aim to test our novel microparticle immunosuppressant delivery system in a rat model of Parkinson's disease, in which rats will receive transplants of human cells to the brain. We will compare the immune response to transplanted cells at 3 weeks in treated and untreated animals, and graft survival and integration after 16 weeks.