Evaluation of Immune-Modulating Therapies For Parkinson\u27s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, second only to Alzheimer’s disease (AD). It is characterized by a progressive loss of dopaminergic neurons along the nigrostriatal axis and the formation of proteinaceous inclusions of alpha-synuclein (α-syn). Secondary to the loss of dopaminergic neurons is a progression in motor and non-motor symptoms. Motor symptoms are characterized by slowness in movement, stiffness and tremor. Non-motor symptoms include depression, constipation, sleep abnormalities and loss of sense of smell. The cause of disease remains incompletely understood. However, age, genetics, environment, viral infection, and interplay between the innate and adaptive immune system can contribute to disease onset and progression. Currently, treatments are palliative, and no known intervention to halt disease progression exists. Drug therapies employ dopamine or a dopamine precursor that affect neurotransmitter signaling while showing no effect on the neurodegenerative process. Nonetheless, the available therapies improve walking, movement and tremor debilities. Therefore, it remains essential that therapies are developed to combat PD itself rather than simply alleviating symptoms. Neuroinflammation and immunity can speed nigrostriatal degeneration in PD. The neuroinflammatory cascade begins with aggregation of misfolded or post-translationally modified alpha synuclein (α-syn) resulting in the occurrence of neuronal cell death and the presence of chronically activated glia. Such changes in the glial phenotypes can affect the central nervous system (CNS) microenvironment by producing pro-inflammatory factors that speed nigrostriatal degeneration. To halt or slow disease progression, a change in the microenvironment of the brain may be necessary. One potential mechanism to achieve this goal is through the induction and/or enhancement of immune-modulating cells such as regulatory T cells (Tregs). Tregs maintain immune homeostasis by suppressing pro-inflammatory immune responses, such as those associated with neuroinflammation and PD. Furthermore, Tregs taken from PD patients compared to control subjects lack the capacity to suppress proliferation of other immune cells, suggesting a dysfunctional Treg response associated with disease. Previously, our laboratory utilized granulocyte-macrophage colonystimulating factor (GM-CSF) to restore Treg numbers and function in animal models and a clinical trial. This cytokine induced a neuroprotective phenotype when assessed in animal models; however, in the clinical setting, some mild to moderately severe adverse events were identified. Thus, it remains important to identify different means for drug delivery or other compounds with Treg-inducing activity and without potential untoward side effects for easy translation to human use. With this goal in mind, our lab evaluated the efficacy of vasoactive intestinal peptide (VIP) analogs in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) mouse model of PD. Our data indicate that treatment with a stable VIP analog results in a decrease in pro-inflammatory cytokine production, decrease in microglial reactivity, increase in neuron survival, and increase in suppressive immune phenotypes. Taken together, these findings support the use of VIP as a potential immunotherapy for the treatment of PD

Understanding the construct of human trust in domestic service robots

Simple robots are already being deployed and adopted by some consumers for use at home. The robots currently in development for home use are far more sophisticated. However, it was not know the extent to which humans would trust them. The purpose of this study was to identify factors that influence trust in domestic service robots across a range of users with different capabilities and experience levels. Twelve younger adults (aged 18-28) and 24 older adults (12 low technology users and 12 high technology users) aged 65-75 participated in a structured interview, card-sorting task, and several questionnaires. Most participants had heard about or seen robots, but indicated they had little experience with them. However, most had positive opinions about robots and indicated they would trust a robot to assist with tasks in their homes, though it was dependent on the task. Before making a decision to trust a robot, participants wanted to know a lot of information about the robot such robot reliability, capabilities, and limitations. When asked to select their trust preference for human versus robot assistance for specific tasks, participants had preferences for both human and robot assistance, although it was dependent on the task. Many participants defined trust in robots similar to definitions of trust in automation (Ezer, 2008; Jian et al., 2000). Additionally, they had high rates of selection for adjectives used to describe trust in automation and also selected some adjectives used to describe trust in humans when asked to select characteristics they most associated with trustworthy and untrustworthy robots. Overall, there were some differences between age and technology experience groups, but there were far more similarities. By carefully considering user needs, robot designers can develop robots that have the potential to be adopted by a wide range of people.Ph.D

Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders.

Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer\u27s disease and Parkinson\u27s disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of antigen-specific CD4+ T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal survival. The destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T cells. Temporally, immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the CNS. Immune responses with predominate T cell subtypes may differentially manifest migratory, regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific stimuli. The final result is altered glial and neuronal behaviors that influence the disease course. Thus, discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression

The Texas Earth and Space Science (TXESS) Revolution: A Model for the Delivery of Earth Science Professional Development to Minority-Serving Teachers

At the time of publication K.K. Ellins, E. Snow, H.C. Olson, M. Willis, and J. Olson were at the University of Texas Austin, E. Stocks and M.R. Odell were at the University of Texas at Tyler.The Texas Earth and Space Science (TXESS) Revolution was a 5-y teacher professional development project that aimed to increase teachers' content knowledge in Earth science and preparing them to teach a 12th-grade capstone Earth and Space Science course, which is new to the Texas curriculum. The National Science Foundation–supported project was designed around six principles that proved to be critical to in its success: (1) model best practices in workshop presentations, (2) use authentic Earth science data and cybertechnology to teach up-to-date content, (3) provide ongoing training to cohorts of learners over a 2-y period, (4) involve geoscience consortia and programs that can provide proven content for classrooms, (5) use ongoing evaluations to guide future workshops, and (6) provide opportunities for leadership development through participation in research and curriculum development projects. The project served 177 science teachers by supporting them with the pedagogical, technological, and scientific tools to teach modern geoscience. TXESS Revolution teachers directly impacted more than 29,000 students, of which about 69% are nonwhite, by exposing students in Texas to the geosciences and planting the seeds for them to pursue geoscience as a field of study. Using a train-the-trainer approach, TXESS Revolution teachers shared their professional development with other Texas teachers, strengthening Earth science education at all K–12 levels throughout the state, an impact that extends beyond preparation in Earth and space science.Petroleum and Geosystems Engineerin

Differential Microglial Responses Induced by N-a-Synuclein-Specific Effector T Cell Clones

Parkinson\u27s disease (PD) is a neurodegenerative movement disorder in which symptoms derive from deficits in dopamine neurotransmitter levels secondary to loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) associated with misfolding and accumulation of α−synuclein. Neuroinflammation via microglia and T effector cells (Teffs) contribute to dopaminergic neuronal cell death. Recognition of cytokine profiles of pro-inflammatory microglia is not well understood and serve as potential therapeutic targets to reduce neuroinflammation. Recent studies demonstrated a novel Th17.1 Teff clonotype increases neurotoxicity. The aim of this study was to demonstrate in vitro cytokine responses by BV-2 microglia induced by Th1, Th17, and Th17.1 clonotypes to assess neuroinflammation mechanisms in PD. Cytokine responses by BV-2 microglia co-cultured with activated Teff clonotypes were analyzed using a cytokine membrane array. Co-culture with Teffs led to significant increases in the majority of cytokine responses from BV-2 microglia compared to control. Cross group analysis relative expression demonstrated variation in cytokine profiles produced between microglia treated with different Teff clonotypes, especially with regard to IFNγ, MIG, MIP-1α, TIMP-1, RANTES, SDF-1, and IL-12 p40/p70. Ingenuity Pathway Analysis (IPA) of cytokines displaying significant relative expression levels for each Teff clonotype showed Th1- and Th17- treated BV-2 microglia demonstrated pathways related to cellular movement, hematological development and function, and immune trafficking while Th17.1-treated microglia upregulated pathways related to disorders of connective tissues, inflammation, and organismal injury. In conclusion, Th1, Th17, and Th17.1 Teffs treatment of BV-2 microglia led to upregulation of most pro-inflammatory cytokines and pathways. However, specific Teff clonotype culture with BV-2 microglia displayed different cytokine profile responses through varying relative expression profiles with significant differences related to IFNγ, MIG, MIP-1α, TIMP-1, RANTES, SDF-1, and IL12 p40/p70 delineating alternative inflammatory pathways. These results provide relevant targets for strategies to attenuate neuroinflammation and protect dopaminergic neurons in PD.https://digitalcommons.unmc.edu/emet_posters/1005/thumbnail.jp

A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson\u27s Disease

A paradigm shift has emerged in Parkinson\u27s disease (PD) highlighting the prominent role of CD4+ Tregs in pathogenesis and treatment. Bench to bedside research, conducted by others and our own laboratories, advanced a neuroprotective role for Tregs making pharmacologic transformation of immediate need. Herein, a vasoactive intestinal peptide receptor-2 (VIPR2) peptide agonist, LBT-3627, was developed as a neuroprotectant for PD-associated dopaminergic neurodegeneration. Employing both 6-hydroxydopamine (6-OHDA) and α-synuclein (α-Syn) overexpression models in rats, the sequential administration of LBT-3627 increased Treg activity without altering cell numbers both in naïve animals and during progressive nigrostriatal degeneration. LBT-3627 administration was linked to reductions of inflammatory microglia, increased survival of dopaminergic neurons, and improved striatal densities. While α-Syn overexpression resulted in reduced Treg activity, LBT-3627 rescued these functional deficits. This occurred in a dose-dependent manner closely mimicking neuroprotection. Taken together, these data provide the basis for the use of VIPR2 agonists as potent therapeutic immune modulating agents to restore Treg activity, attenuate neuroinflammation, and interdict dopaminergic neurodegeneration in PD. The data underscore an important role of immunity in PD pathogenesis

Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice.

UNLABELLED: Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP\u27s rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration used to model Parkinson\u27s disease (PD). Survival of tyrosine hydroxylase neurons in the substantia nigra was determined by stereological tests after MPTP intoxication in mice pretreated with either VIPR1 or VIPR2 agonist or after adoptive transfer of splenic cell populations from agonist-treated mice administered to MPTP-intoxicated animals. Treatment with VIPR2 agonist or splenocytes from agonist-treated mice resulted in increased neuronal sparing. Immunohistochemical tests showed that agonist-treated mice displayed reductions in microglial responses, with the most pronounced effects in VIPR2 agonist-treated, MPTP-intoxicated mice. In parallel studies, we observed reductions in proinflammatory cytokine release that included IL-17A, IL-6, and IFN-γ and increases in GM-CSF transcripts in CD4(+) T cells recovered from VIPR2 agonist-treated animals. Moreover, a phenotypic shift of effector to regulatory T cells was observed. These results support the use of VIPR2-selective agonists as neuroprotective agents for PD treatment. SIGNIFICANCE STATEMENT: Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson\u27s disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating microglial activation and by slowing degradation of neuronal cell bodies and termini in MPTP-intoxicated mice. The protective mechanism arises from altering a Th1/Th2 immune cytokine response into an anti-inflammatory and neuronal sparing profile. These results are directly applicable for the development of novel PD therapies

Defining the Innate Immune Responses for SARS-CoV-2-Human Macrophage Interactions

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV- 2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage

Personalised service? Changing the role of the government librarian

Investigates the feasibility of personalised information service in a government department. A qualitative methodology explored stakeholder opinions on the remit, marketing, resourcing and measurement of the service. A questionnaire and interviews gathered experiences of personalised provision across the government sector. Potential users were similarly surveyed to discuss how the service could meet their needs. Data were analysed using coding techniques to identify emerging theory. Lessons learned from government librarians centred on clarifying requirements, balancing workloads and selective marketing. The user survey showed low usage and awareness of existing specialist services, but high levels of need and interest in services repackaged as a tailored offering. Fieldwork confirmed findings from the literature on the scope for adding value through information management advice, information skills training and substantive research assistance and the need to understand business processes and develop effective partnerships. Concluding recommendations focus on service definition, strategic marketing, resource utilisation and performance measurement

CD4+ Effector T cells Accelerate Alzheimer\u27s Disease in Mice

BACKGROUND: Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. METHODS: In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA RESULTS: The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. CONCLUSIONS: These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs