ABSTRACT
Chronic exposure to low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in marmoset monkeys was used to model the prodromal stage of Parkinson's disease (PD), and to investigate mechanisms underlying disease progression and recovery. Marmosets were subcutaneously injected with MPTP for a period of 12weeks, 0.5mg/kg once per week, and clinical signs of Parkinsonism, motor- and non-motor behaviors were recorded before, during and after exposure. In addition, postmortem immunohistochemistry and proteomics analysis were performed. MPTP-induced parkinsonian clinical symptoms increased in severity during exposure, and recovered after MPTP administration was ended. Postmortem analyses, after the recovery period, revealed no alteration of the number and sizes of tyrosine hydroxylase (TH)-positive dopamine (DA) neurons in the substantia nigra. Also levels of TH in putamen and caudate nucleus were unaltered, no differences were observed in DA, serotonin or nor-adrenalin levels in the caudate nucleus, and proteomics analysis revealed no global changes in protein expression in these brain areas between treatment groups. Our findings indicate that parkinsonian symptoms can occur without detectable damage at the cellular or molecular level. Moreover, we show that parkinsonian symptoms may be reversible when diagnosed and treated early.
Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Behavior, Animal/drug effects , Disease Progression , Dopaminergic Neurons/metabolism , Neostriatum/metabolism , Neurotoxins/pharmacology , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/metabolism , Recovery of Function , Substantia Nigra/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/administration & dosage , Animals , Callithrix , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Female , MPTP Poisoning/chemically induced , MPTP Poisoning/metabolism , MPTP Poisoning/pathology , Male , Neostriatum/pathology , Neurotoxins/administration & dosage , Parkinson Disease, Secondary/pathology , Proteomics , Substantia Nigra/drug effects , Substantia Nigra/pathologyABSTRACT
The identification of FOXP3 expressing cells in recipients of an allograft, in particular inside the graft itself, may help to define criteria for immunosuppressive drug withdrawal. We therefore examined expression patterns of several regulatory T-cell (Treg) markers in kidney biopsies and kidney tissues taken at the time of graft rejection from monkeys treated with alpha CD40, alpha CD86, CsA, a combination of these or after drug withdrawal. In advanced stages of rejection, organized multifocal nodular infiltrates, with mature dendritic cells, T cells and B cells could be found. In contrast, interstitial infiltrates contain more macrophages, less T cells and few B cells. Cells expressing FOXP3, CD25 and CTLA-4 were mainly found in nodular infiltrates of rejected tissue samples. A significant correlation was found between the percentage FOXP3(+) cells and markers for rejection, i.e. creatinine levels and Banff interstitial and tubular infiltrate scores. The type of immunosuppression did not influence the percentage of cells expressing Treg markers. Three animals with prolonged drug-free survival showed low numbers of FOXP3(+) cells. We conclude that the presence of intragraft FOXP3(+) cells is not confined to tolerated grafts, but should be considered as part of the normal immune response during rejection.
