Cell therapy for Parkinson's disease: A translational approach to assess the role of local and systemic immunosuppression

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases. However, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation and differentiation. Parkinsonian primates received wild-type or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 months. Recovery was associated with restoration of dopaminergic activity detected both by PET imaging and histological examination. Local infiltration by T-cells and CD80/86-positive microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that, in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T-cell costimulation. This article is protected by copyright. All rights reserved.