Biomarkers and Immunotherapy for Parkinson's Disease
Rapid Response Innovation Awards, 2010
We theorize that the interplay between the immune system and the brain plays a substantive role in the progression of Parkinson’s disease. Moreover, we posit that the immune system becomes dysfunctional as a result of the continuous presence of misfolded, aggregated, and nitrated proteins released from dead or dying nigral neurons and present in the lymphoid system. The deficit occurs in a class of lymphocytes present in blood and as such may be used as a biomarker for disease. Correcting the deficit may also be a target for therapy.
The project will involve collecting blood specimens from Parkinson’s disease patients and analyzing specific subsets of lymphocytes by “state of the art” immunological assays. Such an analysis will allow the determination of specific immune deficits that would occur in disease. Comparisons with patient care givers matched by age and demographics would serve as controls. A comprehensive set of functional assays for blood cells will be performed to precisely define any/all deficit and the means to correct it. Such an analysis could yield new sets of biomarkers to stage disease and its progression with an eye towards future investigations towards determining whether correction of the dysfunction would improve disease outcomes.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently there are no blood tests that would diagnosis Parkinson’s disease or monitor disease progression. Thus, finding a suitable test is of significant importance as the disease is commonly confused with others and therapies are often delayed. If an interplay between what is ongoing in brain and what is present circulating in blood is operative it would open up new avenues for treatment that have not been previously considered.
It is anticipated that a deficit in the numbers and/or function of classes of peripheral blood lymphocytes may be found and could be readily translated for human use and in developing therapeutics. This would also permit new insights in the cause of disease and new directives into diagnosis and developmental therapeutics.
Evidence implicating the immune system in the biology of Parkinson’s diseases (PD) abounds. We and others have shown that aggregated and aberrant species of a-syn, including nitrated a-syn (N-α-syn), activate glial cells leading to increased oxidative stress and increased neuroinflammation. This effects dopamine neuron loss in pre-clinical models of human disease. These same protein species are found in Lewy bodies in PD brain tissue. We observed N-a-syn is present in draining cervical lymph nodes of PD pre-clinical models where it induces a robust lymphocyte response. We also showed that T cells can also ameliorate disease, while others make disease worse by effecting neuronal degeneration. Based on these observations, we hypothesized that immunological alterations would be present and be part of the disease complex for PD. Most importantly the means to control such immune responses could be used as a therapeutic strategy to halt disease progression. To test our hypothesis, whole blood samples were collected from clinically diagnosed PD patients and healthy caregivers recruited through the University of Alabama at Birmingham (UAB) Movement Disorders Clinic; Neurological consultants of Nebraska (NCNE), and the Department of Neurological Sciences at the University of Nebraska Medical Center (UNMC). Patients and caregivers provided written informed consent using a UAB IRB-approved form or a UNMC IRB-approved form. PD was diagnosed using UK Brain Bank clinical criteria. Controls were identified from among spouses and caregivers. A brief screening was conducted to exclude controls with symptoms likely to represent PD. Data on patients were collected using standard PD-DOC data forms: Demographics, Primary Diagnosis, PD Features, Family History, Environmental Risk, UPDRS 1-3, Hoehn and Yahr and Study Related Medication. At UAB, whole blood samples, 50 ml, were collected in heparin-coated tubes, coded and shipped overnight to the University of Nebraska Medical Center Movement Disorders Laboratory. At NCNE and UNMC, whole blood samples, 70 ml, were collected in heparin-coated tubes. To measure T cell phenotype, we detected cell surface antigens and intracellular FoxP3 expression with fluorescently labeled antibodies using a FACSCalibur flow cytometer.
Samples from PD patients (n = 32) and caregivers (n = 25) were collected and analyzed in an unblinded fashion. Flow cytometric analysis of peripheral blood mononuclear cells in these samples demonstrated alterations in Treg and Teff phenotypes and frequencies in PD patients compared to age-matched but disease-free caregivers. The Treg population was found to have a more memory phenotype in PD patients, while the Teff population has a more naïve phenotype in PD, suggesting a decrease in homeostatic proliferation of naïve Treg with increased production of memory Teff in PD. This is indicative of a strong immune response, and is often seen in autoimmunity.
We propose that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. Our works support the fact that immune regulation can be used as a treatment strategy in PD with the singular goal of restoring homeostatic glial responses in improving disease outcomes. New means to optimize immunization schemes and measure their clinical efficacy can be developed as a result of these studies.
Margaret R. Larson Professor of Internal Medicine and Infectious Diseases, and Chair of the Department of Pharmacology and Experimental Neuroscience at University of Nebraska Medical Center
Location: Omaha, Nebraska, United States