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

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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.