The Role of Subclinical Rejection in Graft-mediated Dyskinesias

The results of two recent Parkinson's disease (PD) clinical trials designed to replace cells lost to the disease have documented that replacing these cells can have negative side effects. In particular, a significant percentage of subjects grafted with the replacement cells developed debilitating 'off-medicine' dyskinesias. Dyskinesias are unwanted, excessive, involuntary movements. The reasons for this adverse side effect are not known, however, some factors are beginning to emerge as possible candidates. Our group of investigators has noted that the emergence of these dyskinesias seems to appear after the patients are withdrawn from immunosuppressive therapy, which is given to prevent rejection of the grafted cells. We have designed a series of experiments to test whether activation of the brain's immune system following withdrawal of immunosuppression results in changes in dyskinetic behavior and whether these potential changes might result from alterations in the contacts that the grafted cells make with the host brain. These studies will be investigated in a pre-clinical model of parkinsonism that has many similarities to PD including development of dyskinetic movements following repeated administration of the antiparkinsonian drug levodopa. Previous studies in our lab have shown that under particular conditions, grafted cells can worsen dyskinesia in these rats similar to that seen in human patients. The current studies, funded by the MJFF will allow us explore whether activation of the brain's immune system plays a role in producing the negative side-effects related to grafting. Understanding the mechanism behind this deleterious side-effect will be very important if this promising therapeutic approach is to be beneficial for individuals suffering from PD.