scholarly journals Experimental Models of Autoimmune Demyelinating Diseases in Nonhuman Primates

2017 ◽  
Vol 55 (1) ◽  
pp. 27-41 ◽  
Author(s):  
Lev Stimmer ◽  
Claire-Maëlle Fovet ◽  
Ché Serguera
Keyword(s):  
Nonhuman Primates ◽  
Rhesus Macaques ◽  
Acute Disseminated Encephalomyelitis ◽  
Experimental Models ◽  
Diagnostic Methods ◽  
Demyelinating Diseases ◽  
Protective Mechanisms ◽  
Common Marmosets ◽  
Neuro Inflammation ◽  
Underlying Mechanisms

Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP.

Bronchoconstriction in nonhuman primates: a species comparison

2011 ◽  
Vol 111 (3) ◽  
pp. 791-798 ◽  
Author(s):  
S. Seehase ◽  
M. Schlepütz ◽  
S. Switalla ◽  
K. Mätz-Rensing ◽  
F. J. Kaup ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Chronic Obstructive ◽  
Ex Vivo Model ◽  
Common Marmosets ◽  
Endothelin 1 ◽  
Human Airway ◽  
Airway Constriction ◽  
Cynomolgus Macaques

Bronchoconstriction is a characteristic symptom of various chronic obstructive respiratory diseases such as chronic obstructive pulmonary disease and asthma. Precision-cut lung slices (PCLS) are a suitable ex vivo model to study physiological mechanisms of bronchoconstriction in different species. In the present study, we established an ex vivo model of bronchoconstriction in nonhuman primates (NHPs). PCLS prepared from common marmosets, cynomolgus macaques, rhesus macaques, and anubis baboons were stimulated with increasing concentrations of representative bronchoconstrictors: methacholine, histamine, serotonin, leukotriene D4 (LTD4), U46619, and endothelin-1. Alterations in the airway caliber were measured and compared with previously published data from rodents, guinea pigs, and humans. Methacholine induced maximal airway constriction, varying between 74 and 88% in all NHP species, whereas serotonin was ineffective. Histamine induced maximal bronchoconstriction of 77 to 90% in rhesus macaques, cynomolgus macaques, and baboons and a lesser constriction of 53% in marmosets. LTD4 was ineffective in marmosets and rhesus macaques but induced a maximum constriction of 44 to 49% in cynomolgus macaques and baboons. U46619 and endothelin-1 caused airway constriction in all NHP species, with maximum constrictions of 65 to 91% and 70 to 81%, respectively. In conclusion, PCLS from NHPs represent a valuable ex vivo model for studying bronchoconstriction. All NHPs respond to mediators relevant to human airway disorders such as methacholine, histamine, U46619, and endothelin-1 and are insensitive to the rodent mast cell product serotonin. Only PCLS from cynomolgus macaques and baboons, however, responded also to leukotrienes, suggesting that among all compared species, these two NHPs resemble the human airway mechanisms best.

scholarly journals Acute Disseminated Encephalomyelitis (ADEM): A Demyelinating Disease with Specific Morphological Features

2021 ◽  
pp. 106689692199356
Author(s):  
Fleur Cordier ◽  
Lars Velthof ◽  
David Creytens ◽  
Jo Van Dorpe
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Differential Diagnosis ◽  
Clinical Case ◽  
Demyelinating Disease ◽  
Acute Disseminated Encephalomyelitis ◽  
Demyelinating Diseases ◽  
Demyelinating Disorder ◽  
Immune Mediated ◽  
The Central Nervous System

Acute disseminated encephalomyelitis (ADEM) is a rare immune-mediated inflammatory and demyelinating disorder of the central nervous system. Its characteristic perivenular demyelination and inflammation aid in the differential diagnosis with other inflammatory demyelinating diseases. Here, we present a clinical case of ADEM, summarize its histological hallmarks, and discuss pitfalls concerning the most important neuropathological differential diagnoses.

Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

2012 ◽  
Vol 302 (3) ◽  
pp. R321-R330 ◽  
Author(s):  
Ahmed A. Elmarakby
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Animal Models ◽  
Vascular Function ◽  
Organ Damage ◽  
Reduce Blood Pressure ◽  
Experimental Models ◽  
Epoxyeicosatrienoic Acids ◽  
Protective Effects ◽  
Protective Mechanisms

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and it is well known that end-stage renal disease (ESRD) is a profound consequence of the progression of CVD. Present treatments only slow CVD progression to ESRD, and it is imperative that new therapeutic strategies are developed to prevent the incidence of ESRD. Because epoxyeicosatrienoic acids (EETs) have been shown to elicit reno-protective effects in hypertensive animal models, the current review will focus on addressing the reno-protective mechanisms of EETs in CVD. The cytochrome P-450 epoxygenase catalyzes the oxidation of arachidonic acid to EETs. EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs) with vasodilatory, anti-inflammatory, antihypertensive, and antiplatelet aggregation properties. EETs also have profound effects on vascular migration and proliferation and promote angiogenesis. The progression of CVD has been linked to decreased EETs levels, leading to the concept that EETs should be therapeutically targeted to prevent end-organ damage associated with CVD. However, EETs are quickly degraded by the enzyme soluble epoxide hydrolase (sEH) to their less active diols, dihydroxyeicosatrienoic acids (DHETs). As such, one way to increase EETs level is to inhibit their degradation to DHETs by using sEH inhibitors. Inhibition of sEH has been shown to effectively reduce blood pressure and organ damage in experimental models of CVD. Another approach to target EETs is to develop EET analogs with improved solubility and resistance to auto-oxidation and metabolism by sEH. For example, stable ether EET analogs dilate afferent arterioles and lower blood pressure in hypertensive rodent animal models. EET agonists also improve insulin signaling and vascular function in animal models of metabolic syndrome.

scholarly journals Sound-identity processing in early areas of the auditory ventral stream in the macaque

2012 ◽  
Vol 107 (4) ◽  
pp. 1123-1141 ◽  
Author(s):  
Paweł Kuśmierek ◽  
Michael Ortiz ◽  
Josef P. Rauschecker
Keyword(s):  
Rhesus Macaques ◽  
Population Analysis ◽  
Activity Patterns ◽  
Dorsal Stream ◽  
Stimulus Onset ◽  
Ventral Stream ◽  
Underlying Mechanisms ◽  
Species Specific ◽  
Rostral Region ◽  
Identity Processing

Auditory cortical processing is thought to be accomplished along two processing streams. The existence of a posterior/dorsal stream dealing, among others, with the processing of spatial aspects of sound has been corroborated by numerous studies in several species. An anterior/ventral stream for the processing of nonspatial sound qualities, including the identification of sounds such as species-specific vocalizations, has also received much support. Originally discovered in anterolateral belt cortex, most recent work on the anterior/ventral pathway has been performed on far anterior superior temporal (ST) areas and on ventrolateral prefrontal cortex (VLPFC). Regions of the anterior/ventral stream near its origin in early auditory areas have been less explored. In the present study, we examined three early auditory regions with different anteroposterior locations (caudal, middle, and rostral) in awake rhesus macaques. We analyzed how well classification based on sound-evoked activity patterns of neuronal populations replicates the original stimulus categories. Of the three regions, the rostral region (rR), which included core area R and medial belt area RM, yielded the greatest classification success across all stimulus classes or between classes of natural sounds. Starting from ∼80 ms past stimulus onset, clustering based on the population response in rR became clearly more successful than clustering based on responses from any other region. Our study demonstrates that specialization for sound-identity processing can be found very early in the auditory ventral stream. Furthermore, the fact that this processing develops over time can shed light on underlying mechanisms. Finally, we show that population analysis is a more sensitive method for revealing functional specialization than conventional types of analysis.

scholarly journals A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra90-290ra90 ◽  
Author(s):  
Fabiano Oliveira ◽  
Edgar Rowton ◽  
Hamide Aslan ◽  
Regis Gomes ◽  
Philip A. Castrovinci ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Nonhuman Primates ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Parasite Burden ◽  
Salivary Protein ◽  
Sand Fly ◽  
Protein Vaccine ◽  
Peripheral Blood Mononuclear ◽  
Phlebotomus Duboscqi

Currently, there are no commercially available human vaccines against leishmaniasis. In rodents, cellular immunity to salivary proteins of sand fly vectors is associated to protection against leishmaniasis, making them worthy targets for further exploration as vaccines. We demonstrate that nonhuman primates (NHP) exposed to Phlebotomus duboscqi uninfected sand fly bites or immunized with salivary protein PdSP15 are protected against cutaneous leishmaniasis initiated by infected bites. Uninfected sand fly–exposed and 7 of 10 PdSP15-immunized rhesus macaques displayed a significant reduction in disease and parasite burden compared to controls. Protection correlated to the early appearance of Leishmania-specific CD4+IFN-γ+ lymphocytes, suggesting that immunity to saliva or PdSP15 augments the host immune response to the parasites while maintaining minimal pathology. Notably, the 30% unprotected PdSP15-immunized NHP developed neither immunity to PdSP15 nor an accelerated Leishmania-specific immunity. Sera and peripheral blood mononuclear cells from individuals naturally exposed to P. duboscqi bites recognized PdSP15, demonstrating its immunogenicity in humans. PdSP15 sequence and structure show no homology to mammalian proteins, further demonstrating its potential as a component of a vaccine for human leishmaniasis.

scholarly journals Plasma Derived Exosomal Biomarkers of Exposure to Ionizing Radiation in Nonhuman Primates

2018 ◽  
Vol 19 (11) ◽  
pp. 3427 ◽  
Author(s):  
Amrita Cheema ◽  
Charles Hinzman ◽  
Khyati Mehta ◽  
Briana Hanlon ◽  
Melissa Garcia ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Nonhuman Primates ◽  
Rhesus Macaques ◽  
Ultra Performance Liquid Chromatography ◽  
Molecular Signature ◽  
Detection And Identification ◽  
Molecular Events ◽  
Plasma Metabolome ◽  
Radiation Induced ◽  
Hydroxyl Fatty Acids

Exposure to ionizing radiation induces a cascade of molecular events that ultimately impact endogenous metabolism. Qualitative and quantitative characterization of metabolomic profiles is a pragmatic approach to studying the risks of radiation exposure since it provides a phenotypic readout. Studies were conducted in irradiated nonhuman primates (NHP) to investigate metabolic changes in plasma and plasma-derived exosomes. Specifically, rhesus macaques (Macaca mulatta) were exposed to cobalt-60 gamma-radiation and plasma samples were collected prior to and after exposure to 5.8 Gy or 6.5 Gy radiation. Exosomes were isolated using ultracentrifugation and analyzed by untargeted profiling via ultra-performance liquid chromatography mass spectrometry (UPLC-MS) based metabolomic and lipidomic analyses, with the goal of identifying a molecular signature of irradiation. The enrichment of an exosomal fraction was confirmed using quantitative ELISA. Plasma profiling showed markers of dyslipidemia, inflammation and oxidative stress post-irradiation. Exosomal profiling, on the other hand, enabled detection and identification of low abundance metabolites that comprise exosomal cargo which would otherwise get obscured with plasma profiling. We discovered enrichment of different classes of metabolites including N-acyl-amino acids, Fatty Acid ester of Hydroxyl Fatty Acids (FAHFA’s), glycolipids and triglycerides as compared to the plasma metabolome composition with implications in mediation of systemic response to radiation induced stress signaling.

scholarly journals Cerebrospinal fluid data compilation and knowledge-based interpretation of bacterial, viral, parasitic, oncological, chronic inflammatory and demyelinating diseases. Diagnostic patterns not to be missed in neurology and psychiatry

2016 ◽  
Vol 74 (4) ◽  
pp. 337-350 ◽  
Author(s):  
Hansotto Reiber
Keyword(s):  
Cerebrospinal Fluid ◽  
Systematic Approach ◽  
Diagnostic Methods ◽  
Demyelinating Diseases ◽  
Psychiatric Diseases ◽  
Csf Flow ◽  
Knowledge Based ◽  
Csf Analysis ◽  
Data Compilation ◽  
Tumor Metastases

ABSTRACT The analysis of intrathecal IgG, IgA and IgM synthesis in cerebrospinal fluid (CSF) and evaluation in combined quotient diagrams provides disease-related patterns. The compilation with complementary parameters (barrier function, i.e., CSF flow rate, cytology, lactate, antibodies) in a cumulative CSF data report allows a knowledge-based interpretation and provides analytical and medical plausibility for the quality assessment in CSF laboratories. The diagnostic relevance is described for neurological and psychiatric diseases, for which CSF analysis can’t be replaced by other diagnostic methods without loss of information. Dominance of intrathecal IgM, IgA or three class immune responses give a systematic approach for Facial nerve palsy, Neurotrypanosomiasis, Opportunistic diseases, lymphoma, Neurotuberculosis, Adrenoleucodystrophy or tumor metastases. Particular applications consider the diagnostic power of the polyspecific antibody response (MRZ-antibodies) in multiple sclerosis, a CSF-related systematic view on differential diagnostic of psychiatric diseases and the dynamics of brain- derived compared to blood-derived molecules in CSF for localization of paracytes.

scholarly journals Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates

2021 ◽  
Author(s):  
Jewell N Walters ◽  
Blake Schouest ◽  
Ami Patel ◽  
Emma L Reuschel ◽  
Katherine Schultheis ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Nonhuman Primates ◽  
First Generation ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Next Generation ◽  
Synthetic Dna ◽  
One Year ◽  
Global Population

The enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.

scholarly journals Advances in the Etiology, Detection, and Clinical Management of Seborrheic Keratoses

Dermatology ◽  
2021 ◽  
pp. 1-13
Author(s):  
Mary D. Sun ◽  
Allan C. Halpern
Keyword(s):  
Therapeutic Potential ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Current Treatment ◽  
Diagnostic Methods ◽  
Treatment Standards ◽  
Oncogenic Mutations ◽  
Malignant State ◽  
Underlying Mechanisms ◽  
Seborrheic Keratoses

Seborrheic keratoses (SKs) are ubiquitous, generally benign skin tumors that exhibit high clinical variability. While age is a known risk factor, the precise roles of UV exposure and immune abnormalities are currently unclear. The underlying mechanisms of this benign disorder are paradoxically driven by oncogenic mutations and may have profound implications for our understanding of the malignant state. Advances in molecular pathogenesis suggest that inhibition of Akt and APP, as well as existing treatments for skin cancer, may have therapeutic potential in SK. Dermoscopic criteria have also become increasingly important to the accurate detection of SK, and other noninvasive diagnostic methods, such as reflectance confocal microscopy and optical coherence tomography, are rapidly developing. Given their ability to mimic malignant tumors, SK cases are often used to train artificial intelligence-based algorithms in the computerized detection of skin disease. These technologies are becoming increasingly accurate and have the potential to significantly augment clinical practice. Current treatment options for SK cause discomfort and can lead to adverse post-treatment effects, especially in skin of color. In light of the discontinuation of ESKATA in late 2019, promising alternatives, such as nitric-zinc and trichloroacetic acid topicals, should be further developed. There is also a need for larger, head-to-head trials of emerging laser therapies to ensure that future treatment standards address diverse patient needs.

scholarly journals The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1074
Author(s):  
Natalia Vacani-Martins ◽  
Marcelo Meuser-Batista ◽  
Carina de Lima Pereira dos Santos ◽  
Alejandro Marcel Hasslocher-Moreno ◽  
Andrea Henriques-Pons
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Clinical Signs ◽  
Cell Types ◽  
Experimental Models ◽  
Chronic Patients ◽  
The Usa ◽  
Multiple Cell ◽  
Underlying Mechanisms

Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver’s participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.

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