The immunological challenges of cell transplantation for the treatment of Parkinson's disease

Abstract

Dopaminergic cell transplantation is an experimental therapy for Parkinson's disease (PD). It has many potential theoretical advantages over current treatment strategies such as providing continuous local dopaminergic replenishment, eliminating motor fluctuations and medication-induced dyskinesias, slowing down disease progression or even reversing disease pathology in the host. Recent studies also show that dopaminergic cell transplants provide long-term neuromodulation in the basal ganglia that simulates the combined effects of oral dopaminergic therapy and surgical therapies like deep brain stimulation, the contemporary therapeutic approach to advanced PD. However, dopaminergic cell transplantation in PD as not been optimized and current experimental techniques have many drawbacks. In published experiments to date of attempted dopaminergic grafting in PD, the major challenges are unacceptable graft-induced dyskinesias or failure of such grafts to exceed the benefits afforded by sham surgery. A deleterious host immune response to the transplant has been implicated as a major putative cause for these adverse outcomes. This article focuses on recent advances in understanding the immunology of the transplantation in PD and possible methods to overcome adverse events such that we could translate cell replacement strategies into viable clinical treatments in the future.

Figure 1. Schematic diagram of a grafting scenario of hRPEC cografted with hES grafts

This diagram depicts hRPEC cografted with hES using stereotactic injection of cell suspension into the striatum. Enlarged schematic of cograft shows possible mechanisms of hRPEC (brown ovoid cells) providing localized immunosuppressed microenvironment that prevent deleterious host immune responses and promote growth and differentiation of hES (blue cells with neurite extensions). A. Possible role of hRPEC secreting immune modulating factors, thus suppressing microglial activation. B. hRPECs inducing apoptosis of cytotoxic T cells, thus decreasing the host cell mediated immune response. C. hRPECs could possibly provide various growth factors (yellow circles and red squares) to promote the growth and differentiation of the hES cells and to provide anti-teratoma effects.