MIP-3β/CCL19 is associated with the intrathecal invasion of mononuclear cells in neuroinflammatory and non-neuroinflammatory CNS diseases in dogs
TL;DR: CCL19 CSF concentrations were markedly elevated in patients affected with the neuroinflammatory diseasesSRMA and MUO and showed a strong correlation with the CSF cell count, suggesting this chemokine may play an important role in the pathogenesis of SRMA andMUO.
Abstract: Background
Chemokines such as MIP-3β/CCL19 are important factors in the mechanism of cell migration and pathogenesis of central nervous system (CNS) inflammatory reactions. The hypothesis of this study is that CCL19, also known as MIP-3β, is involved in the pathogenesis of inflammatory and non-inflammatory CNS diseases of dogs. Experiments were performed on cerebrospinal fluid (CSF) and serum samples of dogs affected with steroid responsive meningitis-arteritis (SRMA) during the acute phase as well as during treatment. Dogs with SRMA were compared to dogs with presumed meningoencephalomyelitis of unknown origin (MUO), and both groups sub-categorized into dogs receiving no therapy and with patients receiving prednisolone therapy. Idiopathic epilepsy (IE), a group with normal CSF cell count, was used as a control. Additionally, dogs with intervertebral disc disease (IVDD) of varying severity were analyzed. Chemokine concentrations were determined by enzyme linked immunosorbent assay. Migration assays were performed on seven selected CSF samples using a disposable 96-well chemotaxis chamber.
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TL;DR: Companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies, however, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models.
Abstract: Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models. Stem Cells 2016;34:1709-1729.
128 citations
TL;DR: A review of immunosuppressive and immunomodulatory therapies for spinal cord injury can be found in this article, where the positive and negative attributes of the innate and adaptive immune systems in neuroinflammation after SCI are discussed.
35 citations
TL;DR: 10 blood-based biomarkers were selected as most promising biomarkers for HGG: α2-Heremans-Schmid glycoprotein (AHSG, AHSG), albumin, glucose, insulin-like growth factor- binding protein 2 (IGFBP-2), macrophage inflammatory protein 1δ (MIP-1 δ, macrophages inflammatory protein 3ß, neutrophil-lymphocyte ratio (NLR), red blood cell distribution width
Abstract: High-grade gliomas (HGG) are the most common malignant primary brain tumor in adults. During the course of disease, several challenges occur, like measuring tumor burden, monitoring of treatment response, estimating the patient's prognosis, and distinguishing between true progression and pseudo-progression. So far, no blood-based biomarker has been established in the clinical routine to address these challenges. The aim of this systematic review was to analyze the present evidence on blood-based biomarkers for HGG. We systematically searched in PubMed, Web of Sciences, Scopus, and Cochrane Library databases for publications before 30th of March 2018 reporting on associations of blood-based biomarkers in HGG patients with different endpoints as overall survival, progression-free survival, and postoperative monitoring. Quality assessment of the studies according to QUIPS and STARD guidelines was performed. In accordance with the GRADE guidelines, level of evidence (I-IV) for each of the tested biomarkers was assessed. One thousand six hundred eighty unique records were identified. Of these, 170 original articles were included to this review. Four hundred fifteen different blood-based biomarkers analyzed in 15.041 patients with HGG as also their corresponding recurrent tumors. Ten predictive biomarkers reached level II of evidence. No biomarker achieved level I of evidence. In this review, 10 blood-based biomarkers were selected as most promising biomarkers for HGG: α2-Heremans-Schmid glycoprotein (AHSG), albumin, glucose, insulin-like growth factor- binding protein 2 (IGFBP-2), macrophage inflammatory protein 1δ (MIP-1 δ), macrophage inflammatory protein 3s (MIP-3s), neutrophil-lymphocyte ratio (NLR), red blood cell distribution width (RDW), soluble glycoprotein 130 (Sgp130), and chitinase-3-like protein 1 (YKL-40). To further assess the clinical significance of these biomarkers, the evaluation in a larger cohort of HGG and their corresponding subgroups would be necessary.
15 citations
TL;DR: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis.
Abstract: Objective: To screen cytokines and chemokines and determine their dynamic changes in the serum and cerebrospinal fluid (CSF) of patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: Eight NMOSD with seropositive aquaporin-4 antibody (AQP4-IgG) were enrolled, as well as 8 matched patients with multiple sclerosis (MS) and 8 with noninflammatory neurological diseases, who were included as controls. In total, 102 cytokines and 34 chemokines were detected in the CSF and serum of NMOSD patients and controls. Results: CSF interleukin (IL)-17A levels were significantly higher in NMOSD patients in the relapsing phase (27.15 ± 11.33) than in those in the remitting phase (10.04 ± 3.11, p = 0.0017), and patients with MS (14.72 ± 3.20, p = 0.0283) and other controls (10.39 ± 11.38, p = 0.0021). CSF IL-6 levels were higher in the NMOSD patients in the relapsing phase (12.23 ± 3.47) than in those in the remitting phase (5.87 ± 2.78, p = 0.0001), and MS patients (7.38 ± 2.35, p = 0.0033) and other controls (7.50 ± 0.37, p = 0.0043). CSF CCL19 levels were also significantly higher in NMOSD patients in the relapsing phase (35.87 ± 27.07) than in those in the remitting phase (10.71 ± 3.62, p = 0.0215). Serum IL-19 levels were lower in NMOSD patients in the relapsing phase (6.23 ± 1.95) than in those in the remitting phase (10.72 ± 4.46, p = 0.0092). Further, there was a positive, significant correlation between serum IL-9 concentration and the Expanded Disability Status Scale score in the NMOSD patients in the relapsing phase ( p = 0.04). Conclusion: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis.
14 citations
TL;DR: It is demonstrated that ASCs and PMSCs have substantial in vitro potential as a cell-based therapy for IBD; however, PM SCs more potently inhibited lymphocyte proliferation by inducing apoptosis of activated lymphocytes.
Abstract: Canine inflammatory brain disease (IBD) is a severe inflammatory disorder characterized by infiltration of activated immune cell subsets into the brain and spinal cord. Multipotent mesenchymal stromal cells (MSCs) are a promising therapy for IBD, based on their potent pro-angiogenic, neuroprotective, and immunomodulatory properties. The aims of this study were to compare the immunomodulatory attributes of canine adipose-derived MSCs (ASCs) and placenta-derived MSCs (PMSCs) in vitro. These data will serve as potency information to help inform the optimal MSC cell source to treat naturally occurring canine IBD. Indoleamine 2,3 dioxygenase (IDO) activity and prostaglandin E2 (PGE2) concentration at baseline and after stimulation with interferon gamma (IFNγ) and/or tumor necrosis factor alpha (TNFα) were measured from canine ASC and PMSC cultures. Leukocyte suppression assays (LSAs) were performed to compare the ability of ASCs and PMSCs to inhibit activated peripheral blood mononuclear cell (PBMC) proliferation. IDO activity and PGE2; interleukin (IL)-2, IL-6, and IL-8; TNFα; and vascular endothelial growth factor (VEGF) concentrations were also measured from co-culture supernatants. Cell cycle analysis was performed to determine how ASCs and PMSCs altered lymphocyte proliferation. Activated canine MSCs from both tissue sources secreted high concentrations of IDO and PGE2, after direct stimulation with IFNγ and TNFα, or indirect stimulation by activated PBMCs. Both ASCs and PMSCs inhibited activated PBMC proliferation in LSA assays; however, PMSCs inhibited PBMC proliferation significantly more than ASCs. Blocking PGE2 and IDO in LSA assays determined that PGE2 is important only for ASC inhibition of PBMC proliferation. Activated ASCs increased IL-6 and VEGF secretion and decreased TNFα secretion, while activated PMSCs increased IL-6, IL-8, and VEGF secretion. ASCs inhibited lymphocyte proliferation via cell cycle arrest in the G0/G1 and PMSCs inhibited lymphocyte proliferation via induction of lymphocyte apoptosis. Our results demonstrate that ASCs and PMSCs have substantial in vitro potential as a cell-based therapy for IBD; however, PMSCs more potently inhibited lymphocyte proliferation by inducing apoptosis of activated lymphocytes. These data suggest that the mechanism by which ASCs and PMSCs downregulate PBMC proliferation differs. Additional studies may elucidate additional mechanisms by which canine MSCs modulate neuroinflammatory responses.
10 citations
References
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TL;DR: Current understanding of the roles played by chemokines in the functional biology of secondary lymphoid organs will be reviewed and a central role for the chemokine family of molecules has been uncovered.
Abstract: As few as one in 100,000 B and T lymphocytes are specific for a single protein antigen, such as tetanus toxin, yet these cells must come together if an antibody response is to occur. Bringing antigen-presenting cells and rare antigen-specific B and T lymphocytes into physical contact is a principal function of secondary lymphoid organs. In the last few years, details have begun to emerge on the cues that guide cell movements inside lymphoid organs, and a central role for the chemokine family of molecules has been uncovered. Here, current understanding of the roles played by chemokines in the functional biology of secondary lymphoid organs will be reviewed.
1,064 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...CCL19 is constitutively expressed in the CNS for fast immunosurveillance [11] and is produced by different cells such as dendritic cells (DC), macrophages and some non-hematopoietic cells [11,12]....
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TL;DR: The immune system is composed of single cells, and its function is entirely dependent on the capacity of these cells to traffic, localize within tissues, and interact with each other in a precisely coordinated fashion.
Abstract: The immune system is composed of single cells, and its function is entirely dependent on the capacity of these cells to traffic, localize within tissues, and interact with each other in a precisely coordinated fashion. There is growing evidence that the large families of chemokines and chemokine receptors provide a flexible code for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. The regulation of chemokine receptor expression during development and following cell activation explains the complex migratory pathways taken by dendritic cells, T and B lymphocytes, providing new insights into the mechanisms that control priming, effector function, and memory responses.
1,042 citations
TL;DR: A novel chemokine-dependent reciprocal cross-talk between neutrophils and Th17 cells is revealed, which may represent a useful target for the treatment of chronic inflammatory diseases.
695 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...Activated neutrophils induced chemotaxis of Th17 cells and in turn could attract more neutrophils [35]....
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...’s study revealed that a novel chemokine-dependent reciprocal cross-talk between neutrophils and Th17 cells exists [35]....
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TL;DR: Insight is provided into the mechanisms that control T-cell priming as well as memory and effector immune responses, following antigenic stimulation.
Abstract: The immune response requires a timely interaction among different cell types within distinct microenvironments. Our studies have focused on the regulation of chemokine receptors in dendritic cells (DC) and T lymphocytes. Chemokine receptors expressed by immature DC promote their migration to inflamed tissues, where antigens are captured and maturation is induced. Maturing DC upregulate CCR7, which drives their migration to the T-cell areas of the draining lymph nodes where antigen is presented to naive T cells. DC produce a variety of chemokines that influence DC recruitment into inflamed tissues and DC-T-cell interaction in the lymph nodes. Chemokine receptors are differentially acquired by developing Th1 and Th2 cells and are differentially expressed on subsets of "central memory" and "effector memory" T cells. Furthermore, following antigenic stimulation, effector T cells can rapidly switch chemokine receptor expression, acquiring new migratory capacities. These studies provide insights into the mechanisms that control T-cell priming as well as memory and effector immune responses.
538 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...It binds to the CCR7 receptor which is expressed on myeloid cells [13], mature DC, T cells, as well as activated B cells [14-16]....
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TL;DR: Results indicate that following SCI, all classes of neural cells initially contribute to the organization of inflammation, whereas recruited immune cells mostly contribute to its maintenance at later time points.
Abstract: We have studied the spatial and temporal distribution of six proinflammatory cytokines and identified their cellular source in a clinically relevant model of spinal cord injury (SCI). Our findings show that interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF) are rapidly (<5 and 15 minutes, respectively) and transiently expressed in mice following contusion. At 30-45 minutes post SCI, IL-1beta and TNF-positive cells could already be seen over the entire spinal cord segment analyzed. Multilabeling analyses revealed that microglia and astrocytes were the two major sources of IL-1beta and TNF at these times, suggesting a role for these cytokines in gliosis. Results obtained from SCI mice previously transplanted with green fluorescent protein (GFP)-expressing hematopoietic stem cells confirmed that neural cells were responsible for the production of IL-1beta and TNF for time points preceding 3 hours. From 3 hours up to 24 hours, IL-1beta, TNF, IL-6, and leukemia inhibitory factor (LIF) were strongly upregulated within and immediately around the contused area. Colocalization studies revealed that all populations of central nervous system resident cells, including neurons, synthesized cytokines between 3 and 24 hours post SCI. However, work done with SCI-GFP chimeric mice revealed that at least some infiltrating leukocytes were responsible for cytokine production from 12 hours on. By 2 days post-SCI, mRNA signal for all the above cytokines had nearly disappeared. Notably, we also observed another wave of expression for IL-1beta and TNF at 14 days. Overall, these results indicate that following SCI, all classes of neural cells initially contribute to the organization of inflammation, whereas recruited immune cells mostly contribute to its maintenance at later time points.
537 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...A study from Pineau and Lacroix on rodent models revealed that cytokine production is time dependent [43]....
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...This would suggest that neural cells are responsible for the initial inflammatory response following SCI but, the recruitment of additional immune cells is responsible for the maintenance of inflammation [43]....
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