Microglia inflammation contributes, in significant measure, to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) during idiopathic Parkinson's disease (PD). Attenuation of such inflammation could attenuate disease. To this end we show that microglial deactivation responses, induced by vaccination, in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxicated mice improves dopaminergic neuronal survival. This was achieved by adoptively transferring spleen cells from copolymer-1 (Cop-1) immunized mice to MPTP-treated recipients. Spleen cells from ovalbumin (OVA) injected mice failed to affect neuronal protection. Thus, our preliminary works show that protection from dopaminergic neurodegeneration can be achieved by adaptive immunity with T cells specific for Cop-1. Based on response kinetics, antigen specificity, and functional adaptive T cell immune responses, we predict that the mechanism(s) of neuroprotective immunity can be realized and could provide novel treatment strategies for human disease. Our hypothesis posits that protection from dopaminergic neurodegeneration by Cop-1 vaccination is generated through immune cell-mediated mechanisms with specificity for Cop-1 peptides and self-antigens. To investigate this we will adoptively transfer T lymphocytes, B cells and monocytes from Cop-1 immunized mice into MPTP-treated animals. Neuroprotection will be assessed by numbers of dopaminergic neurons, neurotransmitter levels, and neuronal metabolites by magnetic resonance spectroscopic imaging (MRSI). Immune cell populations, proven relevant to neuroprotection will be evaluated for the expression of gene products that are cell population specific as candidates for neuroprotection. Genetic fingerprint analysis will include cDNA microarray analysis and proteomics. This approach takes advantage of an integrated and well-established research program within the Center for Neurovirology and Neurodegenerative Disorders and builds upon research activities in PD supported previously through private donations. These approaches could prove useful for treatment of human PD.
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