Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-012-9402-z) contains supplementary material, which is available to authorized users.

Innate and adaptive immune responses can speed nigrostriatal neurodegeneration in Parkinson’s disease (PD). We posit that GM-CSF can attenuate such responses. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice, GM-CSF given prior to MPTP protected nigral dopaminergic neurons coincident with altered microglial morphologies and regulatory T cell (Treg) induction. Adoptive transfer of GM-CSF-induced Treg to MPTP mice protected nigral neurons and their striatal termini. Gene expression analyses revealed novel immune-based neuronal protection pathways. The results provide evidence that GM-CSF modulation of immunity could be of clinical benefit for PD.

We have recently reported that left atrial injections of the thromboxane A 2 (TXA 2 ) mimetic, (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2 -oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid (U46619), induced ventricular arrhythmias in the anesthetized rabbit. Data from this study led us to hypothesize that TXA 2 may be inducing direct actions on the myocardium to induce these arrhythmias. The aim of this study was to further elucidate the mechanism responsible for these arrhythmias. We report that TXA 2 R is expressed at both the gene and protein levels in atrial and ventricular samples of adult rabbits. In addition, TXA 2 R mRNA was identified in single, isolated ventricular cardiac myocytes. Furthermore, treatment of isolated cardiac myocytes with U46619 increased intracellular calcium in a dose-dependent manner and these increases were blocked by the specific TXA 2 R antagonist, 7-(3-((2-((phenylamino)carbonyl)-hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid (SQ29548). Pretreatment of myocytes with an inhibitor of inositol trisphosphate (IP 3 ) formation, gentamicin, or with an inhibitor of IP 3 receptors, 2-aminoethoxydiphenylborate (2-APB), blocked the increase in intracellular calcium. In vivo pretreatment of anesthetized rabbits with either gentamicin or 2-APB subsequently inhibited the formation of ventricular arrhythmias elicited by U46619. These data support the hypothesis that TXA 2 can induce arrhythmias via a direct action on cardiac myocytes. Furthermore, these arrhythmogenic actions were blocked by inhibitors of the IP 3 pathway. In summary, this study provides novel evidence for direct TXA 2 -induced cardiac arrhythmias and provides a rationale for IP 3 as a potential target for the treatment of TXA 2 -mediated arrhythmias.

Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders. KeywordsAlzheimer's disease; amyotrophic lateral sclerosis; fullerene; nanomedicine; nanoparticles; neurodegeneration; neuroregeneration; Parkinson's disease; stroke A significant challenge for 21st century medicine is to positively affect the clinical outcomes for mind, motor and behavioral abnormalities that follow debilitating CNS conditions linked to aging, infections and degeneration. These include, but are not limited to: Alzheimer's and Parkinson's diseases (AD and PD), stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and HIV-1-associated neurocognitive disorders (HAND) [1][2][3][4][5][6]. A myriad of factors affect disease onset and progression that include host genetics, lifestyle, environment, behavior, immunity and aging [7].Unfortunately, with the exception of anti-microbials, few therapies are currently available that can affect disease outcomes. Generally, modern medicine used for treatment of neurodegenerative disorders is at best palliative and manages only the symptoms [8,9]. Adding another level of difficulty is a paucity of early and accurate detection of biomarkers. This is especially important as most neurodegenerative disorders are difficult to diagnose and disease processes are operative for years before either the patient or physician is clear on a specific diagnosis. Another impediment for diagnosis rests with the underlying pathogenic mechanisms for neurodegenerative disorders that include modification, accumulation and aggregation of host proteins, disruption of blood flow, altered tissue homeostasis, low level infection, and/or †Author for correspondence: [10][11][12][13][14][15]. All of these issues could be positively affected if an intervention was made before permanent and long-lasting neural damage ensued. Unfortunately, the translation of promising results from laboratory and animal studies to clinical practice has met with mixed results.We posit that nanotechnology-directed modalities that can specifically target a damaged CNS hold considerable promise if unwanted side effects and tissue barriers can be overcome [16][17][18]. Based on t...

J. Neurochem. (2010) 114, 1261–1276. Abstract Neurodegenerative diseases, notably Alzheimer’s and Parkinson’s diseases, are amongst the most devastating disorders afflicting the elderly. Currently, no curative treatments or treatments that interdict disease progression exist. Over the past decade, immunization strategies have been proposed to combat disease progression. Such strategies induce humoral immune responses against misfolded protein aggregates to facilitate their clearance. Robust adaptive immunity against misfolded proteins, however, accelerates disease progression, precipitated by induced effector T cell responses that lead to encephalitis and neuronal death. Since then, mechanisms that attenuate such adaptive neurotoxic immune responses have been sought. We propose that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. This review summarizes advances in immune regulation to achieve a homeostatic glial response for therapeutic gain. Promising new ways to optimize immunization schemes and measure their clinical efficacy are also discussed.