Vaccine strategies in MPTP mouse model of Parkinson's disease and mutated human SOD transgenic mouse model of ALS. To date, no curative or interventional modalities exist for Parkinson's disease or ALS. We demonstrated that adoptive transfer of T cells from donors vaccinated with Copaxone, an indicated drug for multiple sclerosis, ameliorates dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease. More recently, we have shown that natural and adaptive regulatory T cells (Tregs) effectively attenuate neuroinflammation and protects against neurodegeneration. Thus, the major goals of this research project are to define the neuroprotective mechanisms by which natural and induced regulatory T cells function and delineate efficacious therapeutic vaccine strategies that increase Treg function to provide augmented protection in neurodegenerative disorders.
Mechanisms of T cell-mediated regulation of neurodegeneration in Parkinson's disease and ALS. Microglial inflammation plays a major contributing role in several neurodegenerative disorders. Oxidatively-modified proteins such as α-synuclein not only induce microglial inflammation but also are recognized by the adaptive immune system. We have shown in the MPTP model of Parkinson's disease that T cells from nitrated α-synuclein immune donors exacerbate neuroinflammation and neurodegeneration, thus provide an added mechanism by which Parkinson's disease progresses. The goals for this research program address cellular and molecular mechanisms by which adaptive T cell immunity exacerbate microglial inflammation and drive neurodegeneration in Parkinson's disease. These mechanisms will serve as candidate targets for therapeutic strategies to interdict the inflammatory and degenerative cycles in neurodegenerative disorders.
Immune effector cell trafficking by non-invasive SPECT imaging. Until recently, immune effector cell trafficking into the brain was thought to be minimal or have minimal effect; however, recent evidence indicates that both monocyte- and lymphocyte-derived effector cells can profoundly influence disease progression and neuropathy in mouse models of HIV-1 encephalitis and MPTP-induced Parkinson's disease. With the advent of SPECT and MR imaging technologies dedicated to small animal research, non-invasive and longitudinal evaluation of immune effector cell migration into the brain is now possible. Our goals for this research project is to delineate kinetic migration patterns for subsets of immune effector populations and determine the mechanisms by which HIV-1 encephalitis and MPTP-induced inflammatory responses regulate effector cell trafficking into the brain and surrounding lymphoid tissues.
Effects of aging on the T cell repertoire and immune system. With age, peripheral T lymphocyte function is effectively downregulated; however, the mechanisms responsible for age-associated diminution of T cell function are still not fully understood. In Parkinson's disease, for which age is the most prevalent risk factor, anomalies in peripheral T cell subsets are consistently observed. Recent evidence of idiosyncratically skewed representations of T cell receptor variable region of the beta chain families among both CD4+ and CD8+ T cells of elderly humans and aged mice suggests that clonal sequestration of T cells provide yet another mechanism for age-related alterations in T cell function and that declination of the neuroregulatory T cell repertoire is permissive for age- associated neuroinflammation and neurodegeneration associated with Parkinson's disease. The major goals of these studies address mechanistic and functional implications of age-related deviations in the peripheral T cell repertoire of aged mice. Findings of age-related repertoire contraction by accumulation of T cell subsets with different mechanisms for survival will have important implications for vaccination strategies and may further impact explanations of autoimmunity and age-associated susceptibility to infectious, neoplastic and neurodegenerative diseases.
