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

细胞移植是治疗帕金森氏症等神经系统疾病的一种新疗法，其目的是通过替换因疾病而退化的细胞来改善症状。为了确定要移植到患者体内的细胞是安全的和具有功能功效的，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类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反应，并允许对整合和功能进行评估。目前，这需要通过每天注射免疫抑制药物进行长期治疗，这可能会导致动物的压力和副作用。我们提议的研究旨在通过在一种新的微粒药物传递系统中与移植细胞一起传递免疫抑制治疗来完全避免或减少对这些日常注射的需求。这将大大减少在一系列疾病的细胞治疗中使用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出微粒，可以成功地注射到啮齿动物的大脑中，而不会引起炎症。这些药物中装入了免疫抑制剂他克莫司，这是一种经常用于器官移植的药物，并在至少一个月内缓慢释放药物。我们还证明了这种剂量的药物在预防大鼠周围神经移植的免疫反应方面是有效的。因此，在这个项目中，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药物传递系统，在该模型中，大鼠将接受人类细胞脑部移植。我们将比较治疗动物和未治疗动物在3周时对移植细胞的免疫反应，以及16周后移植物的存活和整合。

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.